Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread rare diseases have a deep impact in the life quality of the patients. Until recently, treatments were limited to palliative measures and kidney/liver transplants in the most severe forms. Efforts made to develop pharmacological treatments succeeded with the biotechnological agent lumasiran, a siRNA product against glycolate oxidase, which has become the first effective therapy to treat PH1. However, small molecule drugs have classically been preferred since they benefit from experience and have better pharmacological properties. The development of small molecule inhibitors designed against key enzymes of glyoxylate metabolism is on the focus of research. Enzyme inhibitors are successful and widely used in several diseases and their pharmacokinetic advantages are well known. In PHs, effective enzymatic targets have been determined and characterized for drug design and interesting inhibitory activities have been achieved both in vitro and in vivo. This review describes the most recent advances towards the development of small molecule enzyme inhibitors in the treatment of PHs, introducing the multi-target approach as a more effective and safe therapeutic option.

Oncogenic fusion proteins, arising from chromosomal rearrangements, have emerged as prominent drivers of tumorigenesis and crucial therapeutic targets in cancer research. In recent years, the potential of small molecular inhibitors in selectively targeting fusion proteins has exhibited significant prospects, offering a novel approach to combat malignancies harboring these aberrant molecular entities. This review provides a comprehensive overview of the current state of small molecular inhibitors as therapeutic agents for oncogenic fusion proteins. We discuss the rationale for targeting fusion proteins, elucidate the mechanism of action of inhibitors, assess the challenges associated with their utilization, and provide a summary of the clinical progress achieved thus far. The objective is to provide the medicinal community with current and pertinent information and to expedite the drug discovery programs in this area.

The beta-galactoside-binding mammalian lectin galectin-1 can bind, via its carbohydrate recognition domain (CRD), various cell surface glycoproteins and has been implicated in a range of cancers. As a consequence of binding to sugar residues on cell surface receptors it has been shown to have a pleiotropic effect across many cell types and mechanisms resulting in immune system modulation and cancer progression. As a result, it has started to become a therapeutic target for both small and large molecules. In previous studies, we have used fluorescence polarisation (FP) assays to determine KD values to screen and triage small molecule glycomimetics that bind to the galectin-1 CRD. In this study surface plasmon resonance (SPR) was used to compare human and mouse galectin-1 affinity measures with FP as SPR has not been applied for compound screening against this galectin. Binding affinities for a selection of mono- and di-saccharides covering a 1,000-fold range correlated well between FP and SPR assay formats for both human and mouse galectin-1. It was shown that slower dissociation drove the increased affinity at human galectin-1 whilst faster association was responsible for the effects at mouse galectin-1. This study demonstrates that SPR is a sound alternative to FP for early drug discovery screening and determining affinity estimates. Consequently, it also allows association and dissociation constants to be measured in a high throughput manner for small molecule galectin-1 inhibitors.

Small molecule kinase inhibitors (SMKIs) are one of the heightened concerns in the field of drug research and development. There are seventy-nine (up to July 2023) small molecule kinase inhibitors have been approved by FDA and hundreds kinase inhibitors candidates in clinical trials, which shed light on the treatment of some major diseases. As an important strategy of drug design, computer-aided drug design (CADD) plays an indispensable role in the discovery of SMKIs. CADD methods, such as docking, molecular dynamic, pharmacophore have been applied to the design and optimization of small molecule kinase inhibitors. In the review, we provide an overview of recent advances in CADD and SMKIs; and the application of CADD for discovery of SMKIs.

There has recently been interest in the development of small-molecule inhibitors of the oligomerization of Bacillus anthracis protective antigen for therapeutic use. Some of the proposed lead compounds have, however, unfavorable solubility in aqueous medium, which prevents their clinical use. In this computational work, we have designed several hundreds of derivatives with progressively higher hydrosolubility and tested their ability to dock the relevant binding cavity. The highest-ranking docking hits were then subjected to 125 ns-long simulations to ascertain the stability of the binding modes. Several of the potential candidates performed quite disappointingly , but two molecules showed very stable binding modes throughout the complete simulations. Besides the identification of these two promising leads, these molecular dynamics simulations allowed the discovery of several insights that shall prove useful in the further improvement of these candidate towards higher potency and stability.

Background: KDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair. These proteins are over-expressed in different kinds of cancer, including breast, prostate and bladder carcinoma, with positive effects on cancer proliferation and chemo-resistance. For these reasons, these enzymes are potential therapeutic cancer targets. Methods: In the present study, we analyzed the effects of three different inhibitors of KDM5 enzymes in MCF-7 breast cancer cells over-expressing JARID1B. In particular we tested H3K4 demethylation (western blot); target gene transcription (RNAseq and real time PCR); radio-sensitivity (citoxicity and clonogenic assays) and damage accumulation (kinetics of H2AX phosphorylation). Results: we show that two compounds with completely different chemical structure can selectively inhibit KDM5 enzymes and that both compounds are capable of increasing sensitivity of breast cancer cells to ionizing radiation and H2AX phosphorylation. Conclusions: These findings confirm the involvement of H3K4 specific demethylases in DNA damage signaling and repair and suggest new strategies for the therapeutic use of their inhibitors.

The main regulatory factors during the adaptation of cancer cells to hypoxic stress are the hypoxia-inducible factors (HIFs), which are being increasingly recognized as an interesting and challenging target for the design of new chemotherapeutic molecules. HIF2A was found to have an large internal hydrophilic cavity within its PAS-B domain, unique to this sub-unit and is suggested to be a possible ligand-binding site. Regulation of HIF2A by cellular molecules is still greatly unknown. In This paper we have employed in-silico techniques, such as molecular docking and dynamic simulation, to design new direct inhibitors against HIF-2A subunit via targeting one of its critical domains and the final top screened molecules have been tested on hypoxic cancer cells for further validation of their inhibitory potential. we targeted the hydrophilic cavity inside the PAS-B domain of the HIF2A to identify novel molecules with a high binding capacity. Virtual Screening methodology was used for molecular docking of NSC library against the target domain inside the HIF2A PAS-B domain with the top 5% compounds with significant MolDock and Re-rank scores were selected for further analysis. The NSC 106416, NSC 217021, NSC 217026, and NSC 215639 compounds were selected based on their docking scores. NSC 215639 had the minimum polar solvation energy and also had a relative strong binding energy. NSC 217026 had the strongest binding energy among other compounds.

Households and businesses are generating unprecedented levels of electrical and electronic wastes (e-waste), fueled by modernisation and rapid obsolescence. While the challenges imposed by e-waste are similar everywhere in the world, disparities in progress to deal with it exists; with developing nations such as South Africa lagging. The increase in e-waste generation increases the need to formulate strategies to manage it. This paper presents an overview of e-waste management on a global and South African scenarios with a specific case for Cathode Ray Tube (CRT) waste management practices in South Africa. CRTs present the biggest problem for recyclers and policy makers because they contain hazardous elements such as lead and antimony. Common disposal practices have been either landfilling or incineration. The research into the South African practices with regards to CRT waste management showed that there is still more to be done to effectively manage this waste stream. This is despite clear waste regulatory frameworks in the country. However, recent developments have placed e-waste as a priority waste stream, which should lead to intensified efforts in dealing with it. Overall, these efforts should aim to maximise diversion from landfilling and to create value-addition opportunities, leading to social and environmental benefits.

Emergence of multi drug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis poses a serious threat to TB control as the available treatment options are less effective in these cases. Therefore, new strategies are required for identification of new drugs and drug targets. The M. tuberculosis dihydrodipicolinate synthase is a putative drug target with no potent inhibitor. Here in this study, we have used a comprehensive computational approach to identify small molecule inhibitors and validated them in vitro. As similar structures tend to have similar functions, therefore 3 approaches, namely, (a) known inhibitor-based approach, (b) substrate analogues, (c) product analogues were used for compound screening from various chemical libraries. The fourth approach we have taken is fragment library screening.In vitro studies revealed that β-hydroxypyruvic acid tartronic acid are inhibitors of Mtb-rDapA with maximum inhibition 48% and 51% at 500µM concentrations respectively. We have also observed that β-hydroxypyruvic acid is a time dependent inhibitor of Mtb-rDapA. Further, thermal shift assays showed that β-hydroxypyruvic acid interacts with Mtb-rDapA and the thermal stability of Mtb-rDapA shifted by 3˚C. Among the product analogues of Mtb-DapA, dipicolinic acid showed to bind to Mtb-rDapB shifting thermal stability of Mtb-rDapB by 0.5˚C in binding. Additionally, we have designed a new approach by combining substrate and product analogues to achieve better inhibitions. In vitro assays validated that this combination approach increased maximum inhibition up to 100%. We envision that these compounds would serve as potent leads for tuberculosis drug discovery.

Natural and synthetic small molecules from the NCI Developmental Therapeutics Program (DTP) were employed in molecular dynamics-based docking with DNA repair proteins whose RNA-Seq based expression was associated with overall cancer survival (OS) after adjustment for the PCNA metagene. The compounds employed were required to elicit a sensitive response (vs. resistance) in more than half of the cell lines tested for each cancer. Methodological approaches included peptide sequence alignments and homology modeling for 3D protein structure determination, ligand preparation, docking, toxicity and ADME prediction. Docking was performed for unique lists of DNA repair proteins which predict OS for AML, cancers of the breast, lung, colon, and ovaries, GBM, melanoma, and renal papillary cancer. Results indicate hundreds of drug-like and lead-like ligands with best-pose binding energies less than -6 kcal/mol. Ligand solubility for the top 20 drug-like hits approached lower bounds, while lipophilicity was acceptable. Most ligands were also blood-brain barrier permeable with high intestinal absorption rates. While the majority of ligands lacked positive prediction for Herg channel blockage and Ames carcinogenicity, there was considerable variation for predicted fathead minnow, honey bee, and Tetrahymena pyriformis toxicity. The computational results suggest the potential for new targets and mechanisms of repair inhibition and can be directly employed for in vitro and in vivo confirmatory laboratory experiments to identify new targets of therapy for cancer survival.

Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Although many small molecules have been proposed as inhibitors of amyloid formation, few have been successful in clinical trials. Amyloid formation is complex and several individual steps could be targeted by small molecules. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light chain dimers, the precursor proteins for AL amyloidosis are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidogenesis.

The World Health Organization (WHO) recently added snakebite envenoming to the priority list of Neglected Tropical Diseases (NTD). It is thought that ~75% of mortality following snakebite occurs outside the hospital setting, making the temporal gap between a bite and antivenom administration a major therapeutic challenge. Small molecule therapeutics (SMTs) have been proposed as potential pre-referral treatments for snakebite to help address this gap. Herein, we discuss the characteristics, potential uses and development of SMTs as potential treatments for snakebite envenomation. We focus on SMTs that are secretory phospholipase A2 (sPLA2) inhibitors and metalloprotease (MP) inhibitors.

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research is focused on development of oral therapies with improved efficacy and safety compared to available alternatives, as exemplified by deucravacitinib, the first oral allosteric Tyk2 inhibitor approved for the treatment of moderate-to-severe psoriasis in adults. Recent advances in our knowledge of psoriasis pathogenesis have also led to the development of targeted topical molecules, mostly focused on intracellular signaling pathways, such as AhR, PDE-4 and Jak-STAT. Topical tapinarof, an AhR modulator, and roflumilast, a PDE-4 inhibitor, have exhibited favorable efficacy and safety outcomes have been approved by the FDA for the topical treatment of plaque psoriasis. This revision focuses on the most recent oral and topical therapies available for psoriasis and specially on those that are currently under evaluation and development for the treatment of psoriasis.

Adenylosuccinic acid (ASA) is a small molecule dicarboxylate that could be a strong clinical development candidate for inherited myopathies involving dysregulated purine nucleotide metabo-lism. Currently, there are no published pharmacokinetic/dynamic or toxicology data available, albeit 10-year clinical trial data in Duchenne muscular dystrophy patients suggests a chronically safe drug. In this study, we tested the toxicity of ASA to cultured myoblasts in vitro and acute systemic toxicity in mice. ASA is a non-toxic small molecule with an LD50> 5000mg/kg. Some background necrotic foci in the liver, kidney and gastrointestinal tract were shown that are likely incidental but warrant follow-up sub-/chronic oral exposure studies.

A total of 473 metabolites were identified from 4 sour cherry genotypes using UPLC-TOF-MS. Untargeted metabolomics revealed the dominant chemical groups present in sour cherries. PCA showed that the diversity in sour-cherry metabolites was due to the genotype differences indicating iditol, malic acid, chlorobenzene, 2-mercaptobenzothiazole, and pyroglutamic acid as the predominant contributors. The variable importance in the projection (VIP > 1.0) in partial least-squares–discriminant analysis described 20 biomarker metabolites, representing the cherry metabolome profiles. A heatmap of Pearson’s correlation analysis between the 20 biomarker metabolites and antioxidant activities identified seven antioxidant determinants that displayed the highest correlations with different types of antioxidant activities. This study of correlating metabolomics and antioxidant activities elucidated that the higher nutritional value and biological functions of select sour cherry genotypes can be useful for the development of nutraceutical and functional foods.

