The study reveals correlations between the parameters of ions and their HOMO and LUMO orbital energy level values. In particular, it demonstrates a clear correlation for the ion adsorption parameters on model electrodes: the aluminum oxide (0001) surface, graphene and Au (111) surface. Correlations are also observed for the parameters of ion binding to water and dimethyl carbonate molecules, which are often used as solvents. In addition, the dipole moment, polarizability and solvation energy of ions are well correlated with the values of the molecular orbital energies, and for anions a dependence on the oxidation potential is observed. The obtained descriptors make it possible to select ions with desired values for a specific problem. As an illustrative example, in this work we consider the problem of displacement of water molecules from the inner electric double layer by ions, which is one of the factors increasing the potential window in electrolytes of aqueous batteries. This approach can be applied in the rapidly developing field of aqueous electrolytes for battery or supercapacitor design, catalysis control through surface composition variations, as well as in studies of heavy metal ion binding to sorption materials.

Structure based biological and chemical properties of 4-(carboxyamino)-benzoic acid has been studied by quantum chemical methods. The revamped geometric structure and its quantum chemical parameters were obtained by DFT-B3LYP/6-311G method. Normal mode analysis is performed to assign the fundamental vibrational frequencies as per the potential energy distribution (PED) by using the VEDA program. Simulation of IR and Raman spectral patterns are observed by refinement of scale factors. TD-DFT approach is used to explore the excited states of molecule and prediction of electronic absorption spectra. NMR chemical shifts of the molecule are determined by the gauge independent atomic orbital method. The molecular docking is performed to recognize the binding energy of the ligand with the dynamic site of protein. In our docking analysis, the protein 5DT6 shows the best results than other three proteins which could be used for further analysis. Further inter and intra molecular interactions, electrophilic, nucleophilic and chemical reactivity sites are found by molecular electrostatic potential, HOMO-LUMO and Global chemical reactivity descriptors. Thermodynamic property of the title compound is also reported. The determined quantum chemical parameters show high reactivity and the dipole moment was sufficiently high enough to induce nonlinear characteristics which are required for applications in optoelectronic devices.

Familial Alzheimer’s disease (FAD) can be caused by mutations in PSEN1 that encodes presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca2+) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD, however it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess early calcium and glutamate phenotypes of FAD by measuring the Ca2+ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA and kainate compared to isogenic control and healthy lines. The data shows that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca2+ responses to glutamate and AMPA, but not NMDA or kainate. Together this suggests that PSEN1 mutations alter Ca2+ and glutamate signaling as an early phenotype of FAD.

Obesity has increasingly become a worldwide epidemic, as demonstrated by epidemiological and clinical studies. Obesity may lead to development of a broad spectrum of cardiovascular diseases (CVDs), such as coronary heart disease (CHD), hypertension, heart failure (HF), cerebrovascular disease, atrial fibrillation (AF), ventricular arrhythmias, and sudden cardiac death (SCD). In addition to hypertension, there are other cardiometabolic risk factors (CRFs) such as visceral adiposity, dyslipidemia, insulin resistance, diabetes, elevated levels of fibrinogen, and C-reactive protein and others, all of which increase the risk of CVD events. Mechanisms involved between obesity and CVD mainly include insulin resistance, oxidative stress, inflammation, and adipokines dysregulation, which cause maladaptive structural and functional alterations of the heart, particularly left ventricular (LV) remodeling and diastolic dysfunction. Natural products of plants, provide a diversity of nutrients and different bioactive compounds, including phenolics, flavonoids, terpenoids, carotenoids, anthocyanins, vitamins, minerals, fibers, and others, which possess a wide range of biological activities including antihypertensive, antilipidemic, antidiabetic, and other activities, thus conferring cardiometabolic benefits. In this review, we discussed the main therapeutic interventions using extracts from herbs and plants in preclinical and clinical trials with protective properties targeting CRFs. Molecular mechanisms and therapeutic targets of herbs and plants extracts for the prevention and treatment of CRFs are also reviewed.

