Precision metagenomic approaches using Oxford Nanopore Technology (ONT) sequencing has been shown to allow recovery of complete genomes of Escherichia coli O157:H7 from overnight enrichments of agricultural waters. This study tests the applicability of a similar approach for Cronobacter genome recovery from powdered infant formula (PIF) overnight enrichments, where Cronobacter typically dominates the overall microbiome (>90%). In this study, we aimed to test whether using ONT sequencing of overnight PIF enrichments could recover a completely closed Cronobacter genome for further genomic characterization. Ten PIF samples, each inoculated with different Cronobacter strains, covering Cronobacter sakazakii, C. muytjensii, C. dublinensis, C. turicensis, and C. universalis, were processed according to the Bacteriological Analytical Manual (BAM) protocol. qPCR was used for initial screening (detection and quantification) of the overnight enrichments and confirmed that the spiked PIF samples after the overnight enrichment have high levels of Cronobacter (107 to 109 CFU/mL). DNA from overnight PIF enrichments was extracted from the enrichment broth and sequenced using ONT. Results showed that ONT sequencing could accurately identify, characterize, and close the genomes of Cronobacter strains from overnight PIF enrichments in 3 days, much faster than the nearly two weeks required by the current BAM method. Complete genome recovery and species differentiation were achieved. This suggests that combining qPCR with ONT sequencing provides a rapid, cost-effective alternative for detecting and characterizing Cronobacter in PIF, enabling timely corrective actions during outbreaks.

To develop aryloxyphenoxypropionate herbicides with novel structure and improved activity, a total of twenty-eight novel quinazolinone–phenoxypropionate derivatives containing a diester moiety were synthesized and tested for herbicidal activity. The bioassay results in the greenhouse showed that QPEP-I-4 exhibited excellent herbicidal activity against E. crusgalli, D. sanguinalis, S. alterniflora, E. indica, and P. alopecuroides with inhibition rates >80% at a dosage of 150 g ha-1, and displayed higher crop safety to G. hirsutum, G. max, and A. hypogaea than the commercial herbicide quizalofop-p-ethyl. Studying of the molecular mode of action by phenotypic observation, membrane permeability evaluation, and transcriptomic analysis revealed that a growth inhibition of plant by QPPE-I-4 was the result from damage of plants biomembrane. The evaluation of ACCase activity in vivo indicated that QPPE-I-4 could inhibit ACCase and may be a new type of ACCase inhibitor. The present work demonstrated that QPPE-I-4 could serve as a lead compound for further developing novel AOPP herbicides.

This study aims to examine the safety profile of antiepileptic drugs (AEDs) using real-world data, with a focus on neurological, skin, and sexual/reproductive disorders. Data were collected from AED-caused reports in the Korea Adverse Event Reporting System Database (KAERS-DB) from 2012 to 2022. Totally, 46,963 adverse drug reaction (ADR)-drug pairs were analyzed. At the system organ class level, the most frequently reported classes for sodium channel blockers (SCBs) were skin (37.9%), neurological (16.7%), and psychiatric disorders (9.7%). However, for non-SCBs, these were neurological (31.2%), gastrointestinal (22.0%), and psychiatric disorders (18.2%). The most common ADRs induced by SCBs were rash (17.8%), pruritus (8.2%), and dizziness (6.7%). In contrast, non-SCBs induced dizziness (23.7%), somnolence (13.0%), and nausea (6.3%). Among the most commonly reported ADRs, rash, pruritus, and urticaria occurred on average two days later with SCBs compared to non-SCBs. Sexual/reproductive disorders were reported at a frequency of 0.23%. SCBs were reported as the cause more frequently than non-SCBs (59.8% vs. 40.2%, Fisher’s exact test, p<0.0001). Based on real-world data, we identified the safety profiles of AEDs. AED-induced ADRs exhibited different patterns depending on the mechanism. Therefore, it is important to establish different pharmacovigilance strategies to ensure proper monitoring.

The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in exacerbation of autoimmune diseases such as Rheumatoid arthritis (RA), Ulcerative colitis (UC), and Crohn’s disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing molecular and signaling networks associated with tumor-immune cross-talk.. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL-6 inhibitors.. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R responsible for initiating signaling cascades underlying irAEs in ICI therapies.

There is a growing trend among consumers to seek out natural foods and products with natural ingredients. This shift in consumer preferences had a direct impact on both food and pharmaceutical industries, leading to a focus of scientific research and commercial efforts to meet these new demands. The aim of this work is to review recent available scientific data on foods of interest, such as artichoke, gooseberry, and polygonoideae plants, as well as olive oil and red raspberries. Interestingly, the urgency of solutions to the climate change emergency has brought new attention to by-products of grapevine bunch stem and cane, which have been found to contain bioactive compounds with potential health benefits. There is a pressing need for a faster process of translating scientific knowledge from the laboratory to real-world applications, especially in the face of the increasing societal burden associated to non-communicable diseases (NCDs), environmental crises, the post-pandemic world, and ongoing violent conflicts around the world.

Abstract: The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational workflow using scRNA-Seq data to assess cellular metabolism during viral infection. With this workflow we predicted the capacity of cells to sustain SARS-CoV-2 virion production in patients and found a tissue-wide induction of metabolic pathways that support viral replication. Expanding our analysis to influenza A and dengue viruses, we identified metabolic targets and inhibitors for potential broad-45 spectrum antiviral treatment. These targets were highly enriched for known interaction partners of all analyzed viruses. Indeed, phenformin, an NADH:ubiquinone oxidoreductase inhibitor, suppressed SARS-CoV-2 and dengue virus replication. Atpenin A5, blocking succinate dehydrogenase, inhibited SARS-CoV-2, dengue virus, respiratory syncytial virus, and influenza A with high selectivity indices. In vivo, phenformin showed antiviral activity against SARS-CoV-2 in a Syrian hamster model. Our work establishes host metabolism as druggable for broad-spectrum antiviral strategies, providing invaluable tools for pandemic preparedness.

The efficient preparation of single-stranded DNA (ssDNA) rings, as a macromolecular construction approach with topological features, has aroused much interest due to their numerous applications in biotechnology and DNA nanotechnology. However, an extra splint is essential for enzymatic circularization, and by-products of multimers are usually present at high concentrations. Here, we proposed a simple and robust strategy of using permuted precursor (linear ssDNA) for circularization by forming an intramolecular dynamic nick using a part of the linear ssDNA substrate itself as the template. After the simulation of the secondary structure for desired circular ssDNA, the linear ssDNA substrate is designed to have its ends on the duplex part (≥5 bp). By using this permuted substrate with 5'-phosphate, the splint-free circularization is simply carried out by T4 DNA ligase. Very interestingly, formation of only several base pairs (2–4) flanking the nick is enough for ligation, although they form only instantaneously under ligation conditions. More significantly, the 5 bp intramolecular duplex part commonly exists in genomes or functional DNA, demonstrating the high generality of our approach. Our findings are helpful for understanding the mechanism of enzymatic DNA ligation from the viewpoint of substrate binding.

Background: First episode psychosis (FEP), schizophrenia and affective disorders are accompanied by activation of the immune inflammatory response system (IRS). The compensatory immune-regulatory reflex system (CIRS) is a regulatory immune response that is induced by the IRS but exerts negative feedback through, for example, increased levels of anti-inflammatory cytokines such as IL-4, IL-13 and IL-10. Different phenotypes of schizophrenia may exhibit distinct IRS and CIRS immune profiles.Aims: This study aims to examine the IRS and CIRS components, including macrophagic M1, T-helper (Th)-1, Th-2, Th-17 and T-regulatory (Treg) phenotypes, in antipsychotic-naïve FEP patients before and after risperidone treatment.Methods: We included 31 antipsychotic-naïve FEP patients who had measurements of IRS and CIRS biomarkers before and after treatment with risperidone for 10 weeks, and 22 healthy controls.Results: Antipsychotic-naive FEP patients showed interrelated increments in M1, Th-1, Th-2, Th-17 and Treg phenotypes and a relatively greater IRS response (especially granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6 and IL-12) as compared with the CIRS response (IL-4, IL-13, IL-5 and IL-10). Inflammatory markers, especially IL-6 and IL-8, were significantly correlated with negative, psychotic, affective and excitation symptom dimensions. Treatment with risperidone significantly suppressed the IRS and CIRS. Baseline levels of CIRS biomarkers, especially higher soluble tumor necrosis factor receptor-1 and IL-10 predicted clinical improvement during treatment.Discussion: Our findings indicate that FEP is characterized by robust IRS (M1 + Th-1 + Th-17) and CIRS responses, suggesting that monocytes, macrophages, Th-1, Th-2, Th-17 and Treg cells are activated. The findings indicate that a) FEP patients are prone to the detrimental effects of M1, Th-1, Th-17 and Th-2 cells, which may contribute to long-lasting abnormalities in brain circuitry; and b) in FEP, the CIRS may contribute to recovery from the acute phase of illness. Enhancing the CIRS is a new drug target to treat FEP.

A parallel between defense powers of sovereign nations and effective immunity that guards health is relevant to demonstrate vulnerability of immune system under external forces (vaccines, drugs). History demonstrated that sovereignty (power within) of small nations often threatened or destroyed by military might of powerful nations (power without) who use false-flags and propaganda for motives that are financial-control-driven. Similarly, we propose that body’s complex immune neuroplasticity (power within, adaptive, horizontal) is stretched-thin and weakened by the external forces, particularly by vaccination of the unborn/newborn or immune-compromised individuals. Validity of genomics (innate, perpendicular) as origins of ‘hereditary’ diseases (eg, allergies, diabetes, cancers) that for a century dominated research and treatment is also challenged. In conclusion, we propose that the pressure/power from within creates life with potential to sustain health, while the pressure/power from without, weaken and destroy life.

In schizophrenia, a single latent trait underlies psychosis, hostility, excitation, mannerism, negative (PHEMN) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR). Schizophrenia is accompanied by a breakdown of gut and blood-brain-barrier (BBB) pathways, increased tryptophan catabolite (TRYCAT) levels, bacterial translocation, and lowered natural IgM and paraoxonase (PON)1 activity. The aim of this study was to examine the factor structure of schizophrenia symptom domains and the biomarker correlates of these factors. We recruited 80 patients with schizophrenia and 40 healthy subjects and assessed the IgA/IgM responses to paracellular/transcellular (PARA/TRANS) ratios, IgA responses to TRYCATs, natural IgM to malondialdehyde and Gram-negative bacteria, and PON1 enzymatic activity.Direct Hierarchical Exploratory Factor Analysis showed a bifactorial oblique model with a) a general factor which loaded highly on all symptom domains, named overall severity of schizophrenia (“OSOS”); and b) a single-group factor (SGF) loading on negative symptoms and PMR. We found that 40% of the variance in the OSOS score was explained by IgA/IgM to PARA/TRANS ratio, male sex and education while 36.9% of the variance in SGF score was explained by IgA to PARA/TRANS, IgM to Gram-negative bacteria, female sex (positively associated) and IgM to MDA, and PON1 activity (negatively associated). Schizophrenia phenomenology comprises two biologically-validated dimensions, namely a general OSOS dimension and a single-group negative symptom dimension, which are associated with a breakdown of gut/BBB barriers, increased bacterial translocation and lowered protection against oxidation, inflammation and bacterial infections through lowered PON1 and natural IgM.

During the COVID-19 pandemic, antibody-based vaccines targeting the SARS-CoV-2 spike glycoprotein were the key focus for development because neutralizing antibodies were associated with protection against the SARS-CoV-2 infection in pre-clinical models and human trials. While deploying these spike-based vaccines saved millions of lives worldwide, it has become clear that the immunological mechanisms of protection against severe disease are multifaceted and involve non-neutralizing antibody components. Here, we describe a novel pan-sarbecovirus T-cell vaccine, ChAdOx1.COVconsv12, designed to complement and broaden the protection of spike vaccines. The vaccine immunogen COVconsv12 employs the two regions in the viral proteome most conserved among sarbecoviruses delivered by replication-deficient vector ChAdOx1. It focuses T cells towards epitopes shared among sarbecoviruses including evolving SARS-CoV-2 variants. Here, we show that ChAdOx1.COVconsv12 induced broad T-cell responses in the BALB/c and C57BL/6 mice. In the Syrian hamster challenge model, ChAdOx1.COVconsv12 alone did not protect against the SARS-CoV-2 infection, but when co-administered with 1/50th of the ChAdOx1 nCoV-19 spike vaccine protective dose, faster recovery and lower oral swab viral load were observed. Induction of CD8+ T cells may decrease COVID-19 severity and extend the T-cell response coverage of variants to match the known (and as yet unknown) members of the beta-coronavirus family.

The immune system is a dynamic network of cells and cytokines are the major mediators of immune responses which combat pathogens. Based on the cytokine production, effector T cells differentiate into subsets known as Th1, Th2, Th17 or Treg (T regulatory). This system serves as a barrier to intracellular pathogens, bacterial infections and stimulates the production of reactive oxygen species (ROS), reactive nitrogen intermediates (RNI) and nitric oxide (NO), which diffuses across membranes and engulfs intracellular pathogens. Oxidative stress occurs when ROS, reactive nitrogen species (RNS) production and antioxidant defences become imbalanced. Oxidative stress generated by infected cells produces a substantial amount of free radicals which enables killing of intracellular pathogens. Intracellular pathogens are exposed to endogenous ROS as part of normal aerobic respiration, also aexogenous ROS and RNS are generated by the host immune system in response to infection. Nanoparticles which are designed for drug delivery are capable of trapping the desired drug in the particles which protects the drug from enzymatic degradation in a biological system. The small (subcellular) size of nanoparticles enables higher intracellular uptake of the drug which results in the reduction of the concentration of free drugs reducing their toxic effect. Research on the modulation of immune response and oxidative stress using nanoparticles used to encapsulate drugs has yet to be explored fully. In this review we illustrate the immune activation and generation of oxidative stress properties which are mediated by nanoparticle encapsulated drug delivery systems which can make the therapy more effective in case of diseases caused by intracellular pathogens.

In the course of our ongoing research targeting the identification of potential biocontrol agents from entomopathogenic fungi (EPF), we explored a solid-state rice fungal extract of Blackwellomyces roseostromatus BCC56290 derived from infected lepidopteran larvae. Chemical and biological prospections afforded four unprecedently reported natural products differentiated into one dimeric naphthopyran bioxanthracene ES-242 derivative (1) and three cyclodepsipeptides (2-4) in addition to two known cyclodepsipeptides, cardinalisamides B (5) and C (6). Chemical structures of the isolated compounds were elucidated through comprehensive 1D/2D NMR and HR-ESI-MS data together with comparisons to the reported literature. The absolute configuration of the isolated cyclodepsipeptide was determined using Marfey’s method. All isolated compounds were assessed for their antimicrobial, cytotoxic and nematicidal activities with some compounds revealed significant activities.