The Dph1•Dph2 heterodimer from yeast is a radical SAM (RS) enzyme that generates the 3-amino-3-carboxy-propyl (ACP) precursor for diphthamide, a clinically relevant modification on eukaryotic elongation factor 2 (eEF2). ACP formation requires SAM cleavage and atypical Cys-bound Fe-S clusters in each Dph1 and Dph2 subunit. Intriguingly, the first Cys residue in each motif locates next to another, ill-defined cysteine that we show in-here is conserved across eukaryotes. As judged from structural modeling, the orientation of these tandem cysteine motifs (TCM) suggests a candidate Fe-S cluster ligand role. Hence, we generated by site-directed DPH1 and DPH2 mutagenesis, Dph1•Dph2 variants with cysteines from each TCM replaced individually or in combination by serines. Assays diagnostic for diphthamide formation in vivo reveal that while single substitutions in the TCM of Dph2 cause mild defects, double mutations almost entirely inactivate the RS enzyme. Based on enhanced Dph1 and Dph2 subunit instability in response to cycloheximide chases, the variants with Cys substitutions in their cofactor motifs are particularly prone to protein degradation. In sum, we identify a fourth functionally cooperative Cys residue within the Fe-S motif of Dph2 and show that the Cys-based cofactor binding motifs in Dph1 and Dph2 are critical for the structural integrity of the dimeric RS enzyme in vivo.

Resolving small molecule mixtures by nuclear magnetic resonance (NMR) spectroscopy has been of great interest for a long time for its precision, reproducibility and efficiency. However, spectral analyses for such mixtures are often highly challenging due to overlapping resonance lines and limited chemical shift windows. The existing experimental and theoretical methods to produce shift NMR spectra in dealing with the problem have limited applicability owing to sensitivity issues, inconsistency and / or requirement of prior knowledge. Recently, we have resolved the problem by decoupling multiplet structures in NMR spectra by the wavelet packet transform (WPT) technique. In this work, we developed a scheme for deploying the method in generating highly resolved WPT NMR spectra and predicting the composition of the corresponding molecular mixtures from their 1H NMR spectra in an automated fashion. The four-step spectral analysis scheme consists of calculating WPT spectrum, peak matching with a WPT shift NMR library, followed by two optimization steps in producing the predicted molecular composition of a mixture. The robustness of the method was tested on an augmented dataset of 1000 molecular mixtures, each containing 3 to 7 molecules. The method successfully predicted the constituent molecules with a median true positive rate of 1.0 against the varying compositions, while a median false positive rate of 0.04 was obtained. The approach can be scaled easily for much larger datasets.

Imbalance of homeostasis between the microbial communities and the host system leads to dysbiosis in oral micro flora. DMTU (1,3-di-m-tolyl-urea), is a biocompatible compound that was shown to inhibit Streptococcus mutansbiofilms by inhibiting its communication system (quorum sensing). Here, we hypothesized that DMTU is able to inhibit multispecies biofilms. We developed a multispecies oral biofilm model comprising an early colonizer Streptococcus gordonii, a bridge colonizer Fusobacterium nucleatum, and late colonizers Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans. We performed comprehensive investigations to demonstrate the effect of DMTU on planktonic cells and biofilms. Our findings showed that DMTU inhibits and disrupts multispecies biofilms without bactericidal effects. Mechanistic studies revealed significant down regulation of biofilm and virulence related genes in P. gingivalis. Taken together, our study highlights the potential of DMTU to inhibit polymicrobial biofilm communities and their virulence.

this review summarizes current knowledge of the hydrogen sulfide role in cardiovascular system, the proposed mechanisms of its action and the prospects for its applicability in the treatment of cardiovascular diseases. Hydrogen sulfide was recently recognized as gasotransmitter – simple signaling molecule which freely penetrates the cell membrane and regulates a number of biological functions. In humans endogenous H2S is generated via enzymatic and non-enzymatic pathways and its content varies in different tissues and is strictly regulated. In cardiovascular system H2S is produced by myocardial, vascular and blood cells and regulates a number of vital functions. Numerous experimental data prove that endogenously generated as well as exogenously administered H2S exerts a wide range of actions in cardiovascular system, including vasodilator/vasoconstrictor effects, regulation of blood pressure, pro-apoptotic and anti-proliferative effects in the vascular smooth muscle cells, influence on angiogenesis and erythropoiesis, myocardial cytoprotection in ischemia-reperfusion injury, oxygen sensing, inhibition of platelet aggregation and blood coagulation, modification of erythrocyte microrheological properties (aggregability and deformability). Understanding of molecular mechanisms of H2S action and molecular crosstalk between H2S, NO, and CO is essential for the development of its diagnostic and therapeutic potential.

Cytochrome P450 monooxygenases (P450s) are promising versatile oxidative biocatalysts. However, the practical use of P450s in vitro is limited by their dependence on the co-enzyme NAD(P)H and the complex electron transport system. Using H2O2 simplifies the catalytic cycle of P450s; however, most P450s are inactive in the presence of H2O2. By mimicking the molecular structure and catalytic mechanism of natural peroxygenases and peroxidases, an artificial P450 peroxygenase system has been designed with the assistance of a dual-functional small molecule (DFSM). DFSMs, such as N-(ω-imidazolyl fatty acyl)-l-amino acids, use an acyl amino acid as an anchoring group to bind the enzyme, and the imidazolyl group at the other end functions as a general acid-base catalyst in the activation of H2O2. In combination with protein engineering, the DFSM-facilitated P450 peroxygenase system has been used in various oxidation reactions of non-native substrates, such as alkene epoxidation, thioanisole sulfoxidation, and alkanes and aromatic hydroxylation, which showed unique activities, and regio- and enantioselectivities when compared with native P450s. Moreover, the DFSM-facilitated P450 peroxygenase system can switch to the peroxidase mode by mechanism-guided protein engineering. In this short review, the design, mechanism, evolution, application, and perspective of these novel non-natural P450 peroxygenases for the oxidation of non-native substrates are discussed.

Animal-based measures are the measure of choice in animal welfare assessment protocols as they can often be applied completely independently to the housing or production system employed. Although there has been a small body of work on potential animal-based measures for farmed crocodilians [1-3], they have not been studied in the context of an animal welfare assessment protocol. Potential animal-based measures, that could be used to reflect the welfare state of farmed crocodilians, were identified and aligned with the Welfare Quality® principles of good housing, good health, good feeding and appropriate behaviour. A consultation process with a panel of experts was used to evaluate and score the potential measures in terms of validity and feasibility. This resulted in a toolbox of measures being identified for further development and integration into animal welfare assessment on the farm. Animal-based measures related to ‘good feeding’ and ‘good health’ received the highest scores for validity and feasibility by the experts. There was less agreement on the animal-based measures that could be used to reflect ‘appropriate behaviour’. Where no animal-based measures were deemed to reliably reflect a welfare criterion nor be useful as a measure on the farm, additional measures of resources or management were suggested as alternatives. Future work in this area should focus on the reliability of the proposed measures and involve further evaluation of their validity and feasibility as they relate to different species of crocodilian and farming system.

The global usage of veterinary antibiotics is significant. These antibiotics can be released into the aquatic environment and exert toxic effects on non-target organisms. To explore the physiological effects of tetracycline antibiotics on aquatic life, the growth characteristics of and toxin release from the cyanobacterium Microcystis aeruginosa (M. aeruginosa) were studied. Results showed that the toxicity order of the three target antibiotics was TC (tetracycline) > CTC (chlortetracycline hydrochloride) > OTC (oxytetracycline) in terms of inhibition occurrence time and the EC₁₀ and EC₂₅ values. Further, the target antibiotics regulated the production of MC-LR (microcystin-LR) to different degrees. CTC destroyed the M. aeruginosa cells and resulted in a decreased MC-LR release but stimulated the ability to synthesise MC-LR. OTC had a relatively weaker toxicity compared with CTC, while TC was the most toxic among the three antibiotics. Therefore, TC is friendly to the aquatic environment because it simultaneously reduced the intracellular and extracellular MC-LR content. These results aid our understanding of the effects of tetracycline antibiotics on Microcystis aeruginosa, which is important for environmental evaluation and protection. These results are also helpful for guiding the application of veterinary antibiotics in agricultural settings.

Toxin/antitoxin (TA) systems are used primarily to inhibit phage, reduce metabolic activity during stress, and maintain genetic elements. Given the extreme toxicity of some of the toxins of these TA systems, we were curious how the cell silences toxins, if the antitoxin is inactivated or when toxins are obtained without antitoxins via horizontal gene transfer. Here we find that the RalR (type I), MqsR (type II), GhoT (type V), and Hha (type VII) toxins are inactivated primarily by a mutation that inactivates the toxin promoter or via the chromosomal mutations iraM and mhpR.

Background: Chronic lateral epicondylitis challenges the therapeutical approach; underlying mechanisms are incompletely understood; neuropathic pain and central and peripheral sensitization may explain the fact that botulinum toxin was found to play a role in pain and function management. Methods: We searched the literature for MeSH terms: lateral epicondylitis or synonyms and botulinum toxin. Results: We found 14 papers containing trials on botulinum toxin injection into the tendon or into the extensor muscles (particularly extensor carpi radialis brevis and extensor communis digitorum). We followed the administration pathways, doses, timing and side effects. Conclusion: With chronic course, the focus of the therapy shifts from the afflicted tendon to the inserting muscles, as muscle contracture may create a vicious loop to perpetuate and aggravate the disease. Doses, timing and side effects are discussed.

Docking the tail of lambs is a standard husbandry procedure and is achieved through several techniques including clamps, hot or cold knives and latex rings, the last of which is the most popular. All tail docking methods cause acute pain which can be reduced by application of local anesthetic, however precise anatomical injection for optimal efficacy requires considerable skill. This pen trial evaluated the ability of local anesthetic delivered with a dual function ring applicator / injector to alleviate acute tail docking pain. Thirty ewe lambs were assigned to one of three treatment groups (n = 10 per group): ring plus local anesthetic (Ring LA), ring only (Ring) and sham handled control (Sham). Lambs were videoed and behavior categorized every 5 minutes for the first hour and every 10 min for the subsequent 2 hours after treatment. There was a significant effect (p < 0.001) of treatment on total active pain related behaviors in the first hour, with Ring lambs showing higher counts compared to Ring LA or Sham. Ring lambs also displayed a significantly higher count of combined abnormal postures (p < 0.001) than Ring LA or Sham lambs. Delivery of 1.5ml of 2% lignocaine via the dual action device abolished abnormal behaviors and signs of pain in Ring LA lambs. However, lambs in the Ring LA group spent less time attempting to suckle compared to Ring and Sham lambs, suggesting that some residual discomfort remained.

The emergence of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment landscape for patients with metastatic non-small cell lung cancer (NSCLC). These achievements inspired investigators and pharmaceutical companies to conduct clinical trials in patients with early-stage NSCLC because both adjuvant and neoadju-vant platinum-based doublet chemotherapies (PT-DCs) showed only a 5% improve-ment in the 5-year overall survival. IMpower010, a phase 3 trial (P3), showed that ad-juvant PT-DC followed by maintenance atezolitumab significantly prolonged dis-ease-free survival than adjuvant PT-DC alone (hazard ratio, 0.79; stage II to IIIA). Since conventional therapies, including chemotherapy and radiotherapy, can promote im-munogenic cell death, which releases tumour antigens from dead tumour cells, ICI combination therapies with conventional therapies are widely proposed. Checkmate 816 trial (P3) indicated a significantly higher pathological complete response rate of neoadjuvant nivolumab/PT-DC combination therapy than neoadjuvant PT-DC alone (odds ratio, 13.9, for stage IB to IIIA). Detection of circulating tumour DNA is highly anticipated for the evaluation of minimal residual disease. Multimodal approaches and new ICI agents are being attempted to improve the efficacy of ICI treatment in phase 2 trials. This review presents the development of perioperative treatment using ICIs in patients with NSCLC while discussing problems and perspectives.

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.

Pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R) has a higher affinity for pituitary adenylate cyclase- activating polypeptide (PACAP) than for vasoactive intestinal peptide (VIP). PACAP exerts its neuroprotective effects through PAC1-R. PAC1-R has become a target for drug development, and we targeted PAC1-R to screen small positive allosteric modulator 1 (SPAM1). SPAM1 has a neuroprotective effects, and in the D-galactose (D-gal) mouse model, SPAM1 improved the structure of the hippocampal dentate gyrus and restored the number of neurons. Compared with D-gal model mice, SPAM1 treatment upregulated the expression of Sirtuin 6 (SIRT6) and Lamin B1, and downregulated the expression of YinYang 1 (YY1) and p16. Consistent with this, the same results were obtained in senescent RGC-5 cells. Meanwhile, SPAM1 was also found to up-regulate SIRT6 and down-regulate YY1 expression in normal RGC-5 cells. Then, we further explored the mechanism of SPAM1 neuroprotection by whole transcriptome sequencing and proteomic analysis, and found that SPAM is involved in the longevity regulating pathway, and confirmed the up-regulation of neurofilament light polypeptide and neurofilament medium polypeptide by western blot, thus laying a pharmacological foundation for SPAM1 as a therapeutic agent for neurodegenerative diseases. polypeptide and neurofilament medium polypeptide. Thus, it lays a pharmacological foundation for SPAM1 as a therapeutic drug for neurodegenerative diseases.