Recurrent Pregnancy Loss (RPL) affects 1-2% of women, and its triggering factors are unclear. Several studies have shown the vaginal, endometrial, and gut microbiota may play a role in RPL. A decrease in the quantity of Lactobacillus crispatus in local microbiota has been associated with an increase in local (vaginal and endometrial) inflammatory response and immune cell activation that leads to pregnancy loss. The inflammatory response may be triggered by gram-negative bacteria, lipopolysaccharides (LPS), viral infections, mycosis, or atypia (tumor growth). Bacterial structures and metabolites produced by microbiota could be involved in immune cell modulation and may be responsible for immune cell activation and molecular mimicry. Gut microbiota metabolic products may increase the amount of circulating pro-inflammatory lymphocytes, which, in turn, will migrate into vaginal or endometrial tissues. Local proinflammatory Th1 and Th17 subpopulations along with a decrease in Treg and tolerogenic NK cells are accountable for the increase in pregnancy loss. Local microbiota may modulate the local inflammatory response increasing pregnancy success. Analyzing local and gut microbiota may be necessary to characterize some RPL patients. Although oral supplementation of probiotics has not been shown to modify vaginal or endometrial microbiota, the metabolites produced by it may benefit patients. Lactobacillus crispatus transplantation into the vagina may enhance the required immune tolerogenic response to achieve a normal pregnancy. The effect of hormone stimulation and progesterone to maintain early pregnancy on microbiota has not been adequately studied, and more research is needed in this area. Well-designed clinical trials are needed to ascertain the benefit of microbiota modulation in RPL.

Music has the innate potential to reach all parts of the brain, stimulates certain brain areas which are not achievable through other modalities. Music Therapy (MT) is being used for more than a century to treat individuals who needs personalized care. MT optimizes motor, speech and language responsibilities of the brain and improves cognitive performance. Pervasive developmentdisorder (PDD) is a multifaceted, neuro developmental disorder and autism spectrum disorder (ASD) comes under PDD, which is defined by deficiencies in three principal spheres: social connection with others, communicative and normal movement skills. The conventional imaging studies illustrate reduced brain area connectivity in people with ASD, involving selected parts of the brain cortex. People with ASD express much interest in musical activities which engages the brain network areas and improves communication and social skills.The main objective of this review is to analyze the potential role of MT in treating the neurological conditions, particularly ASD. Evidence based studies have reported the extensive therapeutic application of music on various part of the brain in a nonverbal child with autism through hearing or making music.Hence we hypothesized that MT intervention can improve the communication capacity in people with ASD, than customary neurorestoration therapy alone.

Recognition, decoding and tracking of vortex patterns is of increasing importance in many fields reaching from astronomical observation of distant galaxies to turbulence phenomena in liquids or gases. Currently, coherent light beams with orbital angular momentum (OAM) are of particular interest for optical communication, metrology, micro-machining or particle manipulation. One common task is to identify characteristic spiral patterns in pixelated intensity maps at real-world signal-to-noise ratios. Recently, Fast Fourier Transform (FFT) was applied to the quantitative analysis of spiral interference patterns of OAM beams. Our study considers this approach in more detail. It is demonstrated that specific information can be extracted by combining conformal mapping by polar transform with determining one- or two-dimensional angular frequency spectra either in spatially fixed or scanning mode. Results of proof-of-principle experiments are presented.

Estrogen receptor-positive (ER+) breast cancer is common among postmenopausal women and is frequently treated with Letrozole. Letrozole inhibits aromatase from synthesizing estrogen from androgens. Decreased estrogen slows the growth of tumors and can be an effective treatment. Letrozole resistance is increasingly being observed, which poses a unique problem for patients. We reanalyzed transcriptomic data comparing individuals who responded to Letrozole therapy (responders) to those who were resistant to treatment (non-responders). We identified SOX11 and S100A9 as two genes that significantly differed between these patients; with “PLK1 signaling events” being the most significant signaling pathway. We also identified PRDX4 and E2F8 as the top transcriptional biomarkers for ER+ treatment resistance. Many of the other significant gene products play a known role in ER+ breast cancer or other types of cancer, which partially validate our results. Several of the gene products we identified do not have a characterized role in ER+ breast cancer. Our analysis identified a set of genes that warrant further research to elucidate the molecular mechanism of Letrozole resistance in this patient population, as well as novel high-performing biomarkers. We anticipate that these findings could contribute to improved therapeutic outcomes in human patients.

Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg/kg of diethylnitrosamine (DEN) and 25 mg/kg of 2-aminofluorene (2-AAF). HCC/PFD group received simultaneous doses of 300 mg/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, β-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPARγ and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.