: Schizophrenia and schizoaffective disorder are generally treated with second-generation antipsychotic drugs. These drugs are mostly D2 and 5-HT2A antagonists. They improve positive schizophrenia symptoms sufficiently well; however, they ameliorate negative schizophrenia symptoms and cognitive functions to a small extent. We review novel antipsychotic drugs exerting a partial agonism at dopaminergic and serotonergic receptors such as cariprazine, brexipiprazole and lumateperone. Besides, the mechanisms of actions of non-anti-dopaminergic antipsychotic drugs are pointed out. Updated neural networks are used to explain the mechanism of action of M4 and M1 receptor agonists, for example xanomeline combined with trospium or emraclidine, and trace-amine-associated receptor 1 agonists (TAAR1), for example ulataront. Phase 3 clinical trials of new third generation antipsychotic drugs are presented. Novel antipsychotic drugs with a partial agonism at D2 and D3 receptors improve positive and negative schizophrenia symptoms as well as cognitive symptoms better than second generation antipsychotic drugs. Besides, they are well tolerated. M4 and M1 receptor agonists, i.e. xanomeline combined with trospium or emraclidine, and TAAR1 agonists, i.e. ulataront, have promising results in clinical trials; they well improve negative schizophrenia symptoms and cognitive functions. Phase 3 clinical trials offer promising results for anti-dopaminergic and non-anti-dopaminergic novel antipsychotic drugs. These new non-anti-dopaminergic antipsychotic drugs better emend negative schizophrenia symptoms, and they better improve cognitive functions than second-generation antipsychotic drugs. Promising new antipsychotic drugs are cariprazine, brexipiprazole, lumateperone, ulataront, and xanomeline combined with trospium. Although phase 3 clinical studies are not yet completed, they showed a therapeutic effect superior to those achieved by second-generation antipsychotic drugs. They are tolerated very well, and they better treat negative schizophrenia symptoms and improve cognitive functions.

Omicron SARS-CoV-2 variants have dominated the strains of COVID-19 circulating worldwide for the last two years. Although the mortality rate of the COVID-19 Omicron variants is only approximately half that of previous variants, vaccines effective against Omicron are needed. Demonstrating that a SARS-CoV-2 vaccine can protect against Omicron in an in vivo infection model, particularly in that of Syrian hamsters, is important for the preclinical characterization of SARS-CoV-2 vaccines. Here, we report on the evaluation of W-PreS-O for its ability to protect Syrian hamsters against infection by Omicron. W-PreS-O is a chimeric vaccine based on a single fusion protein (W-PreS-O), combining RBDs from Wuhan hu-1 wild-type and Omicron adsorbed to aluminum hydroxide. The Syrian hamsters were immunized three times at three-week intervals with W-PreS-O or with aluminum hydroxide (placebo), and then they were infected with Omicron BA.1. Non-infected and non-vaccinated animals served as controls. Neutralizing antibody (nAB) titers, weight, lung symptoms (i.e., edema and pneumonia index), and viral loads, as measured using RT-PCR in the upper and lower respiratory tracts, were determined. In addition, infectious virus titers from the lungs were measured using a plaque-forming assay. W-PreS-O-vaccinated hamsters developed robust nABs against Omicron, showed almost no development of pneumonia, and had significantly reduced infectious virus titers in the lungs. Importantly, the viral loads in the nasal cavities of W-PreS-O-vaccinated hamsters were close to or above the PCR cycle threshold considered to be non-infectious. Our data provide compelling evidence demonstrating that the W-PreS-O vaccine has protective effect against Omicron in a Syrian hamster in vivo infection model. W-PreS-O is therefore a highly promising candidate vaccine for Omicron infections, and it should be further evaluated in clinical studies.

The development of ballistic protection vests (BPVs) has become increasingly significant, particularly in the design of soft panels, which are critical to the overall size and configuration of these vests. Despite their importance, a standardized design process for soft panels is lacking in the literature. This research addresses this gap by creating soft panels tailored to the body types of regional soldiers while adhering to relevant standards. We propose a comprehensive design algorithm and evaluate the applicability of the National Institute of Justice (NIJ) standard 0101.06 test templates for configuring these panels. This study aims to design soft ballistic panels for BPVs that cater to the body type requirements of regional soldiers and comply with NIJ 0101.06 standards. We have developed an algorithm for designing soft panels and analyzed the feasibility of using NIJ test templates for their configuration. The research encompasses a detailed literature review, analysis of existing BPV soft panels, and comparison with NIJ test templates. The panels were designed and scaled using computer-aided design (CAD) systems and evaluated through by physical fitting on mannequins and virtual fitting using the Clo3D program. Our findings indicate that the NIJ standard test templates are only partially applicable to the design of soft panels. The developed methodology includes an algorithm and size specifications tailored to regional covers. A coefficient (K) was identified to calculate the soft panel surface area prior to design, thereby saving time and resources.

This review article aims to delve into several aspects of sweetpotatoes and their leaves, including their nutritional composition, health benefits, culinary uses, and potential future implications as a superfood. It suggests an in-depth exploration of sweet potatoes' history, status, and prospects, highlighting their significance and potential economic value. Sweetpotatoes, often referred to as a powerhouse of nutrients, have gained popularity recently due to their remarkable nutritional composition and versatile culinary uses. This starchy root vegetable comes from the Convolvulaceae family and is consumed worldwide, playing a significant role in diverse cultures and cuisines. Besides their vibrant colors ranging from orange to purple, sweetpotatoes offer many health benefits, making them an essential addition to a well-balanced diet. Its extraordinary nutritional profile and numerous health benefits make it a superfood. Incorporating it into the diet can improve digestion, strengthen immunity, and reduce the risk of chronic diseases. With their versatility in the kitchen, there is no deficiency of charming and healthy recipes to explore. So, make room for sweet potatoes on your plate and unlock their vast potential to enhance your overall health and well-being. Overall, the future of sweetpotatoes looks bright as research and innovation aim to improve their nutritional value, adapt them to changing climate conditions, develop new varieties and products, and promote sustainable production practices. These developments can contribute to food security, economic growth, and healthier diets. Future research should focus on nutritional composition, health benefits, sustainable farming practices, cultivar development, and industrial applications to ensure sustainable and efficient production. By prioritizing research in these areas, we can enhance the utilization of sweet potatoes in various fields and secure their future for the next century.

Background: The control of energy metabolism is fundamental for cell growth and function, and anomalies are implicated in complex diseases and ageing. It is important for cells to carefully tune metabolic pathways to optimize their function in response to different nutrient or physiological conditions. Metabolism in yeast cells can be easily manipulated by supplying different carbon sources: on glucose yeast rapidly proliferates by fermentation, analogous to tumour cells growing by aerobic glycolysis, whereas on non-fermentable carbon sources metabolism shifts towards respiration. Results: We screened deletion libraries of fission yeast to identify over 200 genes required for respiratory growth. The growth medium and auxotrophic mutants strongly influenced respiratory metabolism. Most genes uncovered in the mutant screens have not been implicated in respiration in budding yeast. We applied gene expression profiling approaches to compare steady-state fermentative and respiratory growth and to analyse the dynamic adaptation to respiratory growth. The transcript levels of most genes functioning in key energy metabolism pathways were coherently tuned, reflecting anticipated differences in metabolic flows between fermenting and respiring cells. We show that the acetyl-CoA synthase, rather than the citrate lyase, is essential for acetyl-CoA synthesis in fission yeast. We also investigated the transcriptional response to mitochondrial damage by genetic or chemical perturbations, defining a retrograde response that involves the concerted regulation of distinct groups of nuclear genes that may avert harm from mitochondrial malfunction. Conclusions: These systematic and targeted analyses provide a rich framework of the genetic and regulatory basis of fundamental metabolic states to guide future studies on energy metabolism in fission yeast and beyond. Our study pinpoints weaknesses of commonly used auxotroph mutants for investigating energy metabolism. As a model for cellular energy regulation, fission yeast provides an attractive and complementary system to budding yeast.

The authors propose a novel approach for a comprehensive evaluation of neuroprotective effects using both in vitro and in vivo methods. This approach allows for the initial screening of numerous newly synthesized chemical compounds and substances from plant and animal sources while preserving animal life. In vitro techniques, including mitochondrial suspensions and neuronal cell cultures, enable assessment of neuroprotective activity, which can be challenging in intact organisms. The preliminary methods help outline the neuroprotection mechanism depending on the neurodestruction agent. The authors have validated a model of acute cerebrovascular accident, which simulates key cerebrovascular phenomena such as reduced cerebral blood flow, energy deficit, glutamate-calcium excitotoxicity, oxidative stress, and early gene expression. A significant advantage of this model is its ability to reproduce the clinical picture of cerebral ischemia: impaired motor activity, signs of neurological deficits (paresis, paralysis, etc.), as well as disturbances in attention, learning, and memory. Crucial to this approach is the selection of biochemical, molecular, and cellular markers to evaluate nerve tissue damage and characterize potential neuroprotective agents. Additionally, a comprehensive set of molecular, biochemical, histological, and immunohistochemical methods is proposed for evaluating neuroprotective effects and underlying mechanisms of potential pharmaceutical compounds.

In this paper we propose a novel theoretical framework, which was previously developed for major depression and bipolar disorder, namely the compensatory immune-regulatory reflex system (CIRS), as applied to the neuro-immune pathophysiology of schizophrenia and its phenotypes, including first episode psychosis (FEP), acute relapses, chronic and treatment resistant schizophrenia (TRS), comorbid depression, and deficit schizophrenia. These schizophrenia phenotypes and manifestations are accompanied by increased production of positive acute phase proteins, including haptoglobin and α2-macroglobulin, complement factors, and macrophagic M1 (IL-1β, IL-6 and TNF-α), T helper (Th)-1 (interferon-γ and IL-2R), Th-2 (IL-4, IL-5), Th-17 (IL-17) and T regulatory (Treg; IL-10 and transforming growth factor (TGF)-β1) cytokines, cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway as well as chemokines, including CCL-11 (eotaxin), CCL-2, CCL-3 and CXCL-8. While the immune profiles in the different schizophrenia phenotypes indicate activation of the immune-inflammatory response system (IRS), there are simultaneous signs of CIRS activation, including increased levels of the IL-1 receptor antagonist (sIL-1RA), sIL-2R and tumor necrosis factor-a receptors, Th-2 and Treg phenotypes with increased IL-4 and IL-10 production, and increased levels of TRYCATs and haptoglobin, α2-macroglobulin and other acute phase reactants, which have immune-regulatory and anti-inflammatory effects. Signs of activated IRS and CIRS pathways are also detected in TRS, chronic and deficit schizophrenia indicating that these conditions are accompanied by a new homeostatic setpoint between upregulated IRS and CIRS components. In FEP, increased baseline CIRS activity is a protective factor which may predict favorable clinical outcomes. Moreover, impairments in the CIRS are associated with deficit schizophrenia and greater impairments in semantic and episodic memory. It is concluded that CIRS plays a key role in the pathophysiology of schizophrenia by negatively regulating the primary IRS and contributing to recovery from the acute phase of illness. Components of the CIRS may offer promising therapeutic targets for schizophrenia.

Canada is known to have a complex pathway for new drug approval and reimbursement resulting in delayed access to patients with serious and life-threatening diseases such as cancer. Several recent publications from key stakeholders including patients, physicians and policymakers highlight patient helplessness, physician frustrations and policymakers entangled in a massive network of bureaucracy unable to make headway. Several quantitative assessments using time from regulatory approvals to successful reimbursements confirm long review times and high rejection rates for oncology drugs especially those receiving conditional approvals. A consensus forum of 18 Canadian oncology clinicians recently voiced frustration with the process and inability to deliver guideline-supported efficacious therapies to their patients. This manuscript compares data extracted from publicly available data sources from 2019 to June 2024 to previous publications. Methods: Public databases from Health Canada, the Canadian Agency for Drugs and Technologies in Health (CADTH), which is in the process of changing to Canada’s Drug Agency, and the pan-Canadian Pharmaceutical Alliance (pCPA) were reviewed and data collected were analyzed with descriptive statistics. Results: From the data, three trends emerge, i) an increasing number of oncology drugs are receiving conditional approvals from Health Canada, ii) the percentage of conditionally approved oncology drugs receiving positive reimbursement recommendations from CADTH is still low but appears to be improving, but delays in access are now contingent upon pCPA deciding whether to negotiate price and then the duration of any negotiation, and iii) real-world evidence is no longer part of decision-making for conditional approvals. A slight increase in positive endorsement of RWE used to support CADTH recommendations was observed. Conclusion: Lack of timely access to oncology drugs hurts Canadian patients. While a small trend of improvement appears to be emerging, longer-term data collection is required to ensure sustained patient benefits.

MicroRNAs (miRNA) exert regulatory actions via base-pairing with their binding sites on target mRNAs. Cooperative-binding, i.e., synergism, among binding sites on a mRNA is biochemically well-characterized. We studied whether this synergism is reflected in global relationship between miRNA-mediated regulatory activity and miRNA-binding-site count on the target mRNAs, i.e., leading to a non-linear relationship between the two. Recently, using our own and public datasets, we have enquired into miRNA regulatory actions: first, we analyzed the power-law distribution pattern of miRNA binding sites; second, strikingly, mRNAs for core miRNA regulatory apparatus proteins have extra-ordinarily high binding site counts, forming self-feedback-control loops; third, we revealed that tumor suppressor mRNAs generally have more sites than oncogene mRNAs; and fourth, we characterized enrichment of miRNA target mRNAs in translationally less-active polysomes relative to more-active polysomes. In these four studies, obvious correlation was observed qualitatively between the extent to which a mRNA is miRNA-regulated and its binding sites count. This paper summarizes the used datasets. We also re-analyzed the correlation by comparative linear and non-linear regression analyses. The results support a non-linear, instead of linear, relationship between the two parameters, conceivably a transcriptome-level reflection of cooperative-binding/synergism among miRNA binding sites on a target mRNA.

Iron is an essential nutrient and necessary for biological functions from DNA replication and repair to transcriptional regulation, mitochondrial respiration, electron transfer, oxygen transport, photosynthesis, enzymatic catalysis, and nitrogen fixation. However, due to iron’s propensity to generate toxic radicals which can cause damage to DNA, proteins, and lipids, multiple processes regulate uptake and distribution of iron in living systems. Understanding how intracellular iron metabolism is optimized and how iron is utilized to regulate other intracellular processes is important to our overall understanding of a multitude of biological processes. One of the tools that the cell utilizes to regulate a multitude of functions is ligation of the iron-sulfur (Fe-S) cluster cofactor. Fe-S clusters comprised of iron and inorganic sulfur are ancient components of living matter on earth that are integral for physiological function in all domains of life. Here we will explore the ways in which the cell utilizes Fe-S clusters to sense the intracellular environment and respond to maintain equilibrium.