Natural host defensins, also sometimes termed antimicrobial peptides, are evolutionarily conserved. They have been studied as antimicrobials, but some pharmaceutical properties, undesirable for clinical use, led to the development of synthetic molecules with constructed peptide arrangements and/or peptides not found in nature. The leading development currently is synthetic small molecule nonpeptide mimetics, whose physical properties capture the characteristics of the natural molecules, and share their biological attributes. We studied brilacidin, an arylamide of this type, for its activity in vitro against fungi (40 clinical isolates, 20 species) that the World Health Organization has highlighted as problem human pathogens. We find antifungal activity at low concentrations for many pathogens, which indicates further screening for activity, particularly in vivo, is justified to evaluate this compound, and other mimetics, as attractive leads for development of effective antifungal agents.

Several therapeutic monoclonal antibodies are approved by FDA against the PD-1/PD-L1 (programmed death-1/programmed death ligand-1) immune checkpoint, which has been a great success in cancer treatment. However, existing therapeutics, including small molecules inhibitors against PD-L1 checkpoint have certain drawbacks such as high cost and drug resistance that challenge the current available anti-PD-L1 therapy. Thereof, this study presents the screening of 32552 compounds from Natural Product Atlas database against PD-L1, including three steps of structure-based virtual screening and binding free energy refinement for the selection of potent PD-L1 inhibitors. Subsequently, five natural compounds, i.e., Neoenactin B1, Actinofuranone I, Cosmosporin, Ganocapenoid A, and 3-[3-hydroxy-4-(3-methylbut-2-enyl)phenyl]-5-(4-hydroxybenzyl)-4-methyldihydrofuran-2(3H)-one, were collected based on the ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling and binding free energy (>-70 kcal/mol) for further computational investigation by comparison to co-crystallised ligand, i.e. JQT inhibitor. Based on interaction mapping, explicit 100 ns molecular dynamics simulation, and post binding free energy calculations, all the compounds exhibited intermolecular interactions (hydrogen and hydrophobic) with essential residues and substantial complex stability by comparison to the JQT inhibitor. Collectively, the calculated results advocate the selected natural compounds as the putative potent inhibitors of PD-L1 and, therefore, can be considered for further development of PD-L1 immune checkpoint inhibitor in cancer immunotherapy.

AB toxins have historically been associated with significant morbidity, mortality through infections such as botulinum, anthrax, cholera, and diphtheria. These AB toxin-mediated diseases remain prevalent in low and middle income countries, with intermittent outbreaks of Shiga toxin-producing Escherichia coli (STEC) or whooping cough by Bordetella pertussis in high-income countries. These reports warrant an investigation to better understand the distinct characteristics of AB toxins derived from different pathogens. As toxigenic pathogens broaden their scope and diversity, it amplifies the complexity of the problems posed by their AB toxins. Here, we discuss the history, structure and characteristics of key AB toxins, and report on historical and ongoing research on these toxins. We also explore research avenues that hold great promise in potentially improving clinical management of toxin-mediated diseases in the future.

Use of local anesthesia at the time of ring castration and tail docking can improve lamb welfare. However, few local anesthetics are registered for sheep, and data on their duration of effect is limited. Three studies were conducted to evaluate the efficacy of procaine (P), lidocaine (L) and bupivacaine (B) in terms of observed alleviation of behavioral responses to castration and/or tail docking in 10-min blocks in the first 60 min post treatment. In each study, comparisons were made between two groups of lambs castrated and/or tail docked with rubber rings and either receiving the agent using the NUMNUTS® instrument (N) or receiving no anesthetic agent (RR). Acute pain behavior was lower in NL (n = 28) than RRL (n = 15) males in the first 10 min post procedure (P < 0.05); lower in NB (n = 16) than RRB (n = 16) males in periods 10-20 min (0.05 < P < 0.01), 20-30 min (P < 0.05) and 40-50 min (0.05 < P < 0.01); lower in NB (n = 16) than RRB (n = 16) females between 20 and 40 min post-procedure (0.05 < P < 0.01); lower in NP (n = 8) than RRP (n = 7) males in period 10-20 min (0.05 < P < 0.01), and lower in NP (n = 9) than RRP (n = 9) females in periods 0-10 min (0.05 < P < 0.01), and 10-40 min (P < 0.05). Analgesic benefits were modest, and the effects of procaine appear to last longer than lidocaine, while bupivacaine is slower to take effect than either procaine or lidocaine but may provide longer lasting analgesia. The duration of action of local anesthetics is short in sheep, and detailed behavioral evaluations are required in the first hour post procedure to establish efficacy.

Several pathotypes of enteric E. coli have been identified. The group represented by Shiga toxin-producing E. coli (STEC) is of particular interest. Raw milk and raw milk products are significant sources of STEC infection in humans; therefore, identifying pathogens at the herd level is crucial for public health. Most national surveillance programs focus solely on raw milk and raw milk cheeses that are ready for retail sale, neglecting the possibility of evaluating the source of contamination directly at the beginning of the dairy chain. In order to assess the viability of new molecular methodologies applied to raw milk filters enabling the identification of the presence of STEC serotypes in milk production and apply the same methods to identify the presence of these pathogens in calf feces we analyzed, through a commercial real-time PCR assay, a total of 290 samples coming from 18 different dairy herds; 88 bulk tank milk (BTM), 104 raw milk filters (RMF) and 98 calves’ feces samples. In total 3.4% of BTM, 41.4% of RMF and 73.4% of calves’ feces tested positive for stx presence, supporting our hypothesis that BTM is not a suitable matrix to assess the STEC presence at herd level, underestimating it. Our conclusion is that the surveillance program needs critical and extensive improvements such as RMF and calves’ feces analysis implementation in order to be more efficient in detecting and preventing STEC infections. The epidemiology of these infections and the characteristics of the pathogen clearly show how a One Health approach will be pivotal to improve our capabilities to control the spread of these infections.

Polo-like kinase 1 (PLK1) plays a pivotal role in cell division regulation and emerges as a promising therapeutic target for cancer treatment. Consequently, the development of small-molecule inhibitors targeting PLK1 has become a focal point in contemporary research. The adenosine triphosphate (ATP)-binding site and the polo-box domain in PLK1 present crucial interaction sites for these inhibitors, aiming to disrupt the protein's function. However, designing potent and selective small-molecule inhibitors can be challenging, requiring a deep understanding of protein-ligand interaction mechanisms at these binding sites. In this context, our study leverages the fragment molecular orbital (FMO) method to explore these site-specific interactions in-depth. Through the FMO approach, we used the FMO method to elucidate the molecular mechanisms of small-molecule drug binding to these sites to design PLK1 inhibitors that are both potent and selective. Our investigation further entailed a comparative analysis of various PLK1 inhibitors, each characterized by distinct structural attributes. This comparison enhanced our understanding of the structure-activity relationships of these inhibitors, underscoring the efficacy of the FMO method in identifying critical binding features and predicting binding modes for small-molecule ligands. Furthermore, Our research spotlighted "hot spot" residues instrumental for selective and robust PLK1 binding. Our findings offer profound insights, priming the rational design of innovative potential PLK1 inhibitors with significant implications for developing anticancer therapeutics.

Since the beginning of the COVID-19 pandemic, extensive drug repurposing efforts sought to identify small molecule antivirals with various mechanisms of action. Here we aim to review research progress on small molecule viral entry and fusion inhibitors that directly bind to the SARS CoV-2 Spike protein. Early in the pandemic, numerous small molecules were identified in drug repurposing screens and reported to be effective in vitro SARS CoV-2 viral entry or fusion inhibitors. However, given minimal experimental information regarding the exact location of small molecule binding sites on Spike, it was unclear what the specific mechanism of action was, or where the exact binding sites were on Spike for some inhibitor candidates. The work of countless researchers has yielded great progress, with the identification of many viral entry inhibitors that target elements on the S1 receptor binding domain (RBD) or N-terminal domain (NTD) and disrupt S1 receptor binding function. In this review, we will also focus on highlighting fusion inhibitors that target inhibition of the S2 fusion function, either by disrupting the formation of the postfusion S2 conformation or alternatively by stabilizing structural elements of the prefusion S2 conformation to prevent conformational changes associated with S2 function. We highlight experimentally validated binding sites on the S1/S2 interface and on the S2 subunit. While most mutations to the Spike protein to date in variants of concern (VOCs) have been localized to the S1 subunit, the S2 subunit sequence is more conserved with only a few observed mutations in proximity to S2 binding sites. Several recent small molecules targeting S2 have been shown to have robust activity over numerous recent VOC mutant strains and/or greater broad spectrum antiviral activity for other more distantly related coronaviruses.

BOLD-100, a ruthenium-based complex, sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (also known as IT-139, NKP1339 or KP1339), is a novel small molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity in a phase I clinical trial. BOLD-100 has been reported to inhibit the upregulation of the endoplasmic reticulum stress sensing protein GRP78. However, response to BOLD-100 varies in different cancer models and the precise mechanism of action in high-response versus low-response cancer cells remains unclear. In vitro studies have indicated that BOLD-100 induces cytostatic rather than cytotoxic effects as a monotherapy. To understand BOLD-100 mediated signaling mechanism in breast cancer cells, we used estrogen receptor positive (ER+) MCF7 breast cancer cells to obtain gene-metabolite integrated models. Particularly, BOLD-100 significantly reduced expression of genes involved in the DNA repair pathway. BOLD-100 also induced reactive oxygen species (ROS) and phosphorylation of histone H2AX, gH2AX (Ser139), suggesting disruption of proper DNA surveillance. In estrogen receptor negative (ER-) breast cancer cells, combination of BOLD-100 with a PARP inhibitor, olaparib, induced significant inhibition of cell growth and xenografts and increased gH2AX. Thus, BOLD-100 is a novel DNA repair pathway targeting agent and can be used with other chemotherapies in ER- breast cancer.

Statistical denoising techniques have been well studied, however many challenges still remain. This 9 article focuses on determining the least necessary number of significant samples in a statistical pop-10 ulation sampling, while minimizing the impact on the statistical detection of the fiber Bragg grating 11 (FBG) power spectra. This is achieved by using Bayesian decision making, small population statis-12 tics while excluding false detection. First, we investigate the impact of two-sided sliding window 13 technique applied near the cell under the test. The window size varies from 8 to 60 samples. The 14 considered maximum size of population sampling is connected with the number of wavelength 15 samples within the bandwidth of the symmetrical FBG power spectra peaks. Regarding the sym-16 metry of FBG power spectra peaks and the possible reduction of computational demands, we inves-17 tigate the impact of a one-sided sliding window. This enables to achieve less processing latency for 18 real time applications thus brings benefits to FBG-based fiber optical sensing. Both, two- and one-19 sided small population sampling techniques are then experimentally verified. Detection results are 20 analyzed in depth via calculating detection thresholds by using the small size window sliding along-21 side the waveband. From results achieved, it was found that the normality three-sigma rule does 22 not need to be followed while using the small population sampling. Experimental demonstrations 23 and analyses showed that the proposed concept of denoising and statistical threshold detection 24 based on the sliding window does not depend on the prior knowledge of probability distribution 25 functions of the FBG power spectra peaks level and background noise. We have also found that the 26 thresholds’ adaptability mainly depends on the statistical numerical characteristics of the above ad-27 ditive mixture of the FBG power spectra peaks signals and background noise.

This paper presents a system for identification of wind features, such as gusts and wind shear. These are of particular interest in the context of energy-efficient navigation of Small Unmanned Aerial Systems (UAS). The proposed system generates real-time wind vector estimates and a novel algorithm to generate wind field predictions. Estimations are based on the integration of an off-the-shelf navigation system and airspeed readings in a so-called direct approach. Wind predictions use atmospheric models to characterize the wind field with different statistical analyses. During the prediction stage, the system is able to incorporate, in a big-data approach, wind measurements from previous flights in order to enhance the approximations. Wind estimates are classified and fitted into a Weibull probability density function. A Genetic Algorithm (GA) is utilized to determine the shaping and scale parameters of the distribution, which are employed to determine the most probable wind speed at a certain position. The system uses this information to characterize a wind shear or a discrete gust and also utilizes a Gaussian Process regression to characterize continuous gusts. The knowledge of the wind features is crucial for computing energy-efficient trajectories with low cost and payload. Therefore, the system provides a solution that does not require any additional sensors. The system architecture presents a modular decentralized approach, in which the main parts of the system are separated in modules and the exchange of information is managed by a communication handler to enhance upgradeability and maintainability. Validation is done providing preliminary results of both simulations and Software-In-The-Loop testing. Telemetry data collected from real flights, performed in the Seville Metropolitan Area in Andalusia (Spain), was used for testing. Results show that wind estimation and predictions can be calculated at 1 Hz and a wind map can be updated at 0.4 Hz. Predictions show a convergence time with a 95% confidence interval of approximately 30 s.