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

The keratinocyte carcinomas, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), are the most common cancers in humans. Recently, an increasing body of literature has investigated the role of miRNAs in keratinocyte carcinoma pathogenesis, progression and their use as therapeutic agents and targets, or biomarkers. However, there is very little consistency in the literature regarding the identity of and/or role of individual miRNAs in cSCC (and to a lesser extent BCC) biology. miRNA analyses that combine clinical evidence with experimental elucidation of targets and functional impact provide far more compelling evidence than studies purely based on clinical findings or bioinformatic analyses. In this study, we review the clinical evidence associated with miRNA dysregulation in KCs assessing the quality of validation evidence provided, identify gaps, and provide recommendations for future studies based on relevant studies that investigated miRNA levels in human cSCC and BCC. Furthermore, we demonstrate how miRNAs contribute to the regulation of a diverse network of cellular functions, and that large-scale changes in tumor cell biology can be attributed to miRNA dysregulation. We highlight the need for further studies investigating the role of miRNAs as communicators between different cell types in the tumor microenvironment. Finally, we explore the clinical benefits of miRNAs as biomarkers of keratinocyte carcinoma prognosis and treatment.

Acting as the most abundant and widely distributed volatile secondary metabolites in plants, terpenoids play crucial roles in diverse physiological regulations and metabolic processes. Terpene synthases occupy a decisive proportion in determining the composition and diversity of terpenoids; though their regulatory effects have been extensively investigated across various plant species, limited studies have focused on the upstream transcriptional regulation of terpene synthases. In this study, we unveil linalool as the predominant volatile compound in Freesia hybrida flowers, demonstrating a gradual release pattern during flower blooming. In the context of the transcriptome, a typical MYB transcription factor, FhMYB108, was screened based on digital expression profile correlation analysis and homologous gene comparison. FhMYB108 is capable of regulating the expression of terpene synthase FhTPS1, and both their expression levels exhibit a gradual increase concomitant with flower opening. Moreover, transcriptional regulation and transient expression assays revealed that FhMYB108 exerts a stimulatory effect on the transcription of A. thaliana AtTPS14, while no significant increase in AtTPS14 expression was observed upon stabilization of FhMYB108 in Arabidopsis. Investigate its reason, the highly expressed AtMYC2 in A. thaliana can interact with FhMYB108 to suppress the activation of AtTPS14 by FhMYB108. The present study not only elucidated the regulatory mechanism underlying linalool synthesis, but also discovered the synergistic effect of MYB and bHLH transcription factors in governing the biosynthesis of volatile terpenoids.

Raman scattering has been employed to study in detail the concentration dependence of the vibrational modes for the hexamethylenetetramine (HMTA) aqueous solutions. The formation of protonated and/or aggregated species has been clarified by comparing the experimental with the theoretically predicted vibrational spectra by means of quantum mechanical calculations. The analysis has shown that the vibrational modes of the solutions arise from a contribution of the vibrational modes of the HMTA self-aggregates and hetero-aggregates of HMTA with water molecules that are formed in the low- and intermediate-concentration region, respectively. The protonation of HMTA is ruled out due to the large differences between the experimental and the theoretically calculated spectra of the protonated molecules of HTMA in the fingerprint region. In the low-concentration solutions, the hetero-aggregation reaction of HMTA with water is the dominant mechanism, while at higher concentrations a self-aggregation mechanism occurs. Ultrasonic absorption and velocity measurements were carried out for hexamethylenetetramine aqueous solutions. The acoustic spectra reveal the presence of only one single Debye-type relaxation process that is assigned to the aggregation mechanism of HMTA. The sound absorption data follow two different dependencies on HMTA mole fraction. The crossover 0.018 mole fraction signifies two separate regions with distinct structural characteristics. The relaxation mechanism observed in dilute solutions is attributed to hetero-association of HMTA with water molecules, while at higher concentrations the observed relaxation process is assigned to the self-association reaction of HMTA molecules. This structural transformation is also reflected in several physicochemical properties of the system, including the kinematic viscosity, the mass density, the sound speed, and the adiabatic compressibility of the HMTA aqueous solutions. The combination of vibrational and acoustic spectroscopies with molecular orbital calculations allowed us to disentangle the underlying processes and to elucidate the observed relaxation mechanism in the HMTA aqueous solutions.