Despite the efforts made to stop the tuberculosis (TB) epidemic, it still remains one of the leading causes of death from an infectious disease. Previous work in the group uncovered a new family of amides which showed promising activities against Mycobacterium tuberculosis. A closer look at the literature showed that these compounds are structurally related to the DNB family of DprE1 inhibitors, so, we decided to study a wide range of substituted amides and determine their activity, focusing on unexplored structures related to the dinitrobenzamides (DNB) found in the literature. To synthesize our library of compounds we started from 3,5-dinitrobenzoic acid to form the nitroaromatic core that is characteristic of the DNB’s, to which we then added linear or cyclic amine moieties. Additionally, the impact of terminal aromatic moieties was also assessed for some derivatives, via an ether, ester, or amide bond. In order to obtain the desired derivatives, multiple synthetic approaches were used, mainly focused on nucleophilic addition/elimination reactions, SN2 reactions and Mitsunobu reactions. The activity was impacted mainly by two structural features, the addition of an aromatic moiety as a terminal group and the type of the linker. The most interesting compounds exhibited activities comparable to isoniazid and DNB1. Computational studies were also performed aimed at understanding their possible interactions with DprE1. The most active compounds are a good starting point for further development, and we plan to study an extended family of compounds based in those structures.

Long COVID is a phenomenon in which individuals experience persistent symptoms after recovering from COVID-19. The symptoms are discovered to be unique for every individual and can affect multiple organs systems in the body. This study aims to identify effective natural remedies for long COVID by analyzing hub genes associated with the symptoms of the condition and evaluating the repurposed drugs catered and used for treating the symptoms of long COVID. The most common and prevalent symptoms of long COVID were identified; Fatigue, Shortness of Breath, Loss of Smell, Headache, Brain Fog, Chest Pain, Insomnia, Heart Palpitations, Dizziness, Joint Pain, Depression, Anxiety, Tinnitus, Loss of Appetite. Hub genes for each of the symptoms provided an insight on the key biological pathways of the symptom. Repurposed drugs identified, provided the template to identify the natural compounds with similar structure as a potential therapeutic drug. The natural compounds were retrieved using fingerprint search of the repurposed drugs from the NPASS Database. The findings of this study suggest several natural remedies for each symptom based on the molecular docking of the hub gene and natural compound using iGEMDOCK. The identified natural remedies may hold promise in treating long COVID, but further research is required to explore the efficacy and effectiveness of the proposed natural compounds. The results of the study pose important implications for the development of effective treatments for long COVID.

The most common type of head and neck cancer (HNC) is head and neck squamous cell carcinoma (HNSCC). It describes a heterogenous neoplastic disease that arises from the mucosal epithelium of the of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being is the eighth most common cancer worldwide, with 931,931 newly diagnosed cases and 467,125 deaths according to the latest Global Cancer Statistics (GLOBOCAN) data. Despite the use of modern low-invasive surgical techniques and application of promising new chemoradiotherapies or combination treatment, the frequency of recurrences and the five-year survival of these patients remains unsatisfactory. The microenvironment of head and neck cancer comprises various cells that regulate neoplastic expansion. It is believed that the mesenchymal stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and progression, in the regulation of cancer treatment response, survival rates, patient outcomes and long-term prognosis; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNSCC. MSCs, are multipotent, heterogeneous, mobile cells, which meet specific stemness criteria defined by the International Society for Cellular Therapy (ISCT). Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties, they may play a key role in the process of acquiring drug resistance, and thus treatment failure. MSCs must also demonstrate plastic adherence in vitro and be able to differentiate into specific mesodermal cell types after stimulation i.e., adipocytes, chondrocytes, and osteoblasts when cultured under well-defined conditions. The present narrative review examines the links between mesenchymal stromal/stem cells and HNC, as well as the different mechanisms involved in the development of resistance to current chemo- and radiotherapies in HNSCC. It provides an overview of the current literature, including key opinion-forming systematic reviews, as well as cross-sectional, longitudinal, prospective and interventional studies based on cell culture models in vitro, animal or in vivo models of HNSCC; it also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC. The data concerning tumour-associated MSCs is arranged according to increasing clinical credibility.

Previous high throughput screening studies indicated trans-eQTLs tend to be tissue specific. In this study, I probed if this feature can be used to identify tissue-specific gene regulatory networks. eQTL data (P<5e-8) for 16,259 genes were identified and their summary association statistics were obtained from the eQTLGen database. Next, eQTLs that display both cis and trans regulatory effects were selected and the association between their corresponding genes were examined by Mendelian randomization. 253 genes that exerted trans-regulatory impacts on 1,439 genes were identified. Majority of the identified gene-pairs aggregated into a gene regulatory network significantly enriched in hemo-immune processes. The robustness of finding was confirmed through simulation. Genes with higher gene expression heritabilities displayed broader regulatory impact in the network. The network displayed the scale-free topology, this provided the reason to examine the association of the network’s hub genes with the phenome. The outcome of analyses revealed GSDMB and ORMDL3 impact several disorders of immune origin and higher expression of HHEX is associated with lower triglycerides and risk of type 2 diabetes. This study reports trans-eQTLs can be used to identify tissue-specific gene regulatory networks and describes a workflow to achieve this purpose. The identified network displayed scale-free topology indicating the hub genes of a tissue-specific network could be targeted to prevent disease outcomes.

Canine parvovirus (CPV) infection is a widespread ailment among young dogs globally, characterized by high morbidity, mortality, and significant infectivity. Due to its grim prognosis, it is often likened to canine "cancer" with a medium-term mortality rate of 46.43% and late-stage mortality reaching up to 100%.Current treatment modalities primarily encompass fluid therapy, antiemetics, antimicrobial medications, pain relievers, and enteral nutrition. However, the absence of specific internationally recognized medications necessitates substantial care expenses. This review aims to elucidate recent advancements in pharmacological interventions for mitigating CPV infection symptoms, underscoring the potential of novel pharmaceutical technologies in veterinary medicine to enhance clinical outcomes for afflicted animals and their caregivers，lay a theoretical foundation for the development of specific drugs.

Ferritin is an indirect marker for total body iron stores. Comparison of the ferritin concentrations in the meconium with the concentrations of proteins regulating iron metabolism could aid better understanding of principles behind the adjustment between the fetal iron pool and newborn body size. Ferritin, transferrin, haptoglobin, ceruloplasmin, lactoferrin, myeloperoxidase, neutrophil gelatinase-associated lipocalin (NGAL) and calprotectin concentrations were measured by ELISA in meconium samples from 122 neonates. The neonates were classified according to the meconium ferritin tertiles and the values were collated with the meconium concentrations of other proteins and newborn body weight and length measurements. Increasing ferritin concentrations in meconium in consecutive tertiles (p < 0.05) were parallel to increased NGAL concentrations (p < 0.05). The interrelationships between the meconium concentrations of transferrin, haptoglobin and NGAL as well as between myeloperoxidase, calprotectin and lactoferrin are maintained in all subsequent tertiles of ferritin concentrations, (p < 0.05). In contrast to ferritin, increasing meconium NGAL concentrations in consecutive tertiles were linked to increased concentrations of transferrin, haptoglobin, lactoferrin and myeloperoxidase (p < 0.05) and of calprotectin, ferritin and ceruloplasmin (p < 0.1). Meconium ceruloplasmin concentrations correlate exclusively with neutrophil granule proteins, i.e. myeloperoxidase, NGAL, lactoferrin and calprotectin (p < 0.05). Meconium ferritin concentrations negatively correlates with birth weight (r= -0.20) and length (r= -0.31) of neonates, whereas NGAL concentrations just with birth length (r= -0.26). The remaining proteins did not show such relationships with the size of the newborn. High meconium concentrations of both ferritin and NGAL may specifically characterize neonates of smaller size. High meconium concentrations of both ferritin and NGAL may specifically characterize neonates with lower body measurements. Correlations between meconium transferrin, haptoglobin and NGAL may confirm the interrelationships of these proteins for proper iron control and transport in the intrauterine environment. Meconium ceruloplasmin concentrations may reflect the control of neutrophil activity in utero.

The European Union's recent decision to renew the authorization for the use of glyphosate until 15 December 2033 stimulates the scientific discussion all around the world regarding its toxicity or otherwise for humans. Glyphosate is a chemical used by millions of tons in the last 50 years worldwide to drying weeds in cultivated fields, greenhouses, roadsides. Concern has been raised in many quarters about the possible presence in the food chain and the consequent adverse effects on health: both aspects that argue in favor of toxicity and those that instead may indicate limited toxicity of glyphosate are here discussed. The great debate that has been generated requires further investigations and field measurements to understand its fate once dispersed in the environment and its concentration in the food chain. Hence the need for validated analytical methods that are available to analysts in the field. In the present review, methods for the analytical determination of glyphosate and its main metabolite, AMPA, are discussed, with a specific focus on chromatographic techniques applied to cereal products. The experimental procedures are explained in any detail, including cleanup, derivatization, and instrumental conditions to give the laboratories involved enough information to proceed with the implementation of this line of analysis. The prevalent chromatographic methods used are LC-MS/MS, GC-MS/SIM, and GC-MS/MS but sufficient indications are also given to those laboratories that wish to use the simpler HPLC-FLD, HPLC-UV, GC-NPD or GC-FPD techniques for screening purposes. Concentrations from literature measured in wheat, corn, barley, rye, oats, soybean, and cereal-based foods are reported together with the regulatory status in various parts of the world and the accumulation mechanism. As for the accumulation in cereals, available data show that glyphosate tends to accumulate more in wholemeal flours than in refined ones, that its concentration in the product strictly depends on the treatment period (the closer it is to the time of harvesting, the higher the concentration) and that in cold climates the herbicide tends to persist in the soil for a long time.

Immune checkpoint inhibitors (ICI) are a promising form of immunotherapy that has significantly changed the therapeutic landscape for many advanced cancers. They have shown unique clinical benefit against a broad range of tumour types and a strong overall impact on survival in studied patient populations. However, there are still many limitations holding back this immunotherapy from reaching its full potential as a possible curative option for advanced cancer patients. A great deal of research is being undertaken in the hope of driving advancements in this area, building a better understanding of the mechanisms behind immune checkpoint inhibition and ultimately developing more effective, safer, and wider-reaching agents. Taking into account the current literature on this topic, this review aims to explore in depth the basis of the use of ICIs in the treatment of advanced cancers, evaluate its efficacy and safety, consider its current limitations, and finally reflect on what the future holds for this very promising form of cancer immunotherapy.

Researches on the runoff and sediment reduction effects of soil and water conservation measures are being on the rise, which is of great significance for carrying out strategic on soil and water conservation in the Yellow River Basin. Through the analysis of various soil and water conserva-tion measures, runoff, sediment, and rainfall datas in the Sanchuan River Basin from 1960 to 2019, we use the lagrange multiplier method to determining the threshold year of soil and water con-servation measures on runoff and sediment processes. The preliminary conclusion is as follows: The trend of flood season rainfall and annual rainfall in the Sanchuan River Basin is consistent. The 10-year average rainfall in each periods indicates that before 2000, it gradually decreased and then significantly increased. The 10-year average runoff showed a gradual decrease before 2010, followed by a sudden increase, while the 10-year average sediment has shown a decreasing trend years by years, especially after the centralized treatment period. Terrace and dam measures show a trend of first decreasing, then increasing, and then approaching stability during different treat-ment periods, while the trend of forest and grass measures is slightly decreasing and then in-creasing rapidly. The runoff and sediment reduction effects of various soil and water conservation measures during different treatment periods indicate that the runoff reduction effect reached its peak in 2005, while the sediment reduction benefit reached its best in 2015. Based on the compre-hensive benefits of runoff and sediment regulation, 2015 are considered as the threshold year for various soil and water conservation measures, with each measure areas being 4.86 × 104, 17.91 × 104, 1.20 × 104, and 0.83 × 104hm2, respectively. The research results will have certain reference significance for the high-quality development of soil and water conservation in the Yellow River Basin.

In a recent study, the PD-1 inhibitor has been widely used in clinical trials and shown to improve various cancers. However, PD-1/PD-L1 inhibitors showed a low response rate and showed to be effective for a small number of cancer patients. Thus, it is important to identify key genes, which can enhance the PD-1/PD-L1 response for promoting immunotherapy. Here, we used ssGSEA and unsupervised clustering analysis to identify three clusters to show different immune cell infiltration status, prognosis, and biological action. The cluster C showed a better survival rate, high immune cells infiltration, and immunotherapy effect enriched in a variety of immune active pathways, including T and B cell signal receptors. Besides, it showed more immune subtypes C2 and C3. Further, we used WGCNA analysis to confirm the cluster C correlated genes. The red module highly correlated with cluster C for 111 genes which were enriched in a variety of immune-related pathways. To pick candidate genes in SD/PD and CR/PR patients, we used the Least Absolute Shrinkage and SVM-RFE algorithms. In conclusion, our LASSO analysis and SVM-RFE based research identified targets with better prognosis, activated immune-related pathways, and better immunotherapy. The KLRC3 was identified as the key gene which can efficiently respond to immunotherapy with greater efficacy and better prognosis.

Background: Liver failure profoundly affects the immune system, leading to dysregulation of innate and adaptive immune responses. Body: This review explores the intricate relationship between liver function and immune homeostasis. The role of the liver as a central hub in immune response initiation is elucidated, emphasizing its involvement in hepatic inflammation induction and subsequent systemic inflammation. Cytokines, chemokines, growth factors, and lipid mediators orchestrate these immune processes, serving as both prognostic biomarkers and potential therapeutic targets in liver failure-associated immune dysregulation. Furthermore, the review delves into the mechanisms underlying immunosuppression in liver failure, encompassing alterations in innate immune cell functions such as neutrophils, macrophages, and natural killer cells (NK cells), as well as perturbations in adaptive immune responses mediated by B and T cells. Conclusion: Understanding the immunological consequences of liver failure is crucial for developing targeted therapeutic interventions and improving patient outcomes in liver disease management.