Stallion mules have been used as working equids in several countries. Aggressiveness, under the influence of testosterone, resulted in the necessity for surgical castration before work training. The gonadotropin-releasing hormone (GnRH) vaccine may be an alternative method for immunocastration in mules. The objectives were to evaluate the effect of GnRH vaccine on anti-GnRH antibody production, serum testosterone level, clinical adverse effects, and behavior toward human manipulation. Twenty-five mules were separated into 3 groups: Control-intact, Control-castrated, and Treatment. Treatment was further divided into subgroups according to condition (intact or unilateral cryptorchid) and age. Treatment received 195 µg GnRH vaccine intramuscularly at week 0, 4, and 8. Anti-GnRH antibody increased at week 6 and 10, then gradually decreased to baseline at week 22. Treatment-intact-young had the highest anti-GnRH antibody, resulting in lower serum testosterone levels during week 2-6 and 12-16 compared to Control-intact. Subcutaneous edema adjacent to the injection site was detected only in Treatment-intact after booster vaccination. During week 6-22, the behavioral scores of Treatment significantly changed toward at ease with human contact compared to a score before vaccination. In conclusion, mules responded to GnRH vaccine, which could temporarily suppress testosterone for up to 16 weeks.

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.

This article summarizes the results of a research conducted to create an intelligent platform supporting small farmers growing vegetables. In Bulgaria, many farmers use relatively small areas for their production. Considering this situation, the platform is designed for regional use, trying to make maximum use of the specific climatic features of the monitored microdistrict. Consequently, special attention is paid to the possibilities of adapting the platform to the specific environment in which the observed plants grow. Thus, the platform is implemented as an agent-oriented system providing needed flexibility. The core of the platform is a personal assistant, which is responsible for tracking the vegetation cycle of the monitored crop and, upon detection of anomalies, preparing warnings to the farmer. The general architecture of the platform is also presented. In a distributed knowledge base, agriculture-specific knowledge are stored. Furthermore, a standardized interface for receiving data from the sensor networks located in the production areas is briefly described. Currently, the platform is being tested for monitoring four varieties of tomatoes grown on the territory of the national research center for potato breeding. Special attention is paid to the measurements carried out. Conclusions have been drawn that will help improve the platform.

The outbreak of COVID-19, the disease caused by SARS-CoV-2, continues to affect millions of people around the world. The absence of a globally distributed effective treatment makes the exploration of new mechanisms of action a key step to address this situation. Stabilization of non-native Protein-Protein Interactions (PPIs) of the nucleocapsid protein of MERS-CoV has been reported as a valid strategy to inhibit viral replication. In this study, the applicability of this unexplored mechanism of action against SARS-CoV-2 is analyzed. During our research, we were able to find three inducible interfaces of SARS-CoV-2 N protein NTD, compare them to the previously reported MERS-CoV stabilized dimers, and identify those residues that are responsible for their formation. A drug discovery protocol implemented consisting of docking, molecular dynamics and MM-GBSA enabled us to find several compounds that might be able to exploit this mechanism of action. In addition, a common catechin skeleton was found among many of these molecules, which might be useful for further drug design. We consider that our findings could motivate future research in the fields of drug discovery and design towards the exploitation of this previously unexplored mechanism of action against COVID-19.

The Hepatitis B virus, chronically infects over 240 million persons worldwide. The Hepatitis B vaccine is 90% effective in preventing perinatal transmission if the first dose is given within the first 24 hours of life followed by a minimum of 2 subsequent doses. In October 2021, Antigua and Barbuda, through it’s only public hospital - the Sir Lester Bird Medical Centre, instituted a hospital based Hepatitis B vaccine birth dose policy. Timely birth dose coverage was 72% and total birth dose coverage 81%. 10.5% of parents refused the hepatitis b – birth dose, of which 76% either felt uncomfortable or preferred to wait. 100% of babies born before arrival received timely vaccine administration, likewise 100% of Hepatitis B exposed babies were vaccinated, with 83% of them receiving the Hepatitis B Immunoglobulin. A maternal Hepatitis B surface antigen result was available for 90.4% of mothers. Barriers to timely birth dose administration included vaccination hesitancy, gaps in healthcare worker knowledge, and the consistent supply of Hepatitis B vaccine. Instituting a quality improvement team, health information system, robust educational efforts, and addressing barriers will make achieving the WHO programmatic targets of eliminating mother to child transmission of hepatitis B by 2030 possible.

Activating mutations in the Epidermal Growth Factor Receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20-30% of patients do not respond or respond for a very short time (< 3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

One of the major concerns in structural health management (SHM) is the early detection of a growing crack. Using this, future damage due to crack propagation can be mitigated or eliminated by implementing proper repair and maintenance. Acoustic Emission (AE) is a non-destructive testing (NDT) method with potential applications for locating and monitoring fatigue cracks. The research presented in this paper focuses on SHM using AE. A novel AE signal analysis approach was proposed in order to detect crack initiation and assess small crack lengths. Experimental investigation indicated that initiation of a crack could be identified through the statistical analysis of the resulting features of the AE signals. A probabilistic AE-based model for small fatigue crack sizing was developed and the uncertainties of the model were estimated. In addition, a probabilistic model validation approach was implemented to confirm accurate estimation of the results. The outcome of this research can be used to evaluate the integrity of structures under fatigue loading. The proposed approach can also be applied as an approach to manage health and assess prognosis of structures.

Lung cancer is the most common malignancy across the world. The new era in lung cancer treatments, especially this past decade, has yielded novel categories of targeted therapy for specific mutations and adjuvant therapy, both of which have led to improved survival rates. In the present study, we review the changes and development of treatments, with a special focus on adjuvant therapy using tyrosine kinase inhibitors (TKIs) administered to non-small-cell lung carcinoma patients who had a complete resection of the tumor harboring a mutated epidermal growth factor receptor. The clinical trials are dating from the past (chemotherapy trials), present (TKIs) and future (ongoing trials).

Lumpy skin disease (LSD), caused by a virus within the Poxviridae family and Capripoxvirus genus, induces nodular skin lesions in cattle, spreading through direct contact and insect vectors, significantly affecting global cattle farming. Despite available vaccines, their effectiveness is limited by poor bioavailability and adverse effects. Our study aimed to identify potential inhibitors targeting LSD-associated DNA polymerase protein, selecting LSDV039 for further investigation through comprehensive analysis and computational methods. Virtual screening revealed rhein and taxifolin as potent binders among 380 phytocompounds, with respective affinities of -8.965 and -7.195 kcal/mol. Canagliflozin and tepotinib exhibited strong affinities (-9.858 and -8.856 kcal/mol) among 718 FDA-approved antiviral drugs. Molecular dynamics simulations of canagliflozin, tepotinib, rhein, and taxifolin highlighted taxifolin's superior stability and binding energy. Rhein displayed compactness in RMSD and RMSF but fluctuations in Rg and SASA, while canagliflozin demonstrated stability compared to tepotinib. The study highlights the promising potential of repurposed drugs and phytocompounds as LSD therapeutics. However, extensive validation through in-vitro, in-vivo, and clinical trials is crucial for their practical application.

This study presents a detailed computational investigation aimed at identifying and evaluating potential small organic molecular scaffolds as inhibitors targeting the Pks13 protein, a critical enzyme in tuberculosis (TB) drug discovery. Our approach integrates multiple computational techniques, including quantitative structure-activity relationship (QSAR) modelling, compound library generation, molecular docking, biological activity prediction, re-evaluation of screened compounds, molecular dynamics (MD) analysis, and binding free energy estimation using the MM-GBSA approach. We developed a robust QSAR model using multiple linear regression (MLR) techniques, specifically tailored to predict the minimum inhibitory concentration (MIC) values of potential anti-TB agents. This model demonstrated excellent predictive performance, validated through rigorous internal and external validation procedures. Through molecular docking simulations, we identified five promising inhibitors Ethyl (R,Z)-2-(2-((2-chlorobenzyl) oxy)benzylidene)-5-(4-chlorophenyl)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidine-6-carboxylate (PKD1), (7R,9aR)-7-(2-hydroxyphenyl)-4-(2-methoxyphenyl)-3-methyl-7,8,9,9a-tetrahydroisoxazolo[5,4-b]quinolin-5(6H)-one (PKD2), (7-(4-methoxy phenyl)-2-methyl-3-phenylpyrazolo[1,5-a]pyrimidin-5-yl)(4-(3-(trifluoromethyl)phenyl) piperazin-1-yl)methanone (PKD3), (8S,10S)-10-(((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl tetrahydro-2H-pyran-2-yl)oxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetra-hydrotetracene-5,12-dione (PKD4), 3-(3,4-dimethylphenyl)-5-((2-(4-fluorophenyl)-2-oxoethyl) thio)-6-phenyl-2-thioxo-2,3,5,7a-tetrahydrothiazolo[4,5-d]pyrimidin-7(6H)-one (PKD5)with high binding affinities, prioritizing them based on their binding energies. These selected compounds were further assessed for their biological activity predictions, guiding the selection of candidates for experimental validation. Subsequent re-evaluation using absolute binding free energy estimation and MD simulations provided insights into the stability and dynamics of the protein-ligand complexes over time. Our findings highlighted the potential of identified compounds as stable binders within the Pks13-TE domain binding pocket, underscoring their viability as drug candidates. Additionally, binding free energy analysis using MM-GBSA reaffirmed the strong affinity of the proposed compounds towards Pks13. Our integrated computational approach offers a systematic and detailed framework for the identification and characterization of potential Pks13 inhibitors with specific relevance to TB drug discovery.

Pore Forming Toxins (PFTs), formed mainly by virulence factors of bacteria, belongs to Pore Forming Protein (PFP) family. Secreted as soluble monomers, they bind specific targets in membranes where their oligomerization and insertion place. Lysenin, a member of the PFTs, forms and oligomer after sphingomyelin binding, the so-called prepore, which become inserted forming a pore after a conformational change triggered by a pH decrease. In crowded conditions, oligomers tends to stay in prepore form because the prepore-to-pore transition is sterically blocked. In this study, we investigate the effect of calcium ions in those crowded conditions, finding that calcium act as a trigger for lysenin insertion. We localize the residues responsible for calcium sensitivity in a small α-helix. Our results are not only one of the few complete structural descriptions of prepore-to-pore transitions but the very first that involves a calcium triggering mechanism. The presence of glutamic or aspartic acids in the insertion domains could be an indication that calcium may be a general trigger for PFTs and more generally PFP.

Bartonella species, intracellular parasitic zoonotic pathogens, has drawn increasing attention for their diverse host range and associated human diseases. This study investigates Bartonella infection in small mammals in Yunnan Province, China, focusing on tissue tropism. 333 small mammals were sampled from 13 species, 3 orders, 4 families, and 4 genera in Heqing and Gongshan Counties. Conventional PCR and real-time quantitative PCR (qPCR) were utilized for detection and quantification, followed by bioinformatic analysis of obtained DNA sequences. Results show a 31.5% detection rate, varying across species. Notably, Apodemus chevrieri, Eothenomys eleusis, Niviventer fulvescens, Rattus tanezumi, Episoriculus leucops, Anourosorex squamipes, and Ochotona Thibetana exhibited infection rates of 44.4%, 27.7%, 100.0%, 6.3%, 60.0%, 23.5%, and 22.2%, respectively. Genetic analysis identified 30, 10, and 5 strains based on ssrA, rpoB, and gltA genes, with nucleotide identities ranging from 92.1% to 100.0%. Bartonella strains were assigned to B. grahamii, B. rochalimae, B. sendai, B. koshimizu, B. phoceensis, B. taylorii, and a new species identified in the Episoriculus leucops (GS136). Tissue distribution analysis revealed varied copy numbers across different tissues, with the highest load in spleen. These findings underscore Bartonella's diverse species and host range in Yunnan Province, highlighting its broad tissue tropism in small mammals.

Distributed/semi-distributed models are considered to be sensitive to the spatial resolution of the data input. In this paper, we take a small catchment in high urbanized Yangtze River Delta, Qinhuai catchment as study area, to analyze the impact of spatial resolution of precipitation and the potential evapotranspiration (PET) on the long-term runoff and flood runoff process. The data source includes the TRMM precipitation data, FEWS download PET data, and the interpolated metrological station data. GIS/RS technique was used to collect and pre-process the geographical, precipitation and PET series, which were then served as the input of CREST (Coupled Routing and Excess Storage) model to simulate the runoff process. The results clearly showed that, the CREST model is applicable to the Qinhuai catchment; the spatial resolution of precipitation had strong influence on the modelled runoff results and the metrological precipitation data cannot be substituted by the TRMM data in small catchment; the CREST model was not sensitive to the spatial resolution of the PET data, while the estimation fourmula of the PET data was correlated with the model quality. This paper focused on the small urbanized catchment, suggesting the influential explanatory variables for the model performance, and providing reliable reference for the study in similar area.