Presynaptic Ca²⁺-influx through voltage-gated Ca²⁺ channels (VGCC) is a key signal for synaptic vesicle release. Synaptic neurexins can partially determine the strength of transmission by regulating VGCCs. However, it is unknown whether neurexins modulate Ca²⁺-influx via all VGCC subtypes similarly. Here, we performed live cell imaging of synaptic boutons from primary hippocampal neurons with a Ca²⁺-indicator. We used the expression of inactive and active Cre recombinase to compare control to conditional knockout neurons lacking either all or selected neurexin variants. We found that reduced total presynaptic Ca²⁺-transients caused by the deletion of all neurexins were primarily due to the reduced contribution of P/Q-type VGCCs. The deletion of neurexin1α alone also reduced the total presynaptic Ca²⁺-influx but increased Ca²⁺-influx via N-type VGCCs. Moreover, we tested whether the decrease of Ca²⁺-influx induced by activation of cannabinoid receptor 1 (CB1-receptor) is modulated by neurexins. Unlike earlier observations emphasizing a role for β-neurexins, we found that the decrease of presynaptic Ca²⁺-transients induced by CB1-receptor activation depended more strongly on the presence of α-neurexins in hippocampal neurons. Together, our results suggest that neurexins have unique roles in the modulation of presynaptic Ca²⁺-influx through VGCC subtypes and that different neurexin variants may affect specific VGCCs.

Mesenchymal stem cells due to their multipotent ability are considered one of the best candidates to be used in regenerative medicine. The most used source of those stem cells long the last decades was the bone marrow, despite its limited cell resources and the painful and very invasive surgical treatment. Therefore, the scientific community investigated many alternative sources for the harvesting of these stem cell subpopulations. Adipose tissue attracted the biggest interest thanks to special features, such as great tissue abundance, easy availability, and in the end the large amount of positive mesenchymal stem cells. Once it was verified that these stem cell subpopulations possess the same bone marrow differentiation potential, it became evident that they would be the ideal candidate to be used in regenerative and tissue engineering applications. Even the regenerative use of these cells long become a sensitive point because not all the acquired phenotypes resulted in the best source for plastic procedures. As documented in the literature, the ideal fillers for regenerative is represented by stem cell population. Therefore, it became crucial to investigate any kind of biological mechanism on the differentiative ability of those mesenchymal stem cells, especially their regulative factors. One of the most studied and important regulators are the miRNAs. Indeed, miRNA play a crucial role in the differentiation process of adipose stem cell cultures isolated from patients or obtained by commercial cell lines toward osteocytes, chondrocytes, and adipocytes differentiated populations.

The structures of a number of dimers of sulphur dioxide and ozone have been optimized by means of a series of ab initio calculations. The dimer species have been classified as either genuine energy minima or transition states of first or higher order, and the most probable structures consistent with the experimental data have been confirmed. The molecular orbitals engaged in the interactions resulting in adduct formation have been identified and relations between the orbitals of the dimers of the valence isoelectronic monomer species examined. The vibrational spectra of the most probable structures have been computed, and compared with those reported in the literature, particularly with spectra observed in cryogenic matrices. The calculations have been extended to predict the properties of a number of possible heterodimers formed between sulphur dioxide and ozone.

Cancer develops from abnormal cell growth in the body, causing significant mortalities every year. To date, potent therapeutic approaches have been developed to eradicate tumor cells, but intolerable toxicity and drug resistance can occur in treated patients, limiting the efficiency of existing treatment strategies. Therefore, searching for novel genes critical for cancer progression and therapeutic response is urgently needed for successful cancer therapy. Recent advances in bioinformatic and proteomic techniques have allowed the identification of a novel category of peptides encoded by non-canonical open reading frames (ncORFs) from historically non-coding genomic regions. Surprisingly, many of the ncORFs express functional microproteins that play a vital role in human cancers. In this review, we provide a comprehensive description of different ncORF types with coding capacity and technological methods in discovering ncORFs among human genomes. We also summarize the diagnostic and prognostic value of these ncORF as well as their carcinogenic role in cancer progression and underestimated potential as therapeutic targets.

Circulating tumor cells (CTCs) are cells released from the primary tumor and intravasate into the blood or lymphatic vessels, where they are transported to distant sites and act as seeds that initiate cancer metastases. Recent advances in CTC research have shown their relevance as prognostic markers for early and metastatic disease detection, predictive biomarkers for relapse, and response to medical intervention or therapy. The rapidly evolving landscape of CTC biology has opened new avenues for understanding cancer progression, metastasis, and treatment response. Additionally, translating these findings into clinical applications holds promise for improving cancer diagnostics, prognosis, and personalized therapeutic strategies. This review discusses the significance of CTCs in cancer research and their associated challenges. We explore recent developments in the detection and characterization of CTCs and their implications in cancer research and clinical practice.