Immunosuppressed individuals, such as people living with HIV (PLWH), remain vulnerable to severe COVID-19. We analyzed the persistence of specific SARS-CoV-2 humoral and cellular immune responses in a retrospective, cross-sectional study in PLWH on antiretroviral therapy. Among 104 participants, 70.2% had anti-S IgG antibodies and 55.8% had significant neutralizing activity against the Omicron variant in a surrogate virus neutralization test. Only 38.5% were vaccinated (8.76 ± 4.1 months prior), all displaying anti-S IgG, 75% with neutralizing antibodies and anti-S IgA. 29.8% had no SARS-CoV-2 serologic markers and displayed significantly lower CD4 counts and HIV viral load. Severe immunosuppression (present in 12.5% of participants) was linked to lower levels of detectable anti-S IgG (0.0003), anti-S IgA (p &lt; 0.0001) and lack of neutralizing activity against Omicron variant (p &lt; 0.0001). T-cell responses were present in 86.7% of tested participants, even in those lacking serological markers. In PLWH without severe immunosuppression, neutralizing antibodies and T-cell responses persisted for up to 9 months post-infection or vaccination. Advanced immunosuppression led to diminished humoral immunity, but retained cellular immune.

Background: Psoriasis is a chronic immune-mediated skin disease in which systemic inflammation plays an important role in the pathogenesis. In recent years, neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-monocyte ratio (NMR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) have been shown to be important indicators of inflammation. In this study, our aim is to investigate NLR, NMR, PLR, and SII levels in psoriasis patients treated with biologic agents. Method: Clinical and biochemical data of 209 patients who received systemic therapy for psoriasis were obtained by retrospectively reviewing their medical records. NLR, NMR, PLR, and SII values were calculated from the hemogram values of the patients. Results: In the third month of follow-up, the mean CRP, NLR, NMR, PLR, and SII values were significantly decreased compared to the baseline values. SII values showed strong positive correlations with NLR, NMR and PLR. Adalimumab, etanercept, and infliximab, which are TNF-α blockers, were observed to be more effective on PLR and NLR and especially NMR. Conclusion: NLR, NMR, PLR, and SII, which are data obtained from routine blood tests, can be used in the monitoring of treatment of psoriasis, especially with TNF- α blockers.

Since its conception with the smallpox vaccination, worldwide-used vaccines have thwarted multiple pandemics including the recent COVID-19 outbreak. Insightful studies uncovered complexities of different functional networks of CD4 T cells [T helper 1 (Th1); Th2, Th17] and CD8 T cells (T cytotoxic; Tc) as well as B cells (BIgM, BIgG, BIgA and BIgE) subsets during response to vaccination. Both T and B cell subsets forge central, peripheral and tissue-resident subsets during vaccination. It also became apparent that each vaccination formed the network of T regulatory subsets, namely CD4+CD25+Foxp3+ T regulatory (Treg) cells and interleukin-10 (IL-10)-producing CD4+Foxp3− T regulatory 1 (Tr1) as well as many others, are shaping the quality/quantity of vaccine-specific IgM, IgG, and IgA antibody production. These components are especially critical for immunocompromised patients, such as older individuals and allograft recipients, as their vaccination may be ineffective or less effective. This review focuses on presenting how pre- and post-vaccination Treg/Tr1 levels influence the vaccination efficacy. Experimental and clinical work revealed that the Treg/Tr1 involvement evoked different immune mechanisms in diminishing vaccine-induced cellular/humoral responses. Alternative steps may be considered to improve the vaccination response by increasing a dose, changing the delivery route and/or repeated booster doses of vaccines. Vaccination may be combined with anti-CD25 (IL-2Ra chain) or anti-PD-1 (programmed cell death protein) monoclonal antibody (mAb) to decrease Tregs and boost the T/B cell immune response. All these data and strategies for immunizations are presented and discussed, aiming to improve the efficacy of vaccination in humans and especially in immunocompromised and older individuals as well as organ transplant patients.

Glioma is the most common primary malignant brain tumors. Despite advances in surgical techniques and treatment regimens, the therapeutic effects remain unsatisfactory. Immunotherapy has brought new hope to glioma patients, but the immunosuppressive nature of the tumor microenvironment (TME) has limited the therapeutic outcomes. This study aims to reveal the subpopulations and functional characteristics of tumor-associated macrophages (TAMs), to explore the regulatory effects of chlorogenic acid on the immune microenvironment, and investigate its potential for clinical application. In this study, Chlorogenic acid slowed tumor growth in the mouse model and extended the survival time of the mice. ScRNA-seq analysis elucidated the differentiation trajectories and functional characteristics of BMDMs and microglia, revealing the regulatory effects of chlorogenic acid on these two populations. It enhanced the antigen-presenting function of macrophages and the gene expression related to T-cell immune activation, activated microglia through the JAK-STAT pathway, and improved antitumor functions. Using the target prediction database, a PPI and molecular docking model were constructed, confirming the good affinity of chlorogenic acid with STAT1. A case of a patient treated with chlorogenic acid was reviewed, who survived for 5 years and 6 months, achieved partial remission (PR) after 9 months of treatment, and remains alive with no new symptoms or toxic side effects. Our study revealed the subtypes and differentiation trajectories of tumor-associated macrophages. Chlorogenic acid significantly improved the immune microenvironment of glioma by modulating the function of bone marrow-derived mono-macrophages (BMDMs) and microglia, demonstrating good antitumor effects. This study provides new insights for targeting the regulation of the TME and offers theoretical and practical support for the clinical application of chlorogenic acid.

Drug residues that contaminate food and water represent a serious concern for human health, since their irrational use is constantly increasing the amplitude of exposure. Multiple sources contribute to the overall exposure to contaminants, including agriculture, domestic use, personal, public, and veterinary healthcare, increasing the possible origin of contamination. In this review, we focus on crop pesticides and veterinary drug residues because of their extensive use in modern agriculture and farming, which ensures food production and security for the ever-growing population around the world. We discuss crop pesticides and veterinary drug residues with respect to their worldwide distribution and impacts, with special attention on their harmful effects on human reproduction and embryo development, as well as their link to epigenetic alterations, leading to intergenerational and transgenerational diseases. Among the contaminants, the most commonly implicated in causing such disorders are organophosphates, glyphosate and antibiotics, with tetracyclines being the most frequently reported. This review highlights the importance of finding new management strategies for pesticides and veterinary drugs. Moreover, due to the still limited knowledge on inter- and transgenerational effects of these contaminants, we underlie the need to strengthen research in this field, so as to better clarify the specific effects of each contaminant and their long-term impact.

Gene or genome editing (GE) revises, removes, or replaces a mutated gene at the DNA level; it is a tool. Gene therapy (GT) offsets mutations by introducing a "normal" version of the gene into the body while the diseased gene remains in the genome; it is a medicine. So far, no GE product has been approved, as opposed to 22 GT products that cost up to millions of dollars per dose. The FDA has recently added a guideline specific to gene editing that should be understood to enable faster development of GE products; at the same time, the FDA also needs to bring more clarification and make several amendments to this guideline to make it more rational.

Biofilm formation in unicellular eukaryotes, such as Candida albicans and Saccharomyces cerevisiae, represents a significant challenge in various sectors, including healthcare, agriculture, and industry. These biofilms are resistant to conventional antimicrobial treatments due to their protective extracellular matrix and complex regulatory mechanisms, such as quorum sensing (QS) and cyclic AMP (cAMP) signaling. Recent advances in the understanding of biofilm formation pathways have led to the identification of novel compounds that target these regulatory mechanisms. This review highlights breakthroughs from 2024 research, focusing on the inhibition of quorum sensing, disruption of extracellular matrix synthesis, and transcriptional/post-transcriptional regulation of biofilm-related genes. The application of these discoveries in Vietnam is particularly promising, given the country's challenges with biofilm-related infections in healthcare and productivity losses in agriculture and aquaculture. Natural product-based approaches, especially those derived from Vietnam's marine biodiversity, offer environmentally sustainable solutions for biofilm control. However, translating these laboratory findings into scalable, cost-effective applications faces challenges such as resistance development, environmental sustainability, and regulatory constraints. This review provides a comprehensive overview of compounds targeting biofilm regulatory mechanisms, evaluates their potential applications in Vietnam, and discusses future research directions, emphasizing the need for interdisciplinary collaboration to address the complexities of biofilm control.

Glaucoma, a group of diseases characterized by progressive retinal ganglion cell loss, cupping of the optic disc and by a typical pattern of visual field defects, is a leading cause of severe visual impairment and blindness worldwide. Elevated intraocular pressure (IOP) is the leading risk factor for glaucoma development. However, glaucoma can also develop at normal pressure levels. An increased susceptibility of retinal ganglion cells to IOP, systemic vascular dysregulation, endothelial dysfunction and autoimmune imbalances have been suggested to play a role in the pathophysiology of normal tension glaucoma. Since inflammation and oxidative stress play a role in all forms of glaucoma, the goal of this review article is to resent an overview on the inflammatory and prooxidant mechanisms in the pathophysiology of glaucoma and to discuss immunomodulatory and antioxidant treatment approaches.

Despite the surge in the research of cannabis chemistry and its biological and medical activity, only a few cannabis-based pharmaceutical-grade drugs have been developed and marketed to date. Not many of these drugs are Food and Drug Administration (FDA)-approved and some are still going through regulation processes. Active compounds including cannabinergic compounds (i.e., molecules targeted to modulate the endocannabinoid system) or analogs of phytocannabinoids (cannabinoids produced by the plant) may be developed into single-molecule drugs. However, since in many cases treatment with whole plant extract is preferred over treatment with a single purified molecule, some more recently developed cannabis-derived drugs contain several molecules. Different combinations of active plant ingredients (API) from cannabis with proven synergy may be identified and developed as drugs to treat different medical conditions. However, possible negative effects between cannabis compounds should also be considered, as well as the effect of the cannabis treatment on the endocannabinoid system. FDA registration of single, few or multiple molecules as drugs is a challenging process and certain considerations that should be reviewed in this process, including issues of drug-drug interactions, are also discussed here.

LCK, a member of the Scr kinase family, is a non-receptor tyrosine kinase involved in immune cell activation, antigen recognition, tumor growth, and cytotoxic response. The enzyme has usually been linked to T lymphocyte activation upon antigen recognition. Lck activation is central to CD4, CD8, and NK activation. However, recently, it has become clearer that activating the enzyme in CD8 cells can be independent of antigen presentation and enhance cytotoxic response. The role of Lck in NK cytotoxic function has been controversial in a similar fashion as the role of the enzyme in CAR T cells. Inhibition of Lck has been mainly to treat hematologic malignancies with a high rate of success. They may be useful in treating other tumor types, and they may be useful to prevent cell exhaustion. New, more selective inhibitors have been documented, and they have shown inter-esting activities not only in tumor growth but in the treatment of autoimmune diseases, asthma, and graft vs host disease. Drug repurposing and bioinformatics can aid in solving several unsolved is-sues on the role of Lck in cancer. In summary, the role of Lck in immune response and tumor growth is not a simple event and requires more research.

This article analyzes laws, normative reforms and regulations surrounding the practices and mechanisms of control over the consumption, cultivation and commercialization of cannabis. On the one hand, I investigate regulatory practices that deny rights for the consumption of cannabis classified as recreational. On the other hand, I study regulatory practices that extend rights for the production, consumption and commercialization of cannabis classified as medicinal and industrial. The empirical moment is composed of four stages and methodological tools. First, I conduct an analysis of state policies. Then, I analyze nine laws and codes on cannabis regulation from 1970 to the present. Next, I perform five semi-structured interviews. Finally, I develop two life stories of former people deprived of their liberty for cannabis cultivation and trade. In this way, I trace forms of regulation on multiple demands, knowledge, interests and beliefs. This research focuses on state regulation. Cannabis regulatory regimes are conceived as constructions of political, social and economic truths, meanings and rights. In sum, the answer to the question of how collective demands around cannabis are regulated in Ecuador stipulates that state action reinforces stigmatization and criminalization. In addition, it legitimizes moral entrepreneurs and counter-movements around cannabis.

As with every new technology, safety demonstration is a critical component of bringing products to market and gaining public acceptance for cultured meat and seafood. This manuscript develops research priorities from the findings from a series of interviews and workshops with governmental scientists and regulators from food safety agencies in fifteen jurisdictions globally.  The interviews and workshops aimed to identify the key safety questions and priority areas of research. Participants raised questions about which aspects of cultured meat and seafood production are novel, and the implications of the paucity of public information on the topic. Novel parameters and targets may require the development of new analytical methods or adaptation and validation of existing ones, including for a diversity of product types and processes. Participants emphasized that data sharing of these efforts would be valuable, similar to those already developed and used in the food and pharmaceutical fields. Contributions to such databases from the private and public sectors would speed general understanding as well as efforts to make evaluations more efficient. In turn, these resources, combined with transparent risk assessment, will be critical elements of building consumer trust in cultured meat and seafood products.

In this article, we analyse the determinants of Regulatory Quality-RQ for 193 countries in the period 2011-2020. We use a database from ESG-Environment Social Governance of the World Bank. We apply OLS, Panel Data with Fixed Effects and Panel Data with Random Effects. We found that the variables that have the most positive impact on RQ, among others, are “GHG Net Emission”, “Mean Drought Index”, and “Heat Index”. We also found that the variables that have the most negative impact on RQ are among others “Renewable Energy Consumption”, “Voice and Accountability” and “Rule of Law”. Furthermore, we have applied the k-Means algorithm optimized with the Elbow Method and we find the presence of five clusters. In adjunct, we confront eight machine learning algorithms to predict the value of RQ and we found that the best predictor is Polynomial Regression. The predictive level of RQ for the analysed countries is expected to diminish of -1,29%. In the end, we present a network analysis with the Euclidean distance and we found the presence of a structure of seven networks using augmented data.

Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor ac-tivity in combination with the commonly used six anticancer drugs namely cyclophosphane, fluorouracil, etoposide, cysplatine, ribomustine with different mechanisms of action was investi-gated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting on the С6 rat glioma model cells.

Gestational Diabetes Mellitus (GDM) is related with adverse outcomes for both the mother and the offspring. Immune and senescence play a crucial role in GDM progression. This study aims to explore the diagnostic significance of immune-related senescence (IRS) genes in GDM. We used weighted gene co-expression network analysis (WGCNA) and single sample gene set enrichment analysis (ssGSEA) to compute the immune score and aging score in control and GDM samples. Machine learning identified core IRS genes. Then we performed unsupervised cluster analysis in GDM patients to explore immune infiltration. Finally, we validated the core genes in clinical samples. We used the intersection of MEblack module from WGCNA and differentially expressed genes (DEGs) to obtain the potential genes. Next, a univariate logistic regression model including 23 potential genes were constructed, and these genes were filtered by least absolute shrinkage and selection operator (LASSO) algorithm. There were 5 potential genes (COX17, RRAS2, RRAGC, CECR1, and TACC2), which defined as biomarkers, remained eventually, and the efficacy of these biomarkers was evaluated by nomogram. Finally, the results from both qRT-PCR and western blot analyses demonstrated CECR1 was down-regulated, while TACC2 was up-regulated in GDM placental tissue. Our study identified CECR1 and TACC2 as diagnostic biomarkers for GDM associating with immune and senescence, providing a new perspective on GDM progression.