Non-coding RNAs have been described as crucial regulators of gene expression and guards for cellular homeostasis. Some recent papers are focused on vault RNAs, one of the classes of non-coding RNA, and their role in cell proliferation, tumorigenesis, apoptosis, cancer response to therapy, and autophagy, which made them potential therapy targets in oncology. In the human genome, four vault RNA paralogues can be distinguished. They are associated with vault complexes, considered the largest ribonucleoprotein complex. The protein part of these complexes consists of a major vault protein (MVP) and two minor vault proteins (vPARP and TEP1). The name of the complex, as well as vault RNA, comes from the hollow barrel-shaped structure that reminds a vault. Their sequence and structure are highly evolutionary conserved and show many similarities in comparison with different species, but vault RNAs show various roles. Vaults were discovered in 1986, and their functions remained unclear for many years. Although not much is known about their contribution to cell metabolism, it has become clear that vault RNAs are involved in various processes and pathways associated with cancer progression and modulating cell functioning in normal and pathological stages. In this review, we discuss known functions of the human vault RNAs in the context of cellular metabolism, emphasizing processes related to cancer and cancer therapy efficacy.

Introduction: Atrial fibrillation (AF) is a common cardiac arrhythmia whose prevalence rises with age and is linked to increased morbidity and mortality due to the risk of thromboembolism. Management typically involves anticoagulation and rhythm control, but the treatment of elderly patients with multiple comorbidities requires careful consideration of drug side effects and interactions. Cibenzoline, a Vaughan-Williams class IA antiarrhythmic, is effective against AF but has risks of toxicity, especially in older people and those with renal impairment, due to its renal excretion and prolonged half-life in these populations. Discussion: This paper presents a case of an 80-year-old woman with paroxysmal AF who suffered cardiac arrest due to cibenzoline toxicity despite receiving standard adjusted dosages. The patient's cibenzoline blood concentration was significantly higher than the therapeutic range, leading to cardiotoxicity, which was exacerbated by drug interactions with bisoprolol and edoxaban, both metabolized by the CYP3A4 enzyme. Venoarterial extracorporeal membrane oxygenation (V-A ECMO) and intra-aortic balloon pump (IABP) successfully managed the cardiac arrest. This case emphasizes the unpredictable pharmacokinetics of cibenzoline in elderly patients with renal impairment and the need for vigilant therapeutic drug monitoring to avoid adverse events. Conclusions: Cibenzoline can pose a significant risk of severe toxicity in elderly patients with renal impairment, and drug interactions may potentiate this risk. The paper underscores the importance of careful dose adjustment and monitoring of drug levels in this population. In cases of cibenzoline-induced cardiac arrest, V-A ECMO and IABP are effective treatment modalities. The case study serves as a critical reminder for clinicians to remain vigilant for drug-induced complications and to apply aggressive supportive treatments when necessary.

Metabarcoding of prokaryotic and fungal ribosomal DNA was used to describe the microbial communities in soils of remnant equatorial rainforest, maize-bean intercrop, and sugarcane in western Kenya. Cropping systems influenced the microbial community composition and functional traits (energy source and nutrient cycling) of bulk soil in each crop. Microbial richness and diversity tended to increase with cultivation intensity. Soil of maize-bean intercrop had lower percentages and sugarcane had higher percentages of unique amplicon sequence variants of both bacteria and fungi compared to the remnant forest. Functional traits were altered by cultivation intensity. Compared to remnant forest soils, maize-bean intercrop soil had lower percentages of aerobic chemoheterotrophic bacteria and higher percentages of N-cycling bacteria, while sugarcane had higher percentages of aerobic chemoheterotrophic bacteria and lower percentages of N-cycling bacteria. In the face of increasing forest loss and pressures for agricultural productivity, this landscape provides a rich site for studying the impacts of cropping systems on soil health.

The toxin-antitoxin (TA) systems have been attracting attention due to their role in regulating prokaryotic cell responses to stress and their biotechnological potential. Much recognition has been given to type II TA system of mesophiles, but so far, limited attention has been given to thermophiles. Here, we are presenting the putative type II TA families encoded on the genomes of four Geobacillus strains. We employed the TA finder tool to mine for TA-coding genes and manually curated the results using various tools. We identified 28 putative TA pairs, distributed over 8 TA families. Among the identified TAs, 15 represent putative novel toxins and antitoxins that have been overlooked or annotated as hypothetical proteins in their genome records. We also identified a potentially new TA composite, AbrB-ParE. Furthermore, we are suggesting the Geobacillus acetyltransferase toxin-antitoxin (GacTA) family which potentially represents one of the unique TA families that has a reverse gene order. Moreover, we are proposing a hypothesis on the regulation of the xre-cog2856 gene expression, which seems to involve c-di-AMP. This study aims for highlighting the significance of studying TAs in Geobacillus, since they have special features. It also aims for facilitating future experimental research.

Herein, we are proposing two chalcone molecules, (E)-1-(4-methoxyphenyl)-3-(p-tolyl) prop-2-en-1-one and (E)-3-(4-hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl) prop-2-en-1-one, based on the anticancer bioactive molecule Xanthohumol, which are suitable for further in vitro and in vivo studies. Their ability to create stable complexes with the antiapoptotic X-linked IAP (XIAP) protein makes them promising anticancer agents. The calculations were based on ligand-based and structure-based virtual screening combined for the pharmacophore built. Additionally, the structures passed Lipinski's rule for drug use, and their reactivity was confirmed using density functional theory studies. The candidates were chosen between 10639400 compounds, and the docking protocols were evaluated using molecular dynamics simulations.

(1) Background: TNF inhibitors (TNFi) have revolutionized the treatment of rheumatoid arthritis (RA). However, 30-40 % of RA patients do not respond adequately to those biologics. In addition to neutralizing soluble TNF, TNFi have the ability to bind the transmembrane form of TNF, tmTNF. Importantly, tmTNF can act itself as a receptor that induces a “Reverse Signaling” (RS) in cells. We previously showed that certolizumab, a Fab’ TNFi, activates RS in human primary monocytes, at least in part through the transcription factor NRF2 that is known to regulate the expression of genes involved in anti-inflammatory response and oxidative stress. (2) Methods: Here, we have developed an assay for the prediction of clinical response of RA patients to TNF inhibitors. This assay is based on mRNA quantitation of CD36 activation and of 6 genes induced by NRF2 following tmTNF RS in fresh monocytes. (3) Results: We could predict the response to anti-TNF monoclonal antibodies (mAbs) with 93.3 % accuracy. However, our method was not suitable for the prediction of the response to TNF soluble receptor etanercept. (4) Conclusions: We have developed a rather simple, short-term, test that can be standardized. Predicting the response to TNF mAbs will help physicians offer the best available treatment and provide patients with personalized medicine.

Menin inhibitors are new and promising agents currently in clinical development that target the HOXA/MEIS1 transcriptional program which is critical for leukemogenesis in histone-lysine N-methyltransferase 2A rearranged (KMT2Ar) and in NPM1-mutated (NPM1mut) acute leukemia. The mechanism of action of this new class of agents is based on the disruption of menin-KMT2A complex (constitute of chromatin remodelling proteins), leading to the differentiation and apoptosis of AML cells expressing KMT2A or mutated NPM1. This new class of drugs has been tested alone, or in combination with synergistic drugs, in phase I and II clinical trials (AUGMENT-01 and 02, KOMET-01 and 07, SAVE, COVALENT trial and others), showing promising results in terms of response rates and safety in heavily pre-treated acute leukemia patients. In this review, we summarise the key findings on menin inhibitors, focusing on the mechanism of action and preliminary clinical data of this emerging and promising class of agents, in particular revumenib and ziftomenib.

Objective: to retrospectively evaluate the incidence rate (IR) of echocardiographic signs suspected for pulmonary hypertension (PH) in Systemic sclerosis (SSc) patients after the introduction of a combination therapy with bosentan and sildenafil for treatment or prevention of digital ulcers. Methods: patients attending the Scleroderma Unit of the Universital Hospital of Careggi from July 2010 to July 2023 were enrolled. Patients older than 18 years old, with an history of digital ulcers, treated with bosentan and sildenafil in combination for at least 12 months were included. Patients with a diagnosis of PH preceding the introduction of the therapy were excluded. Demographical data, disease duration, laboratoristic and instrumental data (pulmonary function tests, echocardiographic estimation of pulmonary artery pressure (PAPs) and ultrasonographic value of renal resistive index) were collected. The IR of echocardiographic signs suspected for pulmonary hypertension and their 95% confidence interval were calculated in events/1000 patients-years.Results: forty-seven patients were enrolled; mean disease duration was 12,14 years (SD 5,87). Mean duration of the combination treatment was 78.33 (SD 41.37) months and total at-risk time was 3525 months. Two patients (4,2%) presented echocardiographic signs of PH (sPAP 50 mmHg and 40 mmHg); the IR was calculated to be 6.8/1000 patients-years (95% CI 6,02-7,7). In one of the 2 patients RHC excluded PAH, while the other patient refused to undergo to RHC and PAH could not be confirmed/excluded. A stability of PFTs and echocardiografic PAPs was observed during the observation time. Conclusions: the results of this retrospective study suggest that combination therapy with endothelin receptor antagonist and Phosphodiesterase-5 (PDE5) inhibitors could help in preventing PAH in SSc; prospective case-control studies on larger population are needed to improve knowledge in this field.

Training researchers and stakeholders is crucial to mitigate the risks associated with toxins and venom. By sharing knowledge on the responsible use of toxins, venoms, chemicals, and data from biosecurity and cyberbiosecurity perspectives, we empower laboratorians to make informed choices. We need to remember that cultivating a culture of sustainable biosafety and biosecurity is vital for one health. This technical note highlights the essence of safeguarding biosecurity and cyberbiosecurity in toxin and venom research laboratories workshop designed and implemented to boost biosecurity.

We previously showed that feeding mice a diet containing 1% mantle tissue decreased food consumption, leading to death. We also isolated and identified toxic substances in the mantle tissue. In the present study, we investigated the characteristics and stability of mantle tissue toxicity. Treatment of mantle tissue with 1 mM HCl, 1 mM NaOH, 1 mM dithiothreitol, and 1 mM H2O2 and heating did not reduce the toxicity of mantle tissue in mice. These results suggest that mantle toxins are stable in tissues, particularly when exposed to acidic and digestive enzymes. We examined whether mantle tissue exhibited acute toxicity. Diets containing 1% and 20% mantle extract showed similar levels of toxicity, demonstrating that feeding of mantle tissue does not lead to acute toxicity. Finally, we examined the toxicity of the mantle tissue against small intestinal tissue. Chronic feeding of mantle tissue to mice changed the color of the small intestine. Real-time PCR analysis showed that mantle tissue feeding caused changes of inflammation and endoplasmic reticulum stress markers in the small intestine. These results suggest that feeding of mantle tissue causes toxicity after causing initial damage to the small intestinal tissue.

Bacillus anthracis, the causative agent of anthrax, has two virulence plasmids: pXO1 and pXO2. Plasmid pXO2 carries the genes of an antiphagocytic capsule synthesis. Plasmid pXO1 carries the genes pagA, lef, and cya encoding anthrax toxins, as well as atxA, which encodes the main regulator of pathogenicity factor expression. In the present paper, we evaluated the polymorphism of the pagA, lef, cya, and atxA genes for 85 B. anthracis strains belonging to different evolutionary lineages and canSNP groups and three B. cereus strains possessing pXO1-like plasmids. We found 19 genotypes (GT) strongly correlated with the main evolutionary lineages; they were mainly correlated with the canSNP group within these lines. In some cases, one GT combined the strains of several canSNP groups, and some canSNP groups were divided into several GTs. The most interesting of such cases were 1) the formation of a separate GT by strains of the A.Br.008/009 group isolated in the former USSR; 2) the presence of a unique GT in some American strains of the A.Br.Aust94 group; 3) the division of the A.Br.001/002 group into two subgroups, one of which may be a transitional link to the group A.Br.Ames; 4) the fact that European isolates of the B.Br.CNEVA group and Arctic strains of the B.Br.001/002 group have a common GT.

Functional dependence of the axial zero-field splitting parameter D with respect to a properly chosen geometrical parameter (Dstr) in metal complexes is termed the Magnetostructural D-Correlation. In mononuclear hexacoordinate Ni(II) complexes with the ground electronic term 3B1g (3A2g in the regular octahedron) it proceeds along two intercepting straight lines allowing to predict the sign and magnitude of the D-parameter by knowing the X-ray structure alone; Dstr is constructed from the metal-ligand bond lengths. In hexacoordinate Co(II) complexes it is applicable only in the segment of the compressed bipyramid where the ground electronic term 4B1g is orbitally non-degenerate so that the spin Hamiltonian formalism holds true. The D vs Dstr correlation is strongly non-linear and it is represented by a set of decreasing exponentials. In tetracoordinate Co(II) complexes, on the contrary, the angular distortion from the regular tetrahedron is crucial so that the appropriate structural parameter Dstr is constructed of bond angles. All of these empirical correlations originate in the electronic structure of metal complexes that can be modelled by the generalized crystal-field theory. As the barrier to spin reversal in the single-molecule magnets is proportional to the D-value, for a rational tuning and/or prediction of the single-molecule magnetic behavior knowledge/prediction of the D-parameter is beneficial. In this review, we present the statistical processing of an extensive set of structural and magnetic data of Co(II) and Ni(II) complexes, which were published over the past 15 years. Magnetostructural D-correlations defined for this data set are reviewed in detail.