The BET family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises Brd2, Brd3, Brd4, and Brdt, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code. BET proteins play a crucial role in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones during cellular proliferation and differentiation processes. On the other hand, BET proteins have been reported to mediate latent viral infection in host cells and be involved in oncogenesis. Human BRD4 is involved in multiple processes of the DNA virus life cycle, including viral replication, genome maintenance, and gene transcription through interaction with viral proteins. Aberrant BRD4 expression contributes to carcinogenesis by mediating hyperacetylation of the chromatin containing the cell proliferation-promoting genes. BET bromodomain blockade using small-molecule inhibitors gives rise to selective repression of the transcriptional network driven by c-Myc. These inhibitors are expected to be potential therapeutic drugs for a wide range of cancers. This review presents an overview of the basic roles of BET proteins and highlights the pathological functions of BET and the recent developments in cancer therapy targeting BET proteins in animal models.

The p53 tumor suppressor protein shows antiviral activity. The replication of viruses is also antagonized by interferons (IFNs) – cytokines, which control immunity genes by the STAT transcription factors. The best studied interferons belong to type I (e.g. IFNα) and type II (IFNγ) groups. IFNα and IFNγ both induce activating phosphorylation of STAT1 on Tyr701. Previously, we noticed that p53 activates SOCS1, which is a negative regulator of STAT1 phosphorylation. Thus, we hypothesized that p53 by activating SOCS1 expression reduces phosphorylation of STAT1 and attenuates activation of genes stimulated either by IFNα or IFNγ. To test this hypothesis, we exposed p53-proficient and p53-deficient cells to strong p53 activators, and either to IFNα or IFNγ. Subsequently, we estimated the phosphorylation status of STAT1 and the expression of genes regulated by either of these cytokines. Strong activation of p53 reduced the phosphorylation of STAT1 on Tyr701, however surprisingly it did not lead to reduced expression of most tested interferon-stimulated genes. On contrary, p53 and IFNγ synergized in the activation of CASP1, IFIT1 and IFIT3 genes. We conclude that the interactions between p53 and interferon-activated pathways are more complicated than initially expected, but the apparent cooperation between p53 and IFNγ deserves further studies.

Diffusion magnetic resonance imaging (dMRI) is an imaging technique that provides information on the microstructural organization of biological tissue. dMRI allows for non-invasive visualization and quantitative assessment of white matter architecture in the brain by characterizing restrictions on the random motion of water molecules. Ultra-high field MRI scanners, such as those operating at 7 Tesla (7T) or higher, can boost signal-to-noise ratio (SNR) to improve dMRI compared with what is attainable at conventional field strengths such as 3T or 1.5T. However, at 7T wavelength effects cause lower transmit magnetic field efficiency in the human brain, mainly in the posterior fossa region, manifesting as signal dropouts in this region. Recently, we reported a simple approach of using a wireless radiofrequency (RF) surface array to improve transmit efficiency and signal sensitivity at 7T. Here we demonstrate the feasibility and effectiveness of using this RF enhancer for in-vivo dMRI at 7T. The use of the RF enhancer can effectively recover signal dropouts in the regions with intrinsically lower SNR such as cerebellum, leading to a better depiction of principal fiber orientations and enhanced visualization of extended tracts to the brainstem and pons enabling more comprehensive delineation of the full white matter architecture.

Reconstructing the Tree of Life remains a central goal in biology. Early methods, relying on small numbers of morphological or genetic characters, often yielded conflicting evolutionary histories, undermining confidence in the results. Investigations based on phylogenomics, which use hundreds to thousands of loci for phylogenetic inquiry, have provided a clearer picture of life's history, but certain branches remain problematic. To resolve difficult nodes on the Tree of Life, two recent studies tested the utility of synteny, the conserved collinearity of orthologous genetic loci in two or more organisms, for phylogenetics. Synteny exhibits compelling phylogenomic potential while also raising new challenges. We identify and discuss specific opportunities and challenges that bear on the value of synteny data and other rare genomic changes for phylogenomic studies. Synteny-based analyses of highly contiguous genome assemblies mark a new chapter in the phylogenomic era and the quest to reconstruct the Tree of Life.

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.

From their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses [1]. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3 to 10% of reported cases [2-5]. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches have been taken for the treatment of BRAF mutant cancers. In this review we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors.