Background: We prepared reference materials of fentanyl and amphetamines in hair, and established methods for the certification of reference materials of fentanyl and amphetamines in hair samples. Methods: Hair samples containing 15 drugs were prepared by immersion method (water-dimethylsulfoxide). On the basis of single-factor experiment, Box-Behnken design-response surface was used to optimize the pre-treatment conditions of samples. In MRM/SIM mode, 15 drugs were quantitatively analyzed by LC-MS/MS and GC-MS/MS methods. Results: The contents of 15 drugs in the mixed hair samples were: 1.050 ng mg-1~7.771 ng mg-1, RSDs&lt;7%(n=11). The results showed that the two analytical methods developed were highly sensitive (LODs as low as 0.05 pg mg-1), reproducible (intra-day and inter-day precision RSDs were&lt;10%) and accurate. F-test was performed on the prepared hair samples and the results showed that the homogeneity of the prepared hair samples was good. Conclusions: The established methods were used for the detection of fentanyl and amphetamine drugs in human hair, with high sensitivity, accuracy and specificity. It can be used as a certified method for the development of fentanyl and amphetamine matrix certified reference materials. The developed hair reference materials are expected to be applied in forensic drug abuse detection and laboratory quality control.

Coronavirus disease (COVID-19) is the current global public health threat with no specific, effective, and approved treatment available till date. The outbreak of COVID-19 has led the world into an unimagined and uncertain situation by disrupting the economies, claiming human lives, and leaving many into secondary mental health problems. As per the latest WHO report, approximately 8.2 million people are infected, and nearly 0.44 million lives are lost to COVID. The infection has spread to over 200 countries and territories around the world. The world is in search of efficient diagnostics and therapeutics, including vaccines, biologics and drugs. With the rapid increase in rates of infection and time constraints, drug repurposing seems to be a potential and viable option to find the promising anti-COVID therapeutics. In the wake of a rapid increase in the number of clinical trials involving drugs for repurposing, we aim to provide information on the safety concerns related to the drugs currently investigated in trials. This review also highlights the possible mechanisms of actions, adverse drug reactions, and contraindications of the drugs under repurposing evaluation.

Immune checkpoint inhibitors (ICI’s) are in the forefront of advanced Non Small Cell Lung Cancer (NSCLC) treatment. Still, only 27- 46% of patients respond to initial therapy with ICI’s and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4%-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post-hoc analyses of several clinical trials. Future research of ICI rechallenge for NSCLC should focus on better patient stratification, to reflect the underlying biology of immunotherapy resistance more accurately.

Major Depression Disorder (MDD) is accompanied by an immune response characterized by increased levels of pro-inflammatory and immune-regulatory cytokines and cytokine-induced stimulation of indoleamine-2,3-dioxygenase (IDO). There is also some evidence that anti-inflammatory drugs may have a clinical efficacy in MDD.The aim of this study is to examine the clinical effects of an eight-week combinatorial treatment of ketoprofen (a nonsteroidal anti-inflammatory drug) combined or not with sertraline, on serum levels of IDO, interferon (IFN)-γ, interleukin (IL)-4 and transforming growth factor (TGF)-β1 in association with changes in the Beck-Depression Inventory-II (BDI-II). The study included 140 MDD patients and 40 normal controls. The pre-treatment serum levels of IDO, IFN-γ, TGF-β1 and IL-4 were significantly higher in MDD patients compared with the control group. Treatment with sertraline with or without ketoprofen significantly reduced the increased baseline production of all 4 biomarkers to levels which were similar as those of normal controls. Ketoprofen add-on had a significantly greater effect on IDO and BDI-II as compared with placebo. The reductions in IDO, IL-4 and TGF-β1 during treatment were significantly associated with those in the BDI-II.In conclusion, the clinical efficacy of both sertraline + ketoprofen may be ascribed at least in part to attenuated IDO levels and immune-inflammatory responses in MDD. Moreover, add-on treatment with ketoprofen may augment the efficacy of sertraline by attenuating IDO. However, these treatments may also significantly reduce the more beneficial properties of T helper-2 and T regulatory (Treg) immune subsets. Future research should develop immune treatments that target the immune-inflammatory response in MDD, while enhancing the compensatory immune-regulatory system (CIRS).

The objective of this study was to investigate the transcriptomic profiling of differentially ex-pressed genes between a commercial layer breed and an indigenous Indian breed. RNA was ex-tracted from NDV-infected and uninfected embryo lung tissue samples of Aseel, Kadaknath, and White Leghorn chickens. RNA-Seq was performed, and reads were aligned to the chicken refer-ence genome (Galgal7). A total of 594 genes were significantly differentially expressed, with 264 upregulated and 330 downregulated in infected embryos. Highly overexpressed genes in infect-ed conditions included C8A, FGG, PIT54, FETUB, APOC3, FGA, SPIA1, AvBD13, APOH, AMBP, TTR, PLA2G12B. Additionally, 29 novel transcripts and 20 lncRNAs were upregulated. White Leghorn embryos showed distinct expression patterns for CAV1 and GATA3, while Kadaknath healthy embryos had higher levels of CYTB, HBBA, ND4, ND4L, and ND5, indicating breed uniqueness. The analysis revealed significant gene involvement through Gene Ontology and KEGG pathways, highlighting alterations in gene expression related to immune function, me-tabolism, cell cycle, nucleic acid processes, and mitochondrial activity due to NDV infection. ALDOB, PRPS2, XDH, DCK2, and TK1 genes, which were involved in several metabolic path-ways, clearly displayed an altered expression pattern in the infected embryo. Additionally, ALB, TLR4, TLR2, TLR21, IL1R2, IL22RA2, HSP90AA, HSPB9(p60), and HSPB8 were significantly up-regulated in infected lung samples, while CXCR4, CXCL14, GATA3, IL17REL, and IL22RA1 were downregulated. Notably, higher expression of HSPs in Kadaknath suggests heat tolerance. This research provides insights into the genetic differences between commercial and local breeds and reveals the impact of NDV infection on metabolic processes, potentially identifying candidate genes for breed improvement.

The present minireview assessed the benefits of using artificial intelligence applications in healthcare at predicting the targets of bioactive small molecules in human. Method. The tool is a tuned algorithm, with novel data in web interface. Results. We used tables to order the information of Swiss Target Prediction that allow predictions on combination of chemotherapies and probable side effects. This tool is useful to understand the molecular mechanisms underlying a given phenotype or bioactivity, to rationalize possible favorable or unfavorable side effects and to predict off-targets of known molecules as well as to clear the way for drug repurposing. Predictions are done using a ligand-based approach to compare the similarity between a query molecule and the known ligands of a large collection of protein targets. Conclusion. This study allowed us to formulate recommendations for the use of some of the chemotherapeutic agent groups in cancer patients at a low cost. It is very important and beneficial for patients that take medicine for a longer period and on whose lives depend on such treatment.

Despite recent public health and hygiene advancements, enteric fever, commonly referred to as typhoid fever, remains a common disease in developing nations. The common mode of infection is contaminated water or food. Additionally, person-to-person transmission through poor hygiene and sewage contamination of water supplies has been blamed for most outbreaks. The exact burden of typhoid has yet to be discovered because of the lack of surveillance systems in many developing nations. This makes it difficult to estimate the number of cases. Recent studies have shown that the actual number of cases of typhoid has been estimated to be around 21.6 million annually. The mortality studies suggest that the incidence of typhoid is highest in children under five years old. Typhoid fever and paratyphoid fever have been demonstrated to be life-threatening illnesses. Salmonella serotype Typhi (S. Typhi) is the causative organism of typhoid fever whereas Salmonella serotype Paratyphi is the causative organism for paratyphoid fever. The S. Typhi bacterium is known to be resistant to various drugs. There is a dire need to develop new drugs to treat and overcome the current drug-resistant S. Typhi. The identification of new targets marks the beginning of the process of developing new anti-S. Typhi drugs. The S. Typhic genome sequencing and recent cutting-edge molecular biology tools have led to the discovery of numerous new inhibitors and targets. The goal of this review is to identify the most critical targets in the S. Typhi that are targeted by drugs. It also highlights the various promising vaccines on the market or are still in preclinical studies. A detailed understanding of the targets could help researchers develop safer and more efficient antibacterial agents against S. Typhi.Additionally, the advancement of molecular techniques and the knowledge of the Salmonella pathogenesis pathways have opened better avenues to develop effective antibiotics and vaccines against this pathogen. This review also sought to identify and summarize critical structures of this pathogen that play significant roles in the maturation, development, and pathogenesis of S. Typhi. The endpoint of this work is to provide valuable information on potential therapeutic targets of S. Typhi for drug and vaccine developers.

Influenza viruses cause acute respiratory infections responsible for significant mortality and morbidity around the world. Various factors, such as antigenic drift, allow influenza strains to avoid being fully suppressed by seasonal vaccines. This has led to the increased scrutiny of antivirals as treatment and prophylaxis options for seasonal outbreaks and potential pandemics. Unfortunately, many influenza antivirals suffer from a lack of adequate clinical trials, as well as a lack of toxicity data. This is especially true of umifenovir (arbidol), a drug popularly used for the prevention and treatment of influenza strains in China and Russia. Neuraminidase inhibitors, though widely prescribed, display a potential for future resistance. Adamantanes, while proven to be effective in treating influenza A, are already encountering rapid and widespread cross-resistance and are effectively obsolete. Baloxavir marboxil, a newer antiviral, shows promise in treating acute uncomplicated influenza and may avoid the development of resistance when co-administered with other antiviral drugs. Indeed, the low genetic barrier to resistance associated with influenza antivirals could potentially be overcome by co-administration with other antivirals. This review explores the most widely prescribed antivirals for influenza treatment, their mechanisms of action, and the data currently available about their susceptibility to resistance and efficacy.

Hypertensive disorders of pregnancy (HDP), including preeclampsia (PE) and gestational hypertension (GH), are major causes of maternal and fetal morbidity and mortality. This review elucidates the role of regulatory T cells (Tregs) in the immunological aspects of HDP and explores their therapeutic potential. Tregs, known for maintaining immune tolerance, are crucial in pregnancy to prevent immune-mediated rejection of the fetus. In HDP, Treg numbers and function imbalance are observed, correlating with disease severity. The review highlights that Tregs contribute to immunological adaptation in normal pregnancy, ensuring fetal acceptance and placental development. In contrast, HDP is associated with Treg dysfunction, marked by decreased numbers and impaired regulatory capacity, leading to inadequate immune tolerance and abnormal placental development. This dysfunction is particularly evident in PE, where Tregs fail to adequately modulate the maternal immune response against fetal antigens, contributing to the pathophysiology of the disorder. Therapeutic interventions aiming to modulate Treg activity represent a promising avenue for HDP management. Studies in animal models and limited clinical trials suggest that enhancing Treg functionality could mitigate HDP symptoms and improve pregnancy outcomes. However, the review acknowledges the complexity of translating these findings into effective clinical therapies, given the multifactorial nature of HDP and the intricate regulatory mechanisms of Tregs. In conclusion, while the precise role of Tregs in HDP is still being unravelled, their central role in immune regulation during pregnancy is indisputable. Further research is needed to fully understand the mechanisms by which Tregs contribute to HDP and to develop targeted therapies that can safely and effectively harness their regulatory potential for treating hypertensive diseases of pregnancy.

Dendritic cell (DC) cancer vaccines are a promising therapeutic approach, leveraging the immune system to fight tumors. These vaccines utilize DCs' ability to present tumor-associated antigens to T cells, triggering a robust immune response. DC vaccine development has progressed through three generations. The first generation involved priming DCs with tumor-associated antigens or messenger RNA outside the body, showing limited clinical success. The second generation improved efficacy by using cytokine mixtures and specialized DC subsets to enhance immunogenicity. The third generation uses blood-derived DCs to elicit a stronger immune response. Clinical trials indicate that cancer vaccines have lower toxicity than traditional cytotoxic treatments. However, achieving significant clinical responses with DC immunotherapy remains challenging. Combining DC vaccines with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte Antigen 4 and anti-programmed Death-1 antibodies has shown promise by enhancing T cell responses and improving clinical outcomes. These combinations can transform non-inflamed tumors into inflamed ones, boosting ICIs' efficacy. Current research is exploring new checkpoint targets like LAG-3, TIM-3, and TIGIT, considering their potential with DC vaccines. Additionally, engineering T cells with chimeric antigen receptors or T cell receptors could further augment the anti-tumor response. This comprehensive strategy aims to enhance cancer immunotherapy, focusing on increased efficacy and improved patient survival rates.

The multifactorial nature of some diseases, and in particular neurodegenerative diseases such as Alzheimer’s disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug-drug interactions or adherence to treatment. The concept of pleiotropic drugs, which combine, within a single molecule, several activities directed against distinct therapeutic targets, makes it possible to overcome some of these problems. In addition, these pleiotropic drugs, generally, lead to the expression of a synergy of effects, sometimes greater than that observed with a combination of drugs. This article will review, through recent examples, the different kinds of pleiotropic drugs being studied or already present on the market of medicines.

Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10 % when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical / clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.

Studying models of healthy aging and exceptional longevity is crucial to understand a possible longevity signature as most of them show resistance to age-related diseases. In particular, semi- and supercentenarians are a highly selected group, having survived significant adversities, including the Spanish Flu and COVID-19 pandemics, indicating distinctive immune system characteristics. This paper analyse the inflammatory scores (INFLA-score, Systemic Inflammation Response Index (SIRI)) and Aging-Related Immune Phenotype (ARIP) indicators calculated from the dataset of the DESIGN project, including 249 participants aged 19-111 years, trying to understand the immune-inflammatory (IMFLAM) role to achieve longevity. Statistical analyses, including linear regression and one-way ANOVA, were performed to explore the correlations between these parameters and age. Both INFLA-score and SIRI showed a significant increase with age. However, no statistical difference is observed when analysing the values for semi- and supercentenarians with those for other age groups, whose values are similar to that of adults and less than younger centenariansRegarding ARIP values, it is noteworthy that when comparing the CD8 Naive/Effector scores between groups, no significant differences were observed between the semi- and supercentenarian group and the other groups. These results support the idea that the control of IMFLAM response can promote extreme longevity.

Oncolytic virotherapy is a promising immunotherapy approach for cancer treatment, utilizing viruses to preferentially infect and eliminate cancer cells while stimulating immune responses. In this review we synthesize current literature on the molecular circuits of immune sensing and response to oncolytic virotherapy; focusing on viral DNA or RNA sensing by infected cells, cytokine and danger-associated signal sensing by neighboring cells, and subsequent downstream activation of immune pathways. The sequential sense-and-response mechanisms involve the triggering of molecular sensors by viruses or infected cells to activate transcription factors and related genes for a breadth of immune responses. We describe how molecular signals induced in the tumor upon virotherapy can trigger diverse immune signaling pathways, activating both antigen-presenting cell-based innate and T cell-based adaptive immune responses. Insights into these complex mechanisms provide valuable knowledge for enhancing oncolytic virotherapy strategies.