Serotonin (5-HT) show important relations to stress, and this relationship is crucial to understanding the psychobiology of common mental disorders. Environmental stressors regulate phasic and tonic serotonin levels, which are related to valence and outcome probabilities. This regulation takes place at smaller timescales, but also at the level of gene expression regulation. Moreover, genes related to the synthesis, metabolism, and transport of 5-HT are also involved in this regulation. Genetic variations in these genes modulate how stressors can lead to mental distress, but stressors also modulate gene expression in a genotype-dependent manner. As a result, the relationship between psychosocial stress and the regulation of the expression of 5-HTergic genes is bidirectional. This suggests a “circular causality” in which gene variations control tonic and phasic 5-HT signals (“upward causality”), while configurations and functions of the entire organism determine which genes are up- or downregulated, or which gene products are actually relevant in each situation (“downward causality”). The highly important role of social factors in human psychopathology is highlighted, and factors such as attachment and socioeconomic status modulate how the circular vertical causality between genes, neurotransmitters, and behavior is organized, representing circular horizontal causality. These complex interrelationships also suggest that more refined epistemologies are needed to fully grasp the relationship between 5-HT and common mental disorders.

Blockchain technology (BCT) has the potential for sustainable development, enhancing business efficiency, reducing costs, and strengthening data security. Despite its potential, adoption among small and medium-sized enterprises (SMEs) is low due to the need for significant changes in technology infrastructure and the challenge of interoperability. A cross-sectional survey was done with 226 Hong Kong SMEs. The PLS-SEM results highlighted favorable transformation conditions as the most critical factor for SMEs considering the adoption of BCT. These conditions address both internal and external readiness for adopting the disruptive strategy. Other contributing factors to BCT adoption include trust in BCT developers, perceived usefulness and ease of use, government support, and perceived security. The research results contributed to the literature on disruptive technology acceptance, adoption, transformation conditions, technology readiness, and SMEs’ technology adoption. Government-supported policies and initiatives can promote BCT adoption, including educational programs, case studies, and resources for readiness. Financial support and regulatory frameworks can further encourage adoption. BCT developers can demonstrate the value of their systems, effectively communicate potential ROI and cost savings, and provide user-friendly interfaces to increase SMEs’ intention to adopt BCT.

Anti-interferon (IFN)-γ autoantibodies are linked to varicella-zoster virus (VZV) infection. Given the elevated risks of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKi), we aimed to examine the relationship between anti-IFN-γ autoantibodies with HZ development in JAKi-treated patients. In twenty-four RA patients with new-onset HZ and forty-two without HZ, serum titers of anti-IFN-γ autoantibodies, plasma levels of IFN-γ, monocyte chemoattractant protein-1 (MCP-1), and IFN-γ inducible protein-10 (IP-10) were measured by ELISA. Significantly lower MCP-1 levels were observed in patients with HZ compared to those without (median, 98.21pg/ml, interquartile range (IQR) 77.63-150.30pg/ml versus 142.3pg/ml, IQR 106.7-175.6pg/ml, p&lt;0.05). There was no significant difference in anti-IFN-γ titers, IFN-γ levels, or IP-10 levels between patients with and without HZ. Three of 24 patients with HZ had severe HZ with multi-dermatomal involvement. Anti-IFN-γ titers were significantly higher in patients with severe HZ than in those with non-severe HZ (median 24.8ng/ml, IQR 21.0-38.2ng/ml versus 10.5ng/ml, IQR 9.9-15.0ng/ml, p&lt;0.005). In conclusion, patients with HZ had significantly lower MCP-1 levels than those without HZ, and patients with severe HZ had significantly higher titers of anti-IFN-γ than those with non-severe HZ. Given small sample size, our results need further validation in future studies.

In February 2004, the Food and Drug Administration (FDA) was the first to approve the combination of cisplatin (CDDP) and pemetrexed (PEM) as standard first-line chemotherapy for untreated, unresectable malignant pleural mesothelioma (MPM). However, after that approval, no progress was made in the standard first-line treatment of MPM for almost 15 years. Positive results from a phase 3 study (Mesothelioma Avastin Cisplatin Pemetrexed Study: MAPS) verifying the effect of bevacizumab, an anti-angiogenesis agent added to CDDP/PEM for unresectable MPM, were published in The Lancet in December 2015; however, this did not lead to approval by national drug regulatory agencies. Furthermore, no second-line treatment was established for cases refractory to CDDP/PEM. In August 2018, the Pharmaceuticals and Medical Devices Agency of Japan was the first in the world to approve monotherapy with nivolumab, an immune checkpoint inhibitor (ICI), for previously unresectable, advanced, or recurrent MPM. Following Japan, in October 2020, the FDA approved the combination of nivolumab and ipilimumab for the treatment of previously untreated, unresectable MPM. In this article, we review the transition of drug treatment for MPM, in light of the historical background, focusing on the benefits of ICIs.

The question of the relevance of human and natural capital, as well as the potential adverse effect of natural capital on economic growth, has gained increased attention in development economics. The aim of this paper is to theoretically and empirically assess the relevance of several forms of capital on economic growth in small economies that are dependent upon tourism or natural resources. The empirical framework is based on Impulse Response Functions obtained from Vector Autoregressive models in which we focus on the model where economic growth is the dependent variable for ten small economies that are dependent upon either tourism or natural resources. We find that there is evidence of the ‘’natural resource curse’’, especially in the economies that have a strong dependence on resources that are easily substitutable and whose prices constantly fluctuate. We further find that in the majority of observed cases the type of capital these small economies are most dependent on for their economic growth causes negative impulses in the majority of the observed periods. The main policy recommendation should be to assure that even these small economies should strive towards further diversification and avoid dependence on only one segment of their economy.

Microcystis aeruginosa is a common cyanobacteria found in water blooms and often causes ecological harm. Antibiotics are also increasingly used for the prevention and treatment of bacterial infections in aquaculture. However, since most antibiotics cannot be fully metabolized, they enter the water environment and cause ecological impacts. In this paper, the effects of the two quinolone antibiotics (enrofloxacin and ciprofloxacin) on the population density and microcystins (MCs) production of Microcystis aeruginosa were studied. It is of great significance for the ecological risk assessment of antibiotics to the water environment. The results showed that the 96h EC50 values of enrofloxacin and ciprofloxacin to Microcystis aeruginosa were 56.10mg/L and 49.80mg/L respectively, and the toxicity of ciprofloxacin to Microcystis aeruginosa was slightly stronger than that of enrofloxacin. With the increase of the two quinolone antibiotic concentration, the growth inhibition rate (IR) increased, but when the concentration reached a certain height, the IR would reach its threshold. Long-term exposure to low concentrations of these two quinolone antibiotics is not only more likely to lead to the outbreak of Microcystis aeruginosa, but also increase its toxin production capacity. The highest contents of MCs in enrofloxacin and ciprofloxacin groups were 95.539 μg/g and 93.720 μg/g, respectively. The MCs value of these three enrofloxacin treatment groups was more than above 51.8 times that of control group (CK) on the 4th day; from 8th day to 14th day, the MCs value of these three enrofloxacin treatment groups was more than above 3.2 times that of CK group. For another ciprofloxacin, the MCs value of the treatment group was more than 64.98 times that of the CK group on the 4th day, and from 8th day to 14th day, the MCs value of the treatment group was more than 2.7 times that of the CK group. These findings provide crucial management rationale.

Environmental genetics-related modern methods are shown as important indicators of various cyanotoxins syntheses, and their knowledge and use are critically analyzed. Microcystins and other cyanotoxins loads and syntheses are related to different drivers, like various chemical elements and compounds (especially nutrients, such as nitrogen and phosphorus, and their ratio), then to the light, conductivity, temperature, and other climatical and hydrological factors, to which spatial and geographical features (such as the surface of the water bodies) have to be added. The biotic relationships include different specific and supraspecific, uni- and bilateral links between the cyanobacteria, and subsequently their synthesized toxins, and protozoans (or protoctists), chromists, macrophytes, different systematical and ecological groups of zooplankton, and others. The importance of, but also the gaps in, the knowledge and the scarcity of studies involving ectocrines mediated interactions between different groups of algae and plants are highlighted. The paper ends with an interesting classification of lakes' trophicity, illustrated with conceptual diagrams, based on possible scenarios of cyanobacteria behavior.

Depressions containing partially molten rocks were investigated in Quaternary pebbly sedi-ments in Alpine foreland in Bavaria, Germany. Ruins of limekilns from 18-19th centuries are abundant around Seeshaupt. They are usually associated with earthworks for fuel feeding and protection from wind. Depressions contain partially molten stones from furnace walls, with lime and burnt loam remnants. On the surface of pebbles (typically gneisses), green glass formed with chemical composition possibly affected by moderately volatile components of wood biomass, mainly K and Cu. Thermoplastic deformation of pebbles is limited and the sur-face melt deformation points to slow flow. At Emmerting, on the other hand, two walled circu-lar depressions which lack additional earthworks have been identified as possible impact cra-ters. Thermally affected pebbles show much more intense deformation. Colorless to greenish glass, also K and Cu enriched, usually forms only thin surface coatings, in places covered by younger melt extruded from pebble interior. Burnt loam is missing. At Grabenstätt-Kaltenbach, a depression of unclear origin was investigated. Morphologically, it matches craters rather than limekilns, but anthropogenic contamination (brick-like material) is probable. The rare molten samples do not display extreme deformation features. The thermally affected stones, mainly those from Emmerting, have elevated magnetic susceptibility.

The castor plant (Ricinus communis L.) has been known since time immemorial in traditional medicine in the pharmacopeia of Mediterranean and eastern ancient cultures. Moreover, it is still used in folk medicine worldwide. Castor bean has been mainly recommended as anti-inflammatory, anthelmintic, anti-bacterial, laxative, abortifacient, for wounds, ulcers, and many other indications. Many cases of human intoxication occurred accidentally or voluntarily with the ingestion of castor seeds or derivatives. Ricinus toxicity depends on several molecules, among them the most important is ricin, a protein belonging to the family of ribosome-inactivating proteins. Ricin is the most studied of this category of proteins and it is also known to the general public, having been used for biocrimes in several cases. Here, the main steps of ricin research are reported with particular regards to its enzymatic activity, structure and cytotoxicity. Moreover, we discuss ricin toxicity for animals and humans, as well as the relation amongst bioterrorism and ricin and its impact on environmental toxicity. Ricin has also been of great utility to develop a number of immunotoxins specific for the elimination of unwanted cells, mainly cancer cells; some of these immunotoxins gave promising results also in clinical trials.

Taeniid infections pose a significant threat to both animal and public health, as certain tapeworms within this group can also infect humans, potentially leading to severe health conditions. Therefore, this calls for preventive and control measures, such as regular deworming of dogs. While the efficacy of deworming has been established in developed countries, there is a paucity of reported deworming practices in rural areas of developing countries, such as Tanzania. This study aims to understand determinants for helminth treatment-seeking behavior towards control of cestodial taeniid infections in rural settings in northern Tanzania. A cross-sectional study was undertaken in agropastoral and pastoral areas of northern Tanzania. Comprehensive data from household surveys in selected sub-villages were collected to ascertain dog ownership, dog deworming practices, and the availability of dewormers. Analytical methods were employed to discern how various determinants influenced deworming practices among dog owners in these communities. Awareness of dewormers specifically formulated for dogs emerged as a pivotal factor affecting dog deworming practices. Dog owners who were informed about appropriate dog dewormers were nearly two times more likely to engage in deworming compared to those with limited knowledge (OR = 1.78, 95% CI 1.77 - 4.18, p < 0.001). A majority 32(51.6%, 95% CI: 38.7-64.3) acknowledged accessing dewormers for livestock within their wards. Praziquantel a potent dewormer on cestodes was least known to most dog owners 2(13%, 95% CI: 2.3-41.6). Praziquantel, a potent and common dewormer effective against cestodial taeniid infections, remains relatively unknown in rural areas of northern Tanzania. Therefore, more awareness on appropriate deworming agents against taeniids in dogs should be raised in rural dog-keeping communities.

Most pivotal clinical trials in advanced non-small cell lung cancer (NSCLC) have excluded patients with poor performance status (PS), and data on the efficacy and safety of pharmacotherapy have not been fully accumulated. For NSCLC patients with PS 2 and without druggable genetic alterations, monotherapy with cytotoxic agents or carboplatin-based combination therapy is usually administered based on the results of several randomized trials. However, the evidence of cytotoxic chemotherapy for patients with PS 2 is insufficient, with limited efficacy and toxicity concerns. Immune checkpoint inhibitors (ICIs) are a promising treatment for patients with PS 2 because of lower incidence of severe toxicity compared to cytotoxic chemotherapy. Meanwhile, several reports suggest that anti-PD-1 antibodies monotherapy is less effective for patients with PS 2, especially for those with PS 2 caused by disease burden. Although the combination therapy of nivolumab and ipilimumab is a promising treatment option, there is a divergence in efficacy data between clinical trials. The standard of care for advanced NSCLC with PS 2 has not been established, and future therapeutic strategies should take into account the heterogeneity of the PS 2 population.