Oligopeptide transporters (OPTs) are a group of membrane localized proteins that have a broad range of substrate transport capabilities and contribute to numerous biological processes. However, limited information has been reported on OPTs in higher plants. In this study, a comprehensive analysis of the OPT gene family in Medicago truncatula was performed. A total of 26 OPT genes (MtOPT01-MtOPT26) have been identified in the Medicago truncatula genome. Phylogenetic analyses indicated that MtOPTs consisted of two distinct subgroups, 12 MtOPTs belonged to the peptide transport subgroup (PT-OPT) based on their predicted amino acid sequences containing the two highly conserved motifs (NPG and KIPPR) and 14 MtOPTs belonged to yellow stripe subgroup (YS-OPT). The MtOPTs distributed on each of 8 chromosomes in Medicago truncatula. Sequence analysis verified that MtOPTs significant similar to those in other plants. The copy number of MtOPTs was low and the multiply of MtOPTs was simple relatively. Gene structure analysis showed that most of the MtOPTs have various numbers of introns. The multiple of MtOPTs might play different biological roles which were supported by the fact that MtOPTs have a distinct tissue-specific expression pattern. The data obtained in this study will help to better understand the complexity of the MtOPTs gene family and provide new evidence for the function and evolution of the OPT gene family in higher plants.

Lyme disease is a highly prevalent tick-borne infection caused by Borrelia burgdorferi spirochetes in North America and Eurasia. Diagnosis of the early disease remains difficult with the currently approved serological tests in the absence of noticeable tick bite or erythema migrans due to presentation of non-specific symptoms and the absence of antibodies early in infection. Furthermore, it is difficult to distinguish persistence of disease and reinfection in the endemic regions. If not treated early, infection spreads throughout the body and affects most organs with disease manifestations including arthritis, musculoskeletal pain, neuroborreliosis and acrodermatitis chronicum atrophicans. Although most patients recover after antibiotic treatment, ~10-12% of show recurrence of symptoms known as post-treatment Lyme disease syndrome (PTLDS). Various causes of PTLDS are not well-defined; however, the spirochete persisters, antigenic debris, dysregulation of immunological response in individuals or a combination of these factors are proposed to result in continuation of Lyme disease manifestations. Based on these considerations, this review highlights currently employed treatment approaches with antimicrobials and vaccines being tried for prevention of B. burgdorferi infection. We also summarize combinatorial approaches that could be employed to alleviate symptoms to improve the quality of life of the individuals suffering from long Lyme disease.

Huperzine A is an herbal reversible inhibitor of Acetylcholinesterase (AChE). A molecular docking analysis on Huperzine A molecule has been carried out to understand its structure, conformational flexibility, intermolecular interaction and the binding affinity in the active site of AChE enzyme. Further, the charge density distribution of huperzine A molecule (lifted from the active site of AChE) was determined from the high level quantum chemical calculations coupled with charge density analysis. The binding affinity of Huperzine A towards AChE was calculated from the molecular docking; the lowest docked energy is -8.46 kcal/mol. In the active site, huperzine A molecule interacts with acyl binding pocket-Phe330 of AChE, that is, the bicyclo ring group of huperzine A forms an intermolecular interaction with the oxygen atom of main chain of the amino acid residue Phe330 at the distances 3.02 and 3.25 Å respectively. On the other hand, a gas phase study on huperzine A molecule also performed using HF and DFT (B3LYP) methods with the basis set 6-311G**. The molecular structure, conformation, and the charge density distribution of huperzine A molecule in the gas phase have determined using quantum chemical calculations and the charge density analysis. The comparative studies between the gas phase and the active site forms of huperzine A molecule, explicitly reveals the degree of conformational modification and the charge density redistribution of huperzine A when present in the active site. The dipole moment of the molecule in the active site is 6.85 D, which is slightly higher than its gas phase value (5.91 D). The electrostatic potential (ESP) surface of active site molecule clearly shows the strong electronegative and positive ESP regions of the molecule, which are the expected strong reactive locations of the molecule.

Background: Obesity remains a widely debated issue, often criticized for the limitations in its identification and classification. This study aims to compare two distinct systems for classifying obesity: Body Mass Index (BMI) and body fat percentage (BFP) as assessed by bioelectrical impedance analysis (BIA). By examining these measures, the study seeks to clarify how different metrics of body composition influence the identification of obesity-related risk factors. Methods: The study enrolled 1255 adults, comprising 471 males and 784 females, with a mean age of 36 ± 11.90 years. Participants exhibited varying degrees of weight status, including optimal weight, overweight, and obesity. Body composition analysis was conducted using the TANITA Body Composition Analyzer BC-418 MA III device (T5896, Tokyo, Japan), evaluating the following parameters: current weight, basal metabolic rate (BMR), adipose tissue (%), muscle mass (%), and hydration status (%). Results: Age and psychological factors like cravings, fatigue, stress, and compulsive eating were significant predictors of obesity in the BMI model but not in the BFP model. Additionally, having a family history of diabetes was protective in the BMI model (OR: 0.33) but increased risk in the BFP model (OR: 1.66). The BMI model demonstrates exceptional predictive ability (AUC=0.998). In contrast, the BFP model, while still performing well, exhibits a lower AUC (0.975), indicating slightly reduced discriminative power compared to the BMI model. Conclusions:BMI classification demonstrates superior predictive accuracy, specificity, and sensitivity. This suggests that BMI remains a more reliable measure for identifying obesity-related risk factors compared to the BFP model.