In this work, we report the synthesis of a new thiosemicarbazone-based drug of N'-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) featuring a thiazole spectator for the efficient coordination with Cu(II) to give [CuCl(L)]2 (1) and [Cu(NO3)(L)]2 (2). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL, 1 and 2 are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7, with half maximal inhibitory concentration (IC50) values as low as 3.26 nmol/mL (HL), 2.18 nmol/mL (1), and 2.54 × 10−5 nmol/mL (2) for PLC/PRF/5. While the free ligand HL may elicit its anticancer effect via sequestration of bio-relevant metal ions (i.e. Fe3+ and Cu2+), 1 and 2 are also capable of generating cytotoxic reactive oxygen species (ROS) to inhibit cancer cell proliferation. Our preliminary pharmacokinetic studies revealed that oral administration (per os, PO) of HL has a significantly longer half-life t1/2 of 21.61 ± 9.4 h, nearly doubled as compared to that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying HL as an effective chemotherapeutic drug via PO administration.

Fibrosis is an important health problem and its pathogenetic activation is still largely unknown. It can develop either spontaneously or, more frequently, as a consequence of various underlying diseases, such as chronic inflammatory autoimmune diseases. Fibrotic tissue is always characterized by mononuclear immune cells infiltration. The cytokine profile of these cells shows clear proinflammatory and profibrotic characteristics. Furthermore, the production of inflammatory mediators by non-immune cells, in response to several stimuli, can be involved in the fibrotic process. It is now established that defects in the abilities of non-immune cells to mediate immune regulation may be involved in the pathogenicity of a series of inflammatory diseases. The convergence of several, not yet well identified, factors results in the aberrant activation of non-immune cells, such as epithelial cells, endothelial cells and fibroblasts, that producing pro-inflammatory molecules, exacerbate the inflammatory condition leading to the excessive and chaotic secretion of extracellular matrix proteins. However, the precise cellular mechanisms involved in this process have not yet been fully elucidated. In this review we explore the latest discoveries on the mechanisms that initiate and perpetuate the vicious circle of abnormal communications between immune and non-immune cells, responsible for fibrotic evolution of inflammatory autoimmune diseases.

Magnaporthe oryzae is a filamentous heterothallic ascomycete fungus globally distributed in rice-growing regions and serves as the causative agent of rice blast disease. Populations shaped by environmental factors and human intervention play important roles in the formation of genetic structure. In this study, population structures and spatiotemporal dynamics were investigated based on the large-scale whole genomic sequences of rice-infecting M. oryzae around the world. By analyzing the genetic structures, we identified divergent clades that crossed geographic boundaries. While we observed associations between the isolates and their geographic origins, we also found that there were frequent migration events occurring worldwide. The populations in Asia demonstrated the highest genetic diversity due to the continent’s history of rice domestication, followed by separate gene flows to Africa, North America, South America and Europe. Within Asia, China was the migration origin, facilitating gene flows to Japan and South Korea. Additionally, our analysis of the evolutionary history of global M. oryzae populations provided insights into the population expansion that has taken place in recent decades. Overall, our findings indicate that human-mediated gene flows played a pivotal role in shaping the genetic structure of M. oryzae.

This study simulated the effects of direct predatory pressure, indirect predatory pressure, and conspecific injury signals on the sea cucumber (Apostichopus japonicus) to determine changes in the activity of immune defense enzymes (lysozyme, acid phosphatase, alkaline phosphatase) and antioxidant stress enzymes (catalase, superoxide dismutase, malondialdehyde). Samples of sea cucumber juveniles were collected at 3 hours, 12 hours, 72 hours, and 96 hours post-predatory stress, and six enzymes related to immune defense and antioxidant stress were selected for activity assays, namely lysozyme (LZM), acid phosphatase (ACP), alkaline phosphatase (AKP), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA). The results indicated that under direct predatory pressure, the activity of catalase in sea cucumbers was significantly higher than that of the control group at 3 hours (P < 0.05), while the activities of acid phosphatase, alkaline phosphatase, and catalase were significantly lower at 72 hours (P < 0.05). Under indirect predatory pressure, the activity of malondialdehyde in sea cucumbers was significantly higher than that of the control group at 12 hours (P < 0.05), the activity of alkaline phosphatase was significantly higher at 72 and 96 hours (P < 0.05), catalase was significantly lower at 72 hours, and the activity of superoxide dismutase was significantly higher at 72 hours (P < 0.05). Under the influence of conspecific injury signals, the activity of malondialdehyde in sea cucumbers was significantly higher than that of the control group at 12 hours (P < 0.05), and the activity of superoxide dismutase was significantly higher at 96 hours (P < 0.05). The sea cucumber enhanced its antioxidant capacity 3 hours after facing the predator, while its immune defense mechanism was suppressed at 72 hours. When facing indirect predatory pressure, the sea cucumber may have made immune and antioxidant preparations for the arrival of unknown risks. The experimental results show that predatory pressure has a significant impact on the immune and antioxidant functions of sea cucumbers, which may be related to the physiological state and environmental adaptability of the sea cucumber. This study provides a new perspective for understanding how sea cucumbers cope with predatory pressure in the natural environment and offers theoretical support for the cultivation management of sea cucumbers.

At present there is a huge demand for experimental periodontal models to expand the knowledge in periodontal health related to Microbiome Medicine. Thus far none of the periodontal pathogens or cocktail of pathogens reported as aetiological agents of infectious chronic periodontitis to link with oral squamous cell carcinoma as the way Helicobactor pyroli linked with gastric carcinoma and other related gastric malignancies. Nevertheless, invasive pathogenic mechanisms of virulent strains of Porphyromonas gingivalis and Fusobacterium nucleatum singly as well as a duo demonstrated the progression and devastation of oral, pancreatic, and colorectal cancers in different study populations. Periodontal disease may be an inevitable consequence or complication of oral cancer patients who comprise a section of digestive tract cancers, due to suboptimal or poor oral hygiene practices due to unbearable pain and other complications of stage four oral cancer. Periodontitis is a reversible oral condition when it is treated properly at the correct stage and good oral hygiene practices and treating chronic periodontitis showed successful interventions in the prognosis of oral cancer. In the light of these scientifically proven epidemiological, laboratory, and clinical evidence this communication highlights the implication of ATP scavenging behavior and upregulation of immune regulatory receptors by intracellular Porphyromonas gingivalis based on in-vitro models on the prognosis of digestive tract cancers regarding the oral cancer patients.

Fermented foods have long been known to have immunomodulatory capabilities and fermentates derived from the lactic acid bacteria of dairy products can modulate the immune system. We have used skimmed milk powder to generate novel fermentates using Lb. helveticus strains SC234 and SC232 and we demonstrate here that these fermentates can enhance key immune mechanisms that are critical to the immune response to viruses. We show that our novel fermentates SC234 and SC232 can positively impact on cytokine and chemokine secretion, nitric oxide (NO) production, cell surface marker expression, and phagocytosis in macrophage models. We demonstrate that fermentates SC234 and SC232 increase the secretion of cytokines IL-1β, IL-6, TNF-α, IL-27, and IL-10, promote an M1 proinflammatory phenotype for viral immunity via NO induction, decreases chemokine expression of Monocyte Chemoattractant Protein (MCP), increasing cell surface marker expression, and enhance phagocytosis in comparison to their starting material. These data suggest that these novel fermentates have potential as novel functional food ingredients for the treatment, management and control of viral infection.

This study compared the efficacy of alfaxalone and propofol to induce anesthesia in bitches undergoing an ovariohysterectomy or cesarean sections. 34 healthy and pyometra-affected females were induced with IV propofol administration, 35 healthy and pyometra-affected bitches were induced with the IV administration of alfaxalone. For the cesarean sections, females were induced with propofol (n=14) or alfaxalone (n=14). Maternal physiological parameters (heart rate, blood pressure, temperature) were recorded throughout surgeries; the viability and a modified Apgar score was recorded in the neonates at 5, 60 and 120 minutes after delivery. The use of propofol and alfaxalone did not show relevant differences over parameters assessed, when ovariohysterectomy was performed in healthy bitches or females with pyometra, as well as when cesarean sections were compared; only, a transient tachycardia appeared after alfaxalone administration. However, a higher percentage of bitches needed extra-doses of propofol. Neonatal mortality was similar between both groups, but when alfaxalone was used a higher neonatal viability was observed. Propofol and alfaxalone showed similar efficacy to perform the ovariohysterectomy in all bitches. Both protocols were optimal for cesarean sections, but alfaxalone was associated with a higher neonatal viability and a higher neonatal survival rate.

The mammalian or mechanistic target of rapamycin (mTOR) integrates multiple intracellular and extra-cellular upstream signals involved in the regulation of anabolic and catabolic processes in cells, and plays a key regulatory role in cell growth and metabolism. Activation of the mTOR signaling pathway has been reported to be associated with a wide range of human diseases. A growing number of in vivo and in vitro studies have demonstrated that the gut microbes and its complex metabolites can regulate host metabolic and immune responses through the mTOR pathway, and result in disorders of host phys-iological functions. In this review, we summarize the regulatory mechanisms of gut microbes and mTOR in different diseases, and discuss the crosstalk between gut microbes and their metabolites and mTOR in the disorders in gastrointestinal tract, liver, heart and other organs. We also discuss the promising appli-cation of multiple potential drugs that can adjust the gut microbiota and mTOR signal pathways. Despite the limited findings between gut microbes and mTOR, elucidating their relationship may provide new clues for the prevention and treatment of various diseases.

The global incidence of cutaneous squamous cell carcinoma (cSCC), a prevalent and aggressive skin cancer, has risen significantly, posing a substantial public health challenge. This study investigates the tumor microenvironment (TME) of cSCC by focusing on the spatial distribution patterns of immune and vascular markers (CD31, CD20, CD4, and CD8) using fractal dimension (FD) analysis. Our analysis encompassed 141 cases, including 100 invasive cSCC and 41 specimens with pre-invasive lesions exclusively, and the rest being peripheral pre-invasive lesions from the invasive cSCC class. The FD values for each marker were computed and compared between pre-invasive and invasive lesion classes. The results revealed significant differences in FD values between the two classes for CD20 and CD31 markers, suggesting distinct alterations in B cell distribution and angiogenic activity during cSCC progression. However, CD4 and CD8 markers did not exhibit significant changes individually. Still, the CD4/CD8 ratio showed a significant difference, indicating a potential shift in the immune landscape as lesions progress from pre-invasive to invasive stages. These findings underscore the complexity and heterogeneity of the TME in cSCC and highlight the potential of FD analysis as a quantitative tool for characterizing tumor progression. Further research is needed to elucidate the implications of these differences in the clinical management of cSCC.

Toxoplasma gondii (T. gondii) is one of the most common parasites that infect humans. The parasite exists in approximately 40 million people in the United States. Latent infections are frequently associated with tissue cysts of T. gondii in the skeletal muscle and brain tissue that can lead to mental disorders, congenital disorders, and vision dysfunction. Furthermore, self-directed violence, impulsivity, and aggression are associated with T. gondii infection. Dopamine is associated with human behavior including pleasure, aggression, memory, and substance use disorder; however, the result of the studies on the association of T. gondii infection and drugs of abuse are not well understood. The frequency of substance use may be associated with substance-induced modification of dopamine-receptor densities and basal dopaminergic activity. Likewise, T. gondii can directly or indirectly influence dopaminergic activity in infected cells. Based on this hypothesis, the current paper aimed to systematically review all published literature on the association between drugs of abuse and T. gondii infection. Systematic review of controlled studies on T. gondii infection and substance use effects in adults were searched on the electronic databases. Studies have shown that individuals infected with T. gondii display increased risky behavior, such as excessive alcohol consumption. Furthermore, it was observed that T. gondii seropositive subjects had a reduced likelihood of self-reported substance use compared to T. gondii seronegative subjects. This study confirms that SUD is a potential risk factor for behavioral and psychiatric complications associated with T. gondii infection. Ultimately T. gondii infection in the context of drug dependence and the development of SUD remain to be elucidated. Therefore, it is necessary to conduct further research characterizing the mechanisms associated with dopamine metabolism of drug dependence and withdrawal in the context of a T. gondii infection, evaluating the role of inflammation, and identifying potential drug-and-sex specific underpinnings of these associations.

Hydrogels, hydrophilic polymeric compounds, have been recently put under investigation as regenerative medicine applications and delivery systems for antineoplastic drugs, particularly chemotherapeutics (anthracyclines, alkylating agents), target drugs (trastuzumab) and immunotherapies. Porosity, conductivity, biodegradability and physical states are some of the peculiarities that render hydrogels suitable for therapies implementation. Chemically-modifying agents and enzymes can be also coupled to hydrogels for pharmacokinetical parameters improvement and side effects avoidance. Cardiotoxicity is in fact one of the major issues for oncological patients after treatment efficacy. Heart failure, myocarditis and hypertension are causes of morbidity and mortality that can possibly be avoided. Specific reaching of the target tumor site has been achieved by several authors in preclinical in vivo studies but clinical studies are currently under design processes. Polydioxanone, a hydrogel-mimicking agent, is capable to interact with the elastic properties of pulmonary artery. An advantageous characteristic is that can be also reabsorbed within biological systems and can cause a remodeling process of the vessel wall. Hydrogels currently represent a strong topic of interest for researchers and probably will guide future clinical investigations and practice.

The observation that certain therapeutic strategies for targeting inflammation benefit patients with distinct immune-mediated inflammatory diseases (IMIDs) is exemplified by the success of TNF blockade in conditions including rheumatoid arthritis, ulcerative colitis and skin psoriasis, albeit only for subsets of individuals with each condition. This suggests intersecting "nodes" in inflammatory networks at a molecular and cellular level may drive and/or maintain IMIDs, being “shared” between traditionally distinct diagnoses without mapping neatly to a single clinical phenotype. In line with this proposition, integrative tumour tissue analyses in oncology have highlighted novel cell states acting across diverse cancers, with important implications for precision medicine. Drawing upon advances in the oncology field, this narrative review will first summarise learnings from the Human Cell Atlas in health as a platform for interrogating IMID tissues. It will then review cross-disease studies to date that inform this endeavour, before considering future directions in the field.