: To improve the efficiency of rhizobial inoculation operations and address the current situation of rhizobial inoculation being labor-intensive, a spraying and control system for variable rate application (VRA) of liquid rhizobia was developed. The system can accurately regulate the spraying rate of liquid rhizobia according to the desired rate of rhizobia by incremental Proportional Integral Derivative (PID) closed-loop control algorithm, making it particularly suitable for precise spraying with small amounts. In the laboratory experiment of precise flow control, variation coefficient of spraying nozzle from 0.10 MP to 0.20 MP pressure were no more than 1.2%. A clear linear relationship was observed between the spraying rate and pressure. The maximum response time was 1.93 seconds, while the average response time was 1.62 seconds when controlling the spraying system for small amounts. Field trial was conducted in Heilongjiang Agricultural Xianghe Farm of China. Average seeds number and 100-seed weight of soybean plant with rhizobia inoculation treatment were better than control group, and average yield of spraying liquid rhizobia agent with full base fertilizer increased by 232.5 kg/hm2, representing a significant 7.4% improvement over the control group. The results of these trails clearly showed the positive effect of the spraying and control system for liquid rhizobial inoculation, which has superior to existing inoculation manners, and provides an important technical support for the widespread adoption of rhizobia technology.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a proteolytic enzyme that indirectly regulates serum LDL cholesterol by destroying LDL receptors. In clinical studies, the main role of the proprotein convertase subtilisin/Kexin type9 (PCSK9) inhibitor in cholesterol regulation was elucidated. It is produced in the liver but is also present in the kidney and intestine. It prevents HMGCo from synthesizing cholesterol. SREBP-2 is a reductase that is induced by statins. In a dose-dependent manner, increasing SREBP-2 levels enhanced LDL-R and PCSK9 gene expression. At the minimum, two procedures have been developed to overcome the plasma level of PCSK9. This is the LDLR test, polyclonal antibodies, and sentience oligonucleotide. Lower dosage statin treatment with a proprotein convertase subtilisin/Kexin type9 inhibitor will be most efficient in lowering LDL and avoiding statin adverse effects. In multiple long-term trials, statins have been found to reduce cardiovascular mortality by 30% and stroke incidence by 20%. In this way, we conclude the role of PCSK9 in hypercholesterolemia.

Microalgae have emerged as potential feed stock for third generation biofuel and other bioactive compounds. In the present investigation we have evaluated the two native strains of Oscillatoria (O. subbrevis MTC-20702 and O. sancta MTC-20703) isolated from two different fresh water biotopes of Meerut, U.P., India and were subjected for the characterization of generation time, biomass, bio-molecules including Chlorophyll-a, carotenoids, carbohydrate, lipids, phycobilins and proteins. Both strains of Oscillatoria were grown in batch culture till the initiation of declining phase and were harvested on every 10th day of incubation till the starting of declining phase. Result of the present investigation revealed that O. subbrevis MTC-20702 can be potentially exploited for the production of high algal biomass, feed stock for biofuel, Chl-a, carotenoids, c-Allophycocyanin and maximum yield of these bioactive compounds can be achieved on 20th day. However, O. santa could be very good source for c-Phyocyanin, c-Phycoerythrin, carbohydrate and protein and these also can be achieved highest on 20th day of incubation. In addition, as these two strains were isolated from water reservoirs and they can be cultivated in large scale for the production of desired bio-molecules.

The majority of investigations on microbial communities from various environments are presently built on culture-independent methods. Many studies point to the pivotal, selective role of primers targeting hypervariable regions of 16S rRNA in the metabarcoding of bacteria, including cyanobacterial communities. The selectivity of primers designed to amplify targeted regions of the 16S rRNA gene, which has been highlighted by many authors, limited effective amplification. Moreover, the type and specificity of the studied material can also negatively influence the results of 16S metabarcoding. Most of the studies of cyanobacterial communities have been performed for planktonic microbial communities that are often represented by common, well-studied species. In this study, we present the results of 16S metabarcoding analysis using three primer pairs - two already well-known and a third designed in this study - that amplify divergent regions of the 16S rRNA gene (V3-V4, V4-V6, V6) for benthic, microbial mat-forming cyanobacteria communities. Such communities can be a source of toxigenic cyanobacterial taxa and should be monitored with adequate primers. The comparison of three primer pairs suggested that those designed within the present study describe the structure and composition of highly heterogeneous cyanobacterial mats’ communities better than the others

Raman spectra of [TeX6](Y2) (X, Y - Cl, Br, I) were recorded in the temperature range 5-300 K. The vibration frequency of molecular halogens as function on temperature and the type of halogen X- in the [TeX6]2- complex was obtained. The vibration frequency of the molecular halogen Y2 depends on the type of halogen X- complex [TeX6]2- The temperature dependence of the Y2 frequency is anomalous compared to what was expected for a conventional anharmonic oscillator. It is shown that the interpretation of the experimental results based on the concept of traditional chemical bonding is quite satisfactory in all cases. The study was motivated by the need to consider the mechanism of interaction in the X-Y2 contacts.

Molecule radiation can be used as a tool to study colder regions in switching arc plasmas like arc fringes in contact to walls and ranges around current zero (CZ). This is demonstrated in the present study for the first time for the case of ablation-dominated high–current arcs as key elements of self–blast circuit breakers. The arc in a model circuit breaker (MCB) in CO2 with and an arc in a long nozzle under ambient conditions with peak currents between 5 and 10 kA were studied by emission and absorption spectroscopy in the visible spectral range. The nozzle material was polytetrafluoroethylene (PTFE) in both cases. Imaging spectroscopy was carried out either with high-speed cameras or with intensified CCD cameras. A pulsed high-intensity Xe lamp was applied as background radiator for the broad-band absorption spectroscopy. Emission of Swan bands from carbon dimers was observed at the edge of nozzles only or across the whole nozzle radius with highest intensity in the arc center, depending on current and nozzle geometry. Furthermore, absorption of C2 Swan bands and CuF bands were found with the arc plasma serving as background radiator. After CZ, only CuF was detected in absorption experiments.

We tested the hypothesis that concatemers of ancestral tRNAs gave rise to the 16S ribosomal RNA. We built an ancestral sequence of proto-tRNAs that showed a significant identity of 51.69% and a percentage of structural identity of 0.941 with the 16S ribosomal molecule. We also propose a hypothesis for the emergence of translation.

We have developed a family of N-alkyl-nitrobenzamides that exhibit promising antitubercular ac-tivities. These compounds are a simplification of the structure of known inhibitors of DprE1, an essential Mtb enzyme and an emergent anti-TB target. The compounds were obtained by a simple synthetic methodology and their antitubercular, cyto-toxicity and stability were studied. The most active compounds were the 3,5-dinitro and the 3-nitro-5-trifluoromethyl derivatives. Lipophilicity was shown to be a main parameter modulating activity within each family. The most active compound presented MIC of 16 ng/mL and had in-termediate lipophilicities. The activity was also studied in a macrophage model of infection. In this model the compounds with chain lengths of 6 and 12 carbon atoms presented the best results, ex-hibiting activity profiles comparable to isoniazid. Docking studies performed suggested that the fit of our highly active compounds to the DprE1 binding pocket was very similar to the literature compounds. Furthermore, the metrics used in the analysis were able to distinguish between the families of the highly and least active compounds. Assessment of susceptibility over multiple species and computational together with the structure of the compounds are complementary information that supports DprE1 as a likely target of action for this type of compounds.

This study is the first report of the successful cultivation of Dinophysis norvegica isolated from Japanese coastal waters (7 of 48 isolated cells were established as the clonal cultures, 14.5%) and their toxin content and production. The strains were maintained at relatively high abundance (>2,000 cells mL-1) for more than one year when fed on Mesodinium rubrum with the addition of Teleaulax amphioxeia. At the end of the one-month incubation, the total amounts of pectenotoxin-2 (PTX2), dinophysistoxin-1 (DTX1) and okadaic acid (OA) were 132.0-375.0 ng mL-1 (n = 7), 0.7-3.6 ng mL-1 (n = 3) and trace level OA (n = 1), respectively. Similarly, the cell quota of PTX2 and DTX1 were 60.6-152.4 pg cell-1 (n = 7) and 0.5-1.2 pg cell-1 (n = 3), respectively. These data indicated that toxin production varies depending on the strains in this species. In the growth experiment, D. norvegica grew, but it was very slow first 12 days. However, after that they grew exponentially with the maximum growth rate of 0.56 divisions day-1 (during Day 24-27), reaching a maximum concentration of 3,000 cells mL-1 at the end of incubation (Day 36), suggesting that they have a long lag phase. In the toxin production, OA was not at a detectable level (≤ 0.010 ng mL-1) during the 36 days of incubation except for Day 6. The concentration of DTX1 and PTX2 showed similar patterns as described for vegetative growth, but the toxin production still increased on Day 36 (1.3 ng mL-1 and 154.7 ng mL-1 in DTX1 and PTX2, respectively). The findings of this study provide novel information on the toxin content and production in D. norvegica as well as details on the culturing and maintenance of the species.

In the event of an abrupt sunlight reduction scenario there is a time window that occurs between when food stores would likely run out for many countries (~6 months or less) and ~1 year when resilient foods are scaled up. A promising temporary resilient food is leaf protein concentrate (LPC). Although it is possible to extract LPC from tree biomass (e.g. leaves and needles), neither the yields nor the toxicity of the protein concentrates for humans from the most common tree species has been widely investigated. To help fill this knowledge gap, this study uses high-resolution mass spectrometry and an open source toolchain for non-targeted screening of toxins on five common North American coniferous species: Western Cedar, Douglas Fir, Ponderosa Pine, Western Hemlock, and Lodgepole Pine. The yields for LPC extraction from the conifers ranged from 1% to 7.5%. The toxicity screenings confirm that these trees may contain toxins that can be consumed in small amounts and additional studies including measuring the quantity of each toxin are needed. The results indicate that LPC is a promising candidate to be used as resilient food, but future work is needed before LPCs from conifers can be used as a wide-scale human food.

(1) Background: The diphtheria toxoid antigen is a major component in pediatric and booster combination vaccines and is known to raise a protective humoral immune response upon vaccination. Although antibodies are considered critical for diphtheria protection, little is known about the antigenic determinants that maintain humoral immunity. (2) Methods: One hundred twelve 15-mer peptides covering the entire sequence of DTx protein were prepared by Spot-synthesis. Membrane-bound peptides immunoreactivity with sera from mice immunized with triple DTP vaccine allowed mapping of continuous B-cell epitopes, topological studies, MAPs synthesis, and ELISA development. (3) Results: Twenty epitopes were identified, being 2 in the signal peptide, 5 in the CD, 7 in the HBFT domain, and 5 in the RBD. Two 17-mer (CB/Tx-2/12 and CB/DTx-4-13) derived bi-epitope peptides linked by a Gly-Gly spacer were chemically synthesized. The peptides were used as antigens to coat ELISA plates and assayed with human (huVS) and mice vaccined sera (miVS) for in vitro diagnosis of diphtheria. The assay proved to be highly sensitive (99.96%) and specific (100%) either for huVS and miVS and when compared with a commercial ELISA test, demonstrate high performance. (4) Conclusions: Our work displayed the complete picture of the linear B cell IgG response epitope of the DTx responsible for the protective effect and demonstrated the specificity and eligibility to enter phase IIB studies of some epitopes to develop new and fast diagnostic assays.

T-2 toxin produced by fungi of Fusarium genus is highly toxic to human and animals and has been shown to induce apoptosis in various organs/tissues. Apoptosis and autophagy are interconnected processes and these interactions are important for cellular homeostasis as well as pathogenesis. In this study, we report for the first time that T-2 toxin induced autophagy in human liver cells (L02). We showed that T-2 toxin induced the formation of acidic vesicular organelles, concordant with the time and dose-dependent alterations in LC3-phosphatidylethanolamine conjugate (LC3-II) LC3-I/II and p62/SQSTM1 suggesting an enhanced autophagic flux. The T-2 toxin-induced formation of autophagosome and lysosomal fusion was observed by expressing mRFP-GFP-LC3 in L02 cells by lentiviral transduction, and autophagosome was observed by transmission electron microcopy. We found that while T-2 toxin activated both apoptosis and autophagy, activation of autophagy appears to be a leading event reflecting the protective mechanism of cells against the insults by T-2 toxin. Activating autophagy by rapamycin (RAPA) inhibited the apoptosis while suppressing autophagy by chloroquine greatly enhanced the T-2 toxin-induced apoptosis suggesting the crosstalk of autophagy and apoptosis. In summary, our study showed that activation of autophagy protects liver cells from T-2 toxin-induced apoptosis suggesting autophagy may be targeted for prevention of the T-2 toxin-induced toxicity in human and animals.

β-Lactams are pharmacologically important compounds because of their various biological uses, including antibiotic and so on. β-Lactams were synthesized from benzylidene-inden derivatives and acetoxyacetyl chloride. The inhibitory effect of these compounds was also examined for human carbonic anhydrase I and II (hCA I, and II) and acetylcholinesterase (AChE). The results reveal that β-lactams are inhibitors of hCA I, II and AChE. The K_i values of β-lactams (2a-k) were 0.44-6.29 nM against hCA I, 0.93-8.34 nM against hCA II, and 0.25-1.13 nM against AChE. Our findings indicate that β-lactams (2a-k) inhibit both CA isoenzymes and AChE at low nanomolar concentrations.