More than 20 years after the discovery of the first anelloviruses (AVs), they still remain a mysterious group of viruses. To date, there is no clear understanding of their impact on the host organism, although information is emerging about their participation in various pathologies. However, it is well known that AVs are an important component of the human virome. In the current study we assessed the abundance of AVs in viromes from four nasal and pharyngeal samples from children with respiratory symptoms using a metagenomic approach. It is worth noting that three patients had known respiratory viruses and one did not have any. Regarding AVs, they were detected in all samples, namely Torque teno mini virus (TTMV). The greatest abundance and diversity of AVs (Torque teno virus (TTV), TTMV and Torque teno midi virus (TTMDV)) were shown in a diseased patient with an absence of respiratory viruses, which may indicate the potential involvement of AVs in the maintenance of respiratory symptoms. An activated immune system to combat the main pathogens, against the background of which the number of AVs decreases, is discussed as a possible reason for the reduced diversity of anellome in other patients. We also compared the results of the metagenomic approach and qPCR for major respiratory viruses, which were in agreement. In addition, metagenomic sequencing made it possible to obtain additional data on viral genomes in order to establish their taxonomic identification and characterize individual viral profiles in patients from the Siberian part of Russia.

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.

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

The immune response is crucial in Pregnancy Loss (RPL), which affects 1-2% of women. In RPL, peripheral blood lymphocytes and local immune cells are activated with a concomitant decrease in the leukocyte tolerogenic response in the uterus and decidua. IL-17 plays an essential role in T cell activation, weakening tolerogenic responses of the T cells. The report aims to analyze the IL-17 genetic polymorphism, circulating IL-17 lymphocyte populations, the reaction upon lymphocyte priming, the amount of cytokine in serum, and the number of T-reg cells in a group of 50 RPL and 50 normal women from the admixed Venezuelan population. No differences were observed in the genetic polymorphisms rs2275913 and rs763780. A significant decrease (P&lt;0.001) was observed in RPL patients compared to controls in the IL-17+ cell populations CD3+, CD8+, CD56+, and CD4CD25 FoxP3, but not in the CD4IL17+ cells. The response upon cell priming was significantly decreased (P&lt;0.001) in all subpopulations of RPL as compared to controls. It is concluded that despite the increase in IL-17A in the serum of patients, the number of circulating IL-17 cells and the lymphocyte response to stimulation was significantly decreased (p&lt;0.001). No differences in the genetic polymorphism compared to controls suggest that biological factors influence IL-17 levels in RPL patients, which must be carefully studied.

Metallo-β-lactamases (MBLs) are members of the structurally conserved but functionally diverse MBL-fold superfamily of metallohydrolases. MBLs are a major concern for global health care as they efficiently inactivate β-lactam antibiotics, including the “last-resort” carbapenems, and no clinically suitable inhibitors are currently available. Increasingly, promiscuous β-lactamase activity is also observed in other members of the superfamily, including from viruses, which represents an underexplored reservoir for future pathways to antibiotic resistance. Here, two such MBL-fold enzymes from Bacillus phages, the cyclic mononucleotide-degrading proteins ApycGoe3 and ApycGrass, are shown to efficiently degrade β-lactam substrates in vitro. In particular, ApycGrass displays a distinct preference for carbapenem substrates with a catalytic efficiency that is within one order of magnitude of that of the clinically relevant MBL NDM-1. Mutagenesis experiments also demonstrate that the loss of a metal-bridging aspartate residue reduces nuclease activity up to 35-fold, but improves carbapenemase activity. In addition, we propose that the oligomeric state significantly influences β-lactamase activity by modifying access to the active site pocket. Together, these observations hint at a possible new avenue of resistance via the spread of phage-borne MBL-fold enzymes with β-lactamase activity.