Systemic Lupus Erythematosus (lupus) and B-cell lymphoma (lymphoma) are serious diseases. Lupus and lymphoma co-occur at higher-than-expected rates and primarily depend on B-cells for their pathology, implicating shared inflammation-related B-cell molecular mechanisms as a potential cause of co-occurrence. We consequently implemented a novel Immune Imbalance Transcriptomics (IIT) algorithm and applied IIT to lupus, lymphoma, and healthy B-cell RNA-seq data to find shared- and contrasting mechanisms potentially targetable for treatment. We observed 8,562 genes significantly dysregulated in both lupus and lymphoma. Of those genes, we found 5,335 to have a significant immune imbalance, defined as significant dysregulation by both diseases, as determined by IIT. Gene Ontology (GO) term and pathway enrichment of IIT genes yielded immune-related “Neutrophil Degranulation” and “Adaptive Immune System”, validating that the IIT algorithm isolates biologically relevant genes in immunity and inflammation. We found that 389 IIT gene products are drug-targetable with established or repurposed drugs. Among our results, we found 40 known and 349 novel lupus targets, along with 151 known and 238 novel lymphoma targets. Known disease drug targets in our IIT results further validate that IIT isolates genes with disease-relevant mechanisms. We anticipate the IIT algorithm and shared and contrasting gene mechanisms uncovered here will contribute to the development of immune-related therapeutic options for lupus and lymphoma patients.

Follicular helper CD4+ T cells (TFH) are a major cellular pool for the maintenance of HIV reservoir. Therefore, the delineation of the follicular (F)/germinal center (GC) immune landscape will significantly advance our understanding of HIV pathogenesis. We have applied multiplex confocal imaging, in combination with relevant computational tools, to investigate, F/GC in situ immune dynamics in viremic (vir-HIV), antiretroviral treated (cART HIV) People Living With HIV (PLWH) and compare them to reactive, non-infected controls. Lymph nodes (LNs) from viremic and cART PLWH could be further grouped based on their TFH cell densities in high-TFH and low-TFH subgroups. These subgroups were also characterized by different in situ distribution of PD1hi TFH cells. The significantly accumulated follicular, compared to extrafollicular, FOXP3hi CD4+ T cells found in the low-TFH cART-HIV group were characterized by a less scattered in situ distribution and strongly correlated with the cell density of CD8+ T cells in this group. An inverse correlation between plasma viral load and LN GrzBhiCD8+ T and CD16hiCD15lo cells was found. Our data reveal the complex GC immune landscaping in HIV infection and suggest that follicular FOXP3hi CD4+ T cells could be negative regulators of TFH cell prevalence in cART-HIV.

This study investigated the development of novel probiotic formulations specifically designed for rainbow trout aquaculture. The project evaluated the effects of two formulations containing potential probiotic strains isolated from rainbow trout itself. These effects were assessed on various parameters including growth performance, immune response, liver enzyme activity, gene expression related to immunity, and the composition of the bacterial gut microbiota in rainbow trout (Oncorhynchus mykiss). In a completely randomized experimental design, a total of 450 rainbow trout were randomly divided into 70-liter fiberglass tank. The study included six treatments of three replicates (n=18 tanks). Six dietary treatments were included (A) and (B) containing three strains of Pediococcus sp P15, Lactococcus lactis ml3, Weissella cibaria ml6 at two dosages (300 and 500 mg/kg), treatments (C) and (D) containing five strains of P. sp P15, L. lactis ml3, W. cibaria ml6, Enterococcus faecium E10 and Lactobacillus curvatus 13A at two dosages (300 and 500 mg/kg), a commercial probiotic (E) at 300 mg/kg, and a control group (F) without probiotics. Treatments of (A), (B) and (E) resulted in the highest final weights in compared to control group. Fish fed treatments (A) and (B) had the lowest FCR than other groups. Treatments (A) and (D) showed a significant increase in immunoglobulin M (IgM) concentration compared to other groups. The expression of tumor necrosis factor (TNF) was significantly lower in group (A) than the control. In contrast, the expression of interleukin 6 (IL6) and immunoglobulin T (IgT) was increased 4.4-fold and 41-fold, respectively, in group (A) compared to control group. Among the probiotic fed treatments, group (A) showed a significant higher number of lactic acid bacteria compared to other groups during the experiment. This study highlights the significant role of treatment (A) containing three strains of P. sp P15, L. lactis ml3, and W. cibaria ml6 at a dosage of 300 mg/kg as a potential probiotic product for the rainbow trout industry.

In this study, we repositioned thiopurine drugs used for the treatment of acute leukaemia as new tyrosinase inhibitors. Tyrosinase catalyses two distinct and successive oxidations in melanin biosynthesis: the conversions of tyrosine to dihydroxyphenylalanine (DOPA) and DOPA to dopaquinone. Continuous efforts are underway to discover small molecule inhibitors of tyrosinase for therapeutic, cosmetic, and agricultural purposes. Structure-based virtual screening has predicted inhibitor candidates for mushroom tyrosinase from drugs approved by the US Food and Drug Administration (FDA). Enzyme assays have confirmed the thiopurine leukaemia drug, thioguanine, as a tyrosinase inhibitor. Two other thiopurine drugs, mercaptopurine and azathioprine, were also evaluated for their tyrosinase inhibitory activity; mercaptopurine caused stronger inhibition than thioguanine did, whereas azathioprine was a poor inhibitor. The inhibitory constants of thioguanine and mercaptopurine were calculated as 52 and 16 µM, respectively, and the value of mercaptopurine was comparable to that of the well-known inhibitor kojic acid (13 µM). The cell lysate and melanin content assay in B16F10 melanoma cells confirmed that the compounds inhibited mammalian tyrosinase. In particular, 50 µM thioguanine reduced the melanin content by 57% without cytotoxicity. Furthermore, the thiopurine drugs shared little chemical similarity with the known tyrosinase inhibitors.

In spite of prevalence gaps in several micronutrients supporting immune function, significance of their deficits/supplementation for efficacy of vaccines is underinvestigated. Thus, influence of supplementation combining vitamins C and D, zinc, selenium and manganese, and N-acetyl-cysteine on mouse IgG responses and underlying mechanisms to seasonal quadrivalent influenza vaccine (QIV) was investigated. QIV was given in two doses (28 days apart). The supplementation starting 5 days before the first injection increased the total serum IgG titre, through stimulation of germinal centre (GC) reaction in secondary lymphoid organs (SLOs), as indicated by increase in the frequency of GC B cells and follicular CD4+ T helper (Th) cells, and IL-21-producing Th cells. Additionally, the supplementation “optimized” IgG response following the second QIV injection by supporting more favorable (in respect to virus clearance) IgG2a response through favoring Th1 differentiation as indicating by Th1 (INF-γ) /Th2 (IL-4) signature cytokine level ratio upon QIV restimulation in SLO cell cultures. This most likely reflected partly their antioxidant action (as indicated by redox status analyses) on Th cell differentiation. Thus, the study forms solid base for further research aimed at repurposing use this safe and inexpensive micronutrient combination as an adjuvant for virus influenza vaccine.

Animals are distinguished by their complex developmental programs, in which transcription factors play essential roles in coordinating the regulation of the genome. Thus, it has been hypothesized that animal origins involved the evolution of increasingly complex transcriptional regulatory mechanisms that permit greater spatiotemporal control over gene expression. Here, we revisit this hypothesis in light of new genomic and functional data from diverse phylogenetically-relevant taxa, including early branching animals (sponges, ctenophores) and close relatives of animals (choanoflagellates, filastereans, ichthyosporeans). We argue that many of the mechanisms posited to explain animal transcriptional complexity, such as large increases in transcription factor numbers, new transcription factor families, and distal enhancers, did not factor significantly into animal origins. Instead, we propose that the re-purposing of pre-existing transcriptional regulatory modules through cis-regulatory evolution and gene duplication events, combined with new protein-protein interactions among TFs, may have been fundamental to the transcriptional regulatory architecture of the first animals.

The epidermal cells on the surface of the cotton ovules undergo differentiation to produce fibers, which are single-celled hair-like protrusions resembling the plant trichomes. The initiation of these unicellular fibers from the cotton ovule surface is a complex and tightly regulated process. The initiation step is the cell fate-determining stage, which leads to the commitment of cells that eventually developed into fibers, thus becomes the most crucial phase in fiber development. The in-depth knowledge of molecular regulation is a prerequisite to get a clear view of the fiber initiation process's genetic and epigenetic control. The identification and functional validation of cotton fiber initiation-related genes, few fibreless mutants, transcription factors, microRNAs, epigenetic regulators, as well as the elucidation of the role of phytohormones as signaling molecules, has played a significant role in understanding the cotton fiber initiation process at the molecular level. This review focuses on the comprehensive information regarding the genetic and epigenetic regulation of cotton fiber initiation. Thus, the review will provide readers insight into mechanistic details that operate during cotton fiber initiation.

Small non-coding RNAs (sRNAs) are ubiquitously found in the three domains of life playing large-scale roles in gene regulation, transposable element silencing, and defense against foreign elements. While a substantial body of experimental work has been done to uncover function of sRNAs in Bacteria and Eukarya, the functional roles of sRNAs in Archaea are still poorly understood. Recently, high throughput studies using RNA-sequencing revealed that sRNAs are broadly expressed in the Archaea, comprising thousands of transcripts within the transcriptome during non-challenged and stressed conditions. Antisense sRNAs, which overlap a portion of a gene on the opposite strand (cis-acting), are the most abundantly expressed non-coding RNAs and they can be classified based on their binding patterns to mRNAs (3’ UTR, 5’ UTR, CDS-binding). These antisense sRNAs target many genes and pathways, suggesting extensive roles in gene regulation. Intergenic sRNAs are less abundantly expressed and their targets are difficult to find because of a lack of complete overlap between sRNAs and target mRNAs (trans-acting). While many sRNAs have been validated experimentally, a regulatory role has only been reported for very few of them. Further work is needed to elucidate sRNA-RNA binding mechanisms, the molecular determinants of sRNA-mediated regulation, whether protein components are involved, and how sRNAs integrate with complex regulatory networks.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are significantly changing treatment strategies for human malignant diseases including oral cancer. Cancer cells usually escape from immune system and acquire proliferative capacity and invasive/metastatic potential. We have focused on the two immune checkpoints, PD-1/PD-L1 and CD47/SIRPα in the tumor microenvironment of oral squamous cell carcinoma (OSCC), and performed a retrospective analysis of the expression of seven immune-related factors (PD-L1, PD-1, CD4, CD8, CD47, CD56 and CD11c), and examined their correlation with clinicopathological status. As a result, there were no significant findings relating seven immune-related factors and several clinicopathological statuses. However, the immune-checkpoint related factors (PD-1, PD-L1, CD47) were highly expressed in non-keratinized epithelium-originated tumors when compared to those in keratinized epithelium-originated tumors. It is of interest that immunoediting via immune checkpoint-related factors was facilitated in non-keratinized sites. Several researchers reported that keratinization of oral mucosal epithelia affected the immune response, but our present finding is the first study to show a difference of the tumor immunity in the originating-epithelium of OSCC, keratinized or non-keratinized. Tumor immunity, an immune escape status of OSCC might be different in the originating-epithelium, keratinized or non-keratinized.

Meningitis is a severe disease associated with death in children under five with highest rates of infections under age of one. Vaccines for Neisseria meningitides and Haemophilus influenza are used to prevent the main causative agents of meningitis. Administration of H. influenzae type b (Hib) vaccine is recommended at 2, 4 and 6 months with a booster dose at 18 months. N. meningitidis has two commercially available vaccines, the pure polysaccharide is recommended at 24 months meanwhile the protein-conjugated vaccines at 12 months. We sought in this study to examine if coadministering the vaccines for the two main meningitis causing bacteria might be synergistic as a preliminary step towards the possibility of shuffling immunization schedule. So, we coadministered Hib vaccine with commercially available vaccines either quadrate (ACWY) polysaccharide meningococcal (Men) or conjugated meningococcal (Nim) vaccines in Balb/C mice (n = 6/group) and compared to each vaccine administered separately and controls. Thirty-five days post immunization, we measured specific antibodies titers. Hib vaccine increased Men antibody titers significantly for serotypes Y and W. When Hib vaccine was coadministrated with Nim, antibody titer for Y, W and A significantly increased. For serotype C, there was no significant difference in antibody titers among immunized groups. As for effect of meningococcal vaccines on Hib, Men significantly increased Hib antibody titers while Nim had no effect. Collectively, our data suggested that coadministration of Hib and Men or Nim vaccines was safe and had synergistic effect on immune responses elicited to both vaccines. Further studies are needed before immunization schedule modifications. Such immunization schedule recommendation should provide better protection against this life-threatening disease in young children.

Due to slow progression and susceptibility to radical forms of treatment low-grade PC is associ-ated with high overall survival (OS). With the clinical progression of PC the therapy is getting more complex. The immunosuppressive tumor microenvironment (TME) makes PC a difficult target for most immunotherapeutics. Its general immune resistance is established by i.e. immune evasion through Treg cells, synthesis of immunosuppressive mediators, and defective expression of surface neoantigens. The success of sipuleucel-T in clinical trials initiated several other clinical studies that specifically target the immune escape of the tumor and eliminate the immunosuppres-sive properties of TME. In the settings of PC treatment, this can be commonly achieved with radi-ation therapy (RT). Also, focal therapies usually applied for localized PC, such as high-intensity focused ultrasound (HIFU) therapy, cryotherapy, photodynamic therapy (PDT), or irreversible electroporation (IRE) were shown to boost anti-cancer response. Nevertheless, the present guide-lines restrict their application to localized and low-grade PC. This review explains how RT and focal therapies enhance the immune response. We also provide data supporting the combination of RT and focal treatments with immune therapies.

The Zika virus (ZIKV) epidemic elicited a rapid commitment to the development of animal models for ZIKV research. Non-human primates (NHPs) and mice have made significant contributions to this research, but NHPs are expensive, have a long gestation period, and are available only in small numbers; and non-genetically modified mice are resistant to infection. To address these deficiencies, we have established the laboratory opossum, Monodelphis domestica, as a small animal model that complements the mouse and monkey models. We developed and validated an indirect ELISA for measuring antibodies to ZIKV in opossums, as well as an immunohistochemistry (IHC) method to detect ZIKV NS1 protein in tissue samples and a PCR method to detect ZIKV RNA in tissue samples. Opossum pups inoculated intracerebrally as embryos, juveniles inoculated by several routes, and mothers that cannibalized inoculated pups, became persistently infected with ZIKV. The virus spread to multiple organs and persisted up to 38 weeks (the latest endpoint of the experiments). A robust humoral immune response was mounted, and high titers of antibodies also persisted for 38 weeks. The results establish M. domestica as natural, non-genetically modified animal model in which ZIKV persists long term after experimental infection, and as a unique animal model for research on ZIKV infection, persistence of infection, and biological responses to infection.