Single-molecule magnets (SMMs) have garnered significant interest in the field of molecular magnetism due to their unique magnetic properties at the nanoscale. These molecular systems exhibit magnetisation behaviour reminiscent of conventional bulk magnets but with distinct advantages such as size-dependent properties and potential applications in quantum computing and high-density data storage. However, challenges remain in harnessing their properties for practical applications, including their susceptibility to degradation and limited control over their assembly and organisation.

Trichothecene mycotoxin T-2 toxin is an important environmental pollutant and poses a global threat to human and animal health. T-2 toxin could induce nephrotoxicity, however, the precise molecular mechanism remains unclear. In this study, the mice were intraperitoneally administrated with a single dose of 2 mg/kg T-2 toxin. The kidney function and ultrastructural observation were also assessed and found T-2 toxin exposure could cause kidney damage. Transmission electron microscopy showed a significant swelling and vacuolization of the mitochondria of renal cell. A total of 1122, 58, and 391 differential expression genes (DEGs) that were predominantly expressed in kidney tissues at 1 d, 3 d, and 7 d after T-2 toxin exposure, respectively. Early transcriptomic changes at 1 d after exposure were down-regulation of DEGs involved in the cell cycle, p53 signaling pathway, and cellular senescence, while up-regulation of DEGs referred to the ribosome pathway. The temporal variations in gene expression pattern in T-2 toxin exposure in mice kidney were presented and cellular metabolism was disturbed at the exposure recovery period with 7 d. In conclusion, this study, for the first time, provided a comprehensive comparative transcriptomic analysis of gene regulation in T-2 toxin exposure-induced nephrotoxicity at different temporal periods and explored the nephrotoxicity mechanism of T-2 toxin at the mRNA level.

Extracellular vesicles (EVs), produced during viral infections, are of emerging interest in understanding infectious processes and host-pathogen interactions. EVs and exosomes in particular have the natural ability to transport nucleic acids, proteins, and other components of cellular or viral origin. Thus, they participate in intercellular communication, immune responses, infectious and pathophysiological processes. Some viruses are known to hijack the cell production and content of EVs for their benefit. Here, we investigated whether two pathogenic flaviviruses i.e. Zika Virus (ZIKV) and Dengue virus (DENV2) could have an impact on the features of EVs. Analysis of EVs produced by infected cells allowed us to identify that the non-structural protein 1 (NS1), described as a viral toxin, was associated with exosomes. This observation could be confirmed under conditions of overexpression of recombinant NS1 from each flavivirus. Using different isolation methods (i.e. exosome isolation kit, size exclusion chromatography, Polyethylene Glycol enrichment, and ELISA capture), we showed that NS1 was present as a dimer at the surface of excreted exosomes and that this association could occur in the extracellular compartment. This finding could be of major importance in a physiological context. Indeed, this capacity of NS1 to address EVs and its implication in the pathophysiology during Dengue or Zika diseases should be explored. Furthermore, exosomes that have demonstrated a natural capacity to vectorize NS1 could serve as useful tools for vaccine development.

Small scale carp polyculture plays a key role for food supply in Bangladesh, however, factors including water pollution, limited infrastructure and inadequate disease management hinder its sustainability. This paper reports on a survey of 231 farmers across the 6 major carp producing regions in Bangladesh, analyzing factors including, farmers’ social aspects, farm characteristics, information on disease and approaches adopted to combat them, and biosecurity practices. Almost half (46.8%) of the farms surveyed experienced disease in carp species, with clear regional variations. Eighty four percent of farms reported carp mortalities during disease outbreak, with an average mortality level 10.23±11.81%. Clinical signs during outbreaks lasted between a week and a month, and there was a peak in disease outbreaks in two seasonal periods between June to July and October to December. Disease incidence was related to a range of factors including the farmer experience, ponds/farm type, stocked species, and biosecurity practice. A combination of disinfecting measures during pond preparation and measures during stocking, including discarding fingerling transport water off-farm, fingerling disinfection and check the health of fingerlings before stocking significantly reduced disease occurrence. Treatments involving the antibiotics, ciprofloxacin, erythromycin, and azithromycin were reported as ineffective, raising concerns about non-prudent use, inadequate dosing (perhaps without appropriate veterinary guidance) and the potential for further driving antimicrobial resistance in the environment. The research unveils a concerning pattern of disease high disease incidence across small-scale carp farms in Bangladesh and the significant potential for disease spread highlights the need for responsible disposal practices. The study emphasizes the need for improving training and awareness programs are vital for addressing biosecurity and disease management challenges, ensuring sustainable aquaculture and community well-being.

Live cell imaging is a powerful technique to study the dynamics and mechanics of various biological molecules like proteins, organelles, DNA, and RNA. With the rapid evolution of optical microscopy, our understanding of how these molecules is implicated in the cells’ most critical physiological roles deepens. Here in this review, we focus on how spatiotemporal nanoscale live cell imaging on a single molecule level allows for profound contributions towards new discoveries in life science. This review will start by summarizing how single molecule tracking has been used to analyze membrane dynamics, receptor ligand interactions, protein-protein interactions, inner- and extracellular transport, gene expression/transcription, and whole organelle tracking. We then move on to how current authors are trying to improve single molecule tracking and overcome current limitations by offering new ways in labeling protein of interests, multi-channel/color detection, improvements in time laps imaging, and new methods and programs to analyze colocalization and movement of targets. We later discuss how single molecule tracking can be a beneficial tool used for medical diagnosis. Finally wrapping up with limitation and future perspective of single molecule tracking and total internal refection microscopy.

Microfluidic devices have been extensively investigated in recent years in fields including ligand-binding analysis, chromatographic separation, molecular dynamics, and DNA sequencing. To prolong the observation of a single molecule in aqueous buffer, the solution in a sub-micron scale channel is driven by the electric field and reversed after a fixed delay following each passage, so that the molecule passes back and forth through the laser focus and the time before irreversible photobleaching is extended. However, this practice requires complex chemical treatment to the inner surface of the channel to prevent unexpected sticking to the surface and the confined space renders features, such as a higher viscosity and lower dielectric constant, which slow the Brownian motion of the molecule compared to the bulk liquid. In this paper, we have fixed a capillary microchannel with an inner diameter of 2 microns on top of a piezo stage to recycle the molecule and collected the fluorescence by a confocal microscope. The passing times of the molecule through the laser focus are calculated by a real-time control system based on an FPGA and the commands of translation are given to the piezo stage through a feedback algorithm. We have achieved a maximum number of recycles of more than 200 and developed a maximum-likelihood estimation of the diffusivity of the molecule, which attains results of the same magnitude as previous reports. This technique simplifies the overall procedure of the single-molecule recycling and could be useful for the ligand-binding studies of biomolecules.

With the long-term and large-scale use, herbicides have been well known to influence tritrophic interactions particularly natural enemies of pests in agro-ecosystems. On the other hand, herbivorous insects, especially the generalist pests, have developed antagonistic interaction to different insecticides, toxic plant secondary metabolites and even heavy metals. However, whether exposure to herbicides would affect resistance of insects against insecticides is largely unknown, especially in agricultural pests. Here, we first reported that pre-exposure to two widely used herbicides butachlor and haloxyfop-methyl for 48 h can prime resistance of a generalist agricultural pest Helicoverpa armigera Hübner against insecticide methomyl and fungal toxin aflatoxin B1. In addition, there were no significant differences between control and herbicides-treated caterpillars on weight gain, pupal weight and pupation rates, suggesting that exposure to herbicides induce resistance of H. armigera accompanied with no fitness cost. Moreover, by determining detoxifying enzyme activities and toxicity bioassay with additional inhibitor of cytochrome P450 piperonyl butoxide (PBO), we showed that exposure to herbicides might prime P450-mediated detoxification of H. armigera against insecticide. Based on these results, we propose that exposure to herbicides primes resistance of H. armigera against insecticide by eliciting a clear elevation of predominantly P450 monooxygenase activities in midgut and fat body.

It is well known that X-ray crystallography is based on X-ray diffraction (XRD) by atoms and molecules. The diffraction pattern arises as a result of scattering of incident radiation, which makes it possible to determine the structure of the scattering substance. With the advent of ultrashort radiation sources, the theory and interpretation of X-ray diffraction analysis remained the same. This work shows that when an attosecond laser pulse is scattered on a DNA molecule, including during its nicking and bending, the pulse duration is an important characteristic of the scattering. In this case, the diffraction pattern changes significantly compared to the previously known scattering theory. The results obtained must be used in XRD theory to study DNA structures, their mutations and damage, since the previously known theory can produce large errors and, therefore, the DNA structure can be “deciphered” incorrectly.

HIV-1 assembly is a complex mechanism taking place at the plasma membrane of the host cell. It requires nice spatial and temporal coordination to end up with a full immature virus. Researchers have extensively studied HIV-1 assembly molecular mechanism during the past decades, in order to dissect the respective roles of viral proteins, viral genome and host cell factors. Nevertheless, the time course of the process has been observed in living cells only a decade ago. The very recent revolution of optical microscopy, combining high speed and high spatial resolution now permit to study assemblies and their consequences at the single molecule level within (living) cells. In this review, after a short description of these new approaches, we will show how HIV-1 assembly in cells has been revisited using these advanced super resolution microscopy techniques and how much it could make a bridge in studying assembly from the single molecule to the host cell.

Shiga-like toxin producing Escherichia coli (STEC) is a well-known cause of foodborne acute diarrheic diseases especially in children and the elderly. The potentially fatal complications associated with toxin production range from bloody diarrhoea and ischemic colitis to kidney failure, haemolytic-uremic syndrome (HUS) and colon perforation. We describe a case and literature review of STEC – induced colitis, highlighting the clinical features, and the necessary tools for the best diagnosis approach and management. Facing challenging differential diagnosis ranging from ischemic colitis, inflammatory bowel disease, to infectious process due to a pathogenic or opportunistic agent, we practiced a step-by-step exploration. Beginning with bacteriological investigation, imagistic screening, and colonoscopy, we could rule out some of initial suppositions and reach the final diagnosis, also considering the pathological results. Although antibiotics are not indicated in this pathology, our patient did receive antibiotics, given the risk of translocation and colon perforation, without associating any complications, as HUS or peritonitis. Detailed and rigorous investigations along with a multi-speciality team are required for a prompt medical support. Coping the symptoms and refraining from further complications are the mainstem of the treatment.

Mosquito-borne viral disease dengue is a global public health problem causing a wide spectrum of clinical manifestations ranging from mild dengue fever to severe dengue with plasma leakage and bleeding which are often associated to fatality. To date, there are no specific medications to treat dengue and prevent the risk of hemorrhage. Dengue is caused by one of the four related antigenically distinct serotypes, DENV-1 to DENV-4. The growing burden that represents the four DENV serotypes has intensified both basic and applied researches to better understand the dengue physiopathology. It has been proposed a significant role for the secreted soluble DENV nonstructural protein 1 (sNS1) glycoprotein in the pathogenesis of severe dengue. Here, we provided an overview on current knowledge about the role of sNS1 in the immunopathogenesis of dengue disease. The reasons for the consideration of sNS1 in the design of future dengue vaccine candidates will be discussed.

Three finger toxins (3FTX) are a group of peptides that affect multiple receptor types. One group of proteins affected by 3FTX are nicotinic acetylcholine receptors (nAChR). Structural information on how neurotoxins interact with nAChR is limited and are confined to a small group of neurotoxins. Therefore, in silico methods are valuable in understanding the interactions between 3FTX and different nAChR subtypes, but there are no established protocols to model 3FTX – nAChR interactions. We developed a homology modeling and protein docking protocol to address this issue and tested its success on three different systems. First, neurotoxin peptides co-crystallized with acetylcholine binding protein (AChBP) were re-docked to assess whether Rosetta protein – protein docking can reproduce the native poses. Second, experimental data on peptide binding to AChBP was used to test whether the docking protocol can qualitatively distinguish AChBP-binders from non-binders. Finally, we docked eight peptides with known α7 and muscle-type nAChR binding properties to test whether the protocol can explain the differential activities of the peptides at the two receptor subtypes. Overall, our docking protocol succeeded in predicting both qualitative and specific aspects of 3FTX binding to nAChR and shed light on some unknown aspects of 3FTX binding to different receptor subtypes.

The aim of this review was to search in literature, data regarding the inflammasome, involvement in, oral pathologies (mainly periodontitis) and other diseases and the approaches to control the inflammasome-related pathogenic mechanisms. The review also investigated how phytochemicals and pharmaceutical substances could be used to inhibit the inflammasome activity. Inflammasomes are involved in inflammatory, autoimmune and autoinflammatory diseases. Pharmaceutical substances can control the inflammasome by three mechanisms: inhibiting of intracellular signaling pathways (Allopurinol and SS-31), blocking inflammasome components (VX-765, Emricasan and VX-740), and inhibiting cytokines mediated by the inflammasome (Canakinumab, Anakinra and Rilonacept). Phytochemical inhibit the inflammasome, by neutralization of reactive oxygen species. Biomaterials functionalized by the adsorption of therapeutic agents on different nanomaterials may represent a future research direction to facilitate multimodal and sequential treatment in oral pathologies.