Self-regulatory Self-efficacy belief (i.e., SRSE) represents a fundamental factor for adjustment in adolescence, as a vehicle to promote positive behaviors and protect youths from transgressions and maladjustment Bandura et al., 2003; LaRose et al., 2010). Research attested that, during adolescence, boys are more vulnerable to externalizing behaviors than girls, especially when they perceive themselves as scarcely capable of managing and orienting their behaviors, and when they possess impairments in impulsivity (Bandura et al., 2001; Muris, 2006). Previous studies firmly supported the key role of SRSE especially in the offline context in adolescence, but very few studies investigated its impact in the online context, although nowadays Internet represents one of the most significant environments for youths’ daily lives (LaRose et al., 2010; Favini et al., 2023). Thus, we aimed to examine the protective moderating role of SRSE in online and offline aggressive behaviors, beyond youths’ temperamental vulnerabilities, such as high levels of impulsivity. A sample of 318 Italian adolescents (Mage=15.21; SD=.51; 57% boys; 40% girls; 3% third gender) were asked to complete the Impulsivity Scale at Wave1, online and offline aggressive behaviors scales at Wave 2, and SRSE at Wave 2. Multiple-group-by-gender moderation model evidenced that, for what concerns online aggression, beyond the direct effects of impulsivity in boys and girls, SRSE directly affected online aggression and mediated the effect of impulsivity in girls. In contrast, impulsivity significantly affected offline aggressive behaviors only indirectly through the effects of SRSE, and SRSE directly influenced these behaviors in both genders. These results hold for the effects of youth’s age, sexual orientation, socioeconomic status, and years of education completed. This work preliminary evidenced that, contrary to previous studies which focused especially on the vulnerability of boys to aggressive conduct, impulsivity had direct effects on online aggressive behaviors in girls, and SRSE can protect adolescents of both genders in the online context, by predicting low online aggression, and represent a protective factor from the indirect effects that im-pulsivity impairments can have also in the offline context.

Parkinson-like events are side effects that may persist for an extended period even after drug administration is discontinued. Although these events can be triggered by various drugs, the mechanisms underlying their diverse symptoms remain largely unclear. To investigate this, we used the Japanese Adverse Drug Event Reporting Database, which is maintained by the Phar-maceuticals and Medical Devices Agency, to analyze the risk factors associated with Parkinson-like events along with associated drug trends and characteristics. Our findings indicate that similar to　Parkinson’s disease, age-related differences affect the onset of these events, with older individuals being more susceptible. Hierarchical clustering and principal component analysis revealed that the mechanisms triggering these Parkinson-like events are consistent across reports, suggesting a common underlying cause. However, even with a consistent mechanism, side effects can vary depending on the site of action. These insights underline the importance of swift identification of the drugs suspected of causing these events and implementation of measures to reduce their side effects.

The low water solubility of any pharmacoactive molecules limits their pharmacological potential but the solubility parameter cannot compromise, so different approaches are employed to enhance their bioavailability. Pharmaceutically active molecules with low solubility convey a higher risk of failure for drug innovation and development. Pharmacokinetics, pharmacodynamics, and several other parameters, such as drug distribution, protein binding and absorption, are majorly affected by their solubility. Among all pharmaceutical dosage forms, the oral dosage forms cover more than 50 %, and the drug molecule should be water-soluble. For good therapeutic activity by the drug molecule on the target site, solubility and bioavailability are crucial factors. The pharmaceutical industry screening programs identified that around 40% of new chemical entities (N.C.E.s) face various difficulties at the formulation and development step. These pharmaceuticals are attributed to their less solubility and bioavailability. The bioavailability and drug solubility enhancement are significant challenges in the area of pharmaceutical formulations. According to the Classification of Biopharmaceutics, Class II and IV drugs (APIs) exhibits poor solubility, lower bioavailability, and less dissolution. Various technologies are discussed in this article to improve the solubility of the poorly water-soluble drug, for example, complexation of active molecules, utilization of emulsion formation, micelles, microemulsions, cosolvents, polymeric micelles preparation, particle size reduction technologies, pharmaceutical salts, prodrugs, solid-state alternation technique, soft gel technology, drug nanocrystals, solid dispersion methods, crystal engineering techniques and nanomorph technology. This review mainly describes several other advanced methodologies for solubility and bioavailability enhancement, such as crystal engineering, micronization, solid dispersions, nano sizing, use of cyclodextrins, solid lipid nanoparticles, colloidal drug delivery systems and drug conjugates, by some appropriate research reports.

Brazil chicken production is around 13 million tons and about a third is exported to over 150 countries, placing Brazil as the world largest chicken meat producer, and therefore it is crucial to follow the legislation of all importer markets. This study conducted a survey by chance in 45 meat industries able to export. Therefore, 2580 chicken meat samples were collected and submitted to 11 analyte extraction and chromatographic verification of compliance in an accredited laboratory. Ten chemical residues (amoxicillin, bacitracin, colistin, dinitolmide + zoalene, spectinomycin, roxarsone, tiamulin, tylosin, trenbolone acetate and virginiamycin) were investigated in chicken meat and one (halofuginone hydrobromide) in chicken liver. The results showed that no compound exceeded the maximum residue limits established by seven legislations. All residue concentrations found were below the method quantification limit, thereby confirming the capability of Brazilian chicken meat industries in complying to foreign markets.

Many approaches have been developed over time to counter the bioavailability limitations of poorly soluble drugs. With advances in nanotechnology in recent decades, science and industry have been approaching this issue through the formulation of drugs as nanocrystals, which consist of pure drugs and a minimum of surface active agents required for stabilization. They are carrier-free submicron colloidal drug delivery systems with a mean particle size in the nanometer range, typically between 10 and 800 nm. By reducing particle size to nanoscale, the particle surface area available for the molecule dissolution in the direction of dissolution medium is increased, and thus bioavailability is enhanced. This approach has proven successful, as demonstrated by the number of such drug products on the market. R&D and industry have offered many technological solutions to reduce the particle size to nanoscale, and also devised solutions for the handling of particle of nanodimensions, such as methods to accurately measure nanoparticle size and techniques to prevent physicochemical and stability related problems, such as aggregation. The present work provides an overview of the more recent achievements in improving the bioavailability of poorly soluble drugs according to their administration route, and describes the methods developed to overcome physicochemical and stability related problems.

Solventogenic Clostridium species are important for establishing sustainable industrial bioproduction of fuels and important chemicals. The inherent versatility of these species in substrate utilization and the range of solvents produced during acetone butanol-ethanol (ABE) fermentation make solventogenic Clostridium an attractive choice for biotechnological applications such as production of fuels and chemicals. The functional qualities of these microbes have thus been identified to be due to complex regulatory networks that play essential roles in modulating the metabolism of this group of bacteria. Genomes of solventogenic Clostridium species have relatively greater prevalence of genes that are intricately controlled by various regulatory molecules than most other species. Consequently, the use of genetic or metabolic engineering strategies that do not consider the underlying regulatory mechanisms will not be effective. Several regulatory factors involved in substrate uptake/utilization, sporulation, solvent production, and stress responses (Carbon Catabolite Protein A, Spo0A, AbrB, Rex, CsrA) have been identified and characterized. In this review, the focus is on newly identified regulatory factors in solventogenic Clostridium species, the interaction of these factors with previously identified molecules, and potential implications on substrate utilization, solvent production, and resistance/tolerance to lignocellulose-derived microbial inhibitory compounds.

Money launderers prefer to use financial services as the ideal medium to launder. The study aimed to provide an overview of the global AML/CFT regulations, application and how they should evolve in this dynamic environment. To gather more insight, a qualitative study was undertaken with relevant documents analysed. The main findings were: country implementation of the global AML/CFT regulations differed due to political and economic factors amongst others. While the various AML/CFT enforcements done by sampled countries were mainly cease and desist orders and monetary penalties which were publicized; and drawbacks of global AML/CFT regulations centered on application of these regulations and emerging trends. These include among other definitions of money laundering, reference to the three stage of money laundering, link between penalty and violations, technological innovations and regulations paradigm shift, cyber-attacks and data privacy. The study contributes to application and growing body of knowledge in that the advent of technology has resulted in better consumer experiences, new payment platforms, products, and services. However, these innovations have broadened emerging money laundering risks and risks in general to the financial system. Hence the need to conduct research based FATF Recommendations as risk is dynamic and not static.

Epithelial-mesenchymal transition (EMT) has been well recognized for its essential role in cancer progression as well as normal tissue development. In cancer cells, activation of EMT permits the cells to acquire migratory and invasive abilities and stem-like properties. However, simple categorization of cancer cells into epithelial and mesenchymal phenotypes misleads the understanding of the complicated metastatic process, and contradictory results from different studies also indicate the limitation of application of EMT theory in cancer metastasis. Nowadays, growing evidence suggests the existence of an intermediate status between epithelial and mesenchymal phenotypes, i.e., the “hybrid epithelial-mesenchymal (hybrid E/M)”state, provides a possible explanation for those conflicting results. Appearance of hybrid E/M phenotype offers a more plastic status for cancer cells to adapt the stressful environment for proceeding metastasis. In this article, we review the biological importance of the dynamic changes between the epithelial and the mesenchymal states. The regulatory mechanisms encompassing the translational, post-translational, and epigenetic control for this complex and plastic status are also discussed .

Increasing evidence points to host Th17 inflammatory responses as contributing to the severe lung pathology and mortality of lower respiratory tract infections from coronaviruses. This includes host inflammatory and cytokine responses to COVID-19 caused by the SARS-2 coronavirus (SARS CoV2). From studies conducted in laboratory animals, there are additional concerns about immune enhancement and the role of potential host immunopathology resulting from experimental human COVID-19 vaccines. Here we summarize evidence suggesting there may be partial overlap between the underlying immunopathologic processes linked to both coronavirus infection and vaccination, and a role for Th17 in immune enhancement and eosinophilic pulmonary immunopathology. Such findings help explain the link between viral-vectored coronavirus vaccines and immune enhancement and its reduction through alum adjuvants. Additional research may also clarify links between COVID-19 pulmonary immunopathology and heart disease.

Extracellular vesicles (EV) released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP), by which immune evasion can be established. Heat shock proteins (HSPs) are an evolutionarily conserved family of molecular chaperones, which stabilize proteins, minimize protein misfolding and aggregation within the cell, besides facilitating protein translocation, refolding and degradation. (i) Releases of extracellular HSPs (ex-HSP) and EV-associated HSPs (EV-HSP) are essential in RASP, by which molecular cotransfer of HSPs with oncogenic factors into recipient cells can promote cancer progression and resistance against stress such as hypoxia, radiation, chemicals, and immune system. (ii) RASP of tumor cells can eject anticancer drugs, molecularly targeted therapeutics, and immune checkpoint inhibitors with EVs. (iii) Cytotoxic lipids can be also released from tumor cells as RASP. Nevertheless, ex-HSP and EV-HSP can play immunostimulatory and immunosuppressive roles by binding to receptors such as LRP1/CD91/A2MR, scavenger receptors, and toll-like receptors expressed on recipient cells. Liquid biopsy of HSPs in body fluids may be useful in diagnosis, prognosis, and treatment in cancer. Regarding HSP90-targeted therapeutics, we summarize the pros, cons, and problem solutions in this review. Although production of HSPs are canonically induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), recent studies discovered that production of HSPs is also regulated by matrix metalloproteinase 3 (MMP3) and heterochromatin protein 1 (HP1) and production of cochaperone CDC37 is reciprocally regulated by myeloid zinc finger 1 (MZF1) and SCAN-D1.

Human metapneumovirus is one of major causes of common cold among children, especially infants. Its key enzyme is RNA-dependent RNA-polymerase, which performs both replication and transcription, including capping and cap methylation. The goal of the work is to find possible inhibitors of RNA-dependent RNA-polymerase across the active compounds of Rosaceae plants. The candidates were selected by molecular docking to cap-transferring domain of RNA-polymerase (PDB ID: 4UCZ) in Autodock VINA. Among all the substances tested by docking, ellagic acid derivatives showed the most promising results (affinity values below -10 kcal/mol). Hence, they could be treated as possible candidate drugs against metapneumoviral infection after experimental examination. The main advantage of using these substances should be their low toxicity, which is quite uncommon for selective RNA polymerase inhibitors used in clinical practice. Occurrence of ellagic acid derivatives among the plants from Rosaceae family like raspberry could explain their effect during common cold.

Overexpression of BRF2, a selective subunit of RNA polymerase III, has been shown to be crucial in the development of several types of cancers, including breast cancer and lung squamous cell carcinoma . Predominately, BRF2 acts as a central redox-sensing transcription factor (TF) and is involved in rescuing oxidative stress (OS) -induced apoptosis. Here, we showed a novel link between BRF2 and DNA damage response. Due to the lack of BRF2 specific inhibitors, through virtual and molecular dynamics screening, we identified potential drug candidates that interfere with BRF2-TATA-binding Protein (TBP)-DNA complex interactions based on binding energy, intermolecular, and torsional energy parameters. We experimentally tested Bexarotene as a potential BRF2 inhibitor. We found that Bexarotene (Bex) treatment resulted in a dramatic decline in oxidative stress (Tert-butylhydroquinone (tBHQ))-induced levels of BRF2 and consequently, lead to a decrease in cellular proliferation of cancer cells which may in part be due to drug pretreatment induced reduction of ROS generated by the oxidizing agent. Our data thus, provide the first experimental evidence that BRF2 is a novel player in DNA damage response pathway and Bexarotene can be used as a potential inhibitor to treat cancers with the specific elevation of oxidative stress.

Objectives: The mechanism of action of drugs that depress the central nervous system (CNS) was unknown until molecular pharmacology discovered each drug's exact role. The benefit of knowing the mechanism of action is to design a new drug that could have the same efficacy as the prototype drug but with fewer side effects. Some of the available CNS depressant drugs that were abused or illegally used could be modified to make them used medically. Methods: We reviewed various published articles in PubMed and Google Scholar that focused on CNS depressants' molecular pharmacology.Results: It was clear that at specific plasma concentrations of ethyl alcohol showed almost same mode of action of propofol by targeting the extrasynaptic GABA-A receptors, which causes tonic GABAergic inhibition. Besides, the High affinity of some benzodiazepines (e.g., midazolam) to α1 subunit of GABA-A receptor causes sedative, hypnotic, amnesic, and some antiepileptic effects; however, some other benzodiazepines (e.g., diazepam) have high affinity to α3 subunits, which causes anxiolytic, muscle relaxant, and strong antiepileptic effects. The CB1 receptor partial agonism effect of tetrahydrocannabinol has a sedative advantage over full agonism due to desensitization of CB1 receptors. Conclusion: From the molecular pharmacology prospect, it is possible to design new drugs with more specific CNS depressants effect and fewer side effects by targeting particular receptors with a precise reaction.