The mutation in NF2 is the most common alteration associated with meningioma oncogenesis, and it is related to the loss of a suppressing protein called merlin. At the same time, alterations in energy production are visible in cancer cells where increased demand for energy is observed. Fatty acid oxidation could be one of the ways cancer cells obtain energy. This metabolic pathway uses the acylcarnitine shuttle system, which is responsible for the acylation of fatty acids and their transport through mitochondria. Therefore, this study aimed to profile acylcarnitines with short-, medium- and long-acyl chain length in meningiomas to assess their changes in tumors with different NF2 mutation statuses. For the analysis, solid-phase microextraction (SPME) coupled with liquid chromatography high resolution mass spectrometry (LC-HRMS) was used. The presented sampling method enables low invasive and easy collection of the analytes from the studied lesions, which can be crucial for future analysis of potential biomarkers in the surgery room. It was observed that higher levels of these analytes characterized meningiomas with NF2 mutation. Moreover, increased energy consumption and elevated levels of acylcarnitines show that these analytes can be considered as a marker of increased fatty acid oxidation in NF2 mutated cells.

The extensive metabolic diversity of microalgae, coupled with their rapid growth rates and cost-effective production, position these organisms as highly promising resources for a wide range of biotechnological applications. These characteristics allow microalgae to address crucial needs in both the agricultural, medical, and industrial sectors. Microalgae are proving to be val-uable in various fields, including the remediation of diverse wastewater types, the production of biofuels and biofertilizers, and the extraction of various products from their biomass. For decades, the microalga Chlamydomonas has been widely used as a fundamental research model organism in various areas such as photosynthesis, respiration, sulfur and phosphorus metabolism, nitrogen metabolism, and flagella synthesis, among others. However, in recent years, the potential of Chlamydomonas as a biotechnological tool for bioremediation, biofertilization, biomass, and bio-products production has been increasingly recognized. Bioremediation of wastewater using Chlamydomonas presents significant potential for sustainable reduction of contaminants and fa-cilitates resource recovery and valorization of microalgal biomass, offering important economic benefits. Chlamydomonas has also established itself as a platform for the production of a wide va-riety of biotechnologically interesting products, such as different types of biofuels, and high-value-added products. The aim of this review is to achieve a comprehensive understanding of the potential of Chlamydomonas in these aspects, and to explore their interrelationship, which would offer significant environmental and biotechnological advantages.

New Schiff base ofN'-((E)-3,3-diphenyl-2,3-dihydro-1H-inden-1-ylidene)-2-((Z)-2-oxoindolin-3-ylidene)hydrazine-1-carbothiohydrazide (HL) and its Co(II),Ni(II), Fe(III), Cu(II), Cd(II), Zn(II) and Mn(II) complexes were created, isolated, and characterized by analytical analysis in good yields of 60 to 90%, UV–Vis, magnetic measurements, molar conductivity, and FT-IR. Additionally, mass spectrometry was used to examine the new ligand complexes' structural characteristics.1H NMR spectroscopy and elemental analysis. Depending on the electronic spectra and magnetic susceptibility measurements, these complexes are predicted to have octahedral molecular geometry. As an example, the quantum chemical properties, bond lengths, and bond angles were discussed. The structural formula for the examined ligand was improved using the Gaussian09 tool. The DFT/B3LYP method was used to calculate the energy gaps and other crucial theoretical features. The prepared hydrazine ligand complexes Co (II), Ni (II), Fe (III), Cu (II), Cd (II), Zn (II) and Mn (II) complexes were evaluated for its antimicrobial properties. As antimicrobial agents, it was found that the organic ligand was less biologically active than the targeted complexes. Gram positive bacteria (3ty7-Staphylococcus), Gram negative bacteria (3t88-Escherichia coli), and fungi (5k04-Candida albicans) all have crystal structures that interact well with the chemicals in the title, according to molecular docking.

Enveloped viruses represent a significant category of pathogens that cause serious diseases in animals. These viruses express envelope glycoproteins that are singularly important during infection of host cells by mediating fusion between the viral envelope and host cell membranes. Despite low homology at protein levels, three classes of viral fusion proteins have, as of yet, been identified based on structural similarities. Their incorporation into viral particles is dependent upon their proper sub-cellular localization after being expressed and folded properly in the endoplasmic reticulum (ER). However, viral protein expression can cause stress in the ER, and host cells respond to alleviate the ER stress in the form of the unfolded protein response (UPR); the effects of which have been observed potentiating or inhibiting viral infection. One important arm of UPR is to elevate the capacity of the ER-associated protein degradation (ERAD) pathway, which is comprised of host quality control machinery that ensures proper protein folding. In this review, we provide relevant details regarding viral envelope glycoproteins, UPR, ERAD, and their interactions in host cells.

Currently, SARS-CoV-2 has evolved into various variants, including the numerous highly mutated Omicron sub-lineages, significantly increasing immune evasion ability. The development raises concerns about possibly diminished effectiveness of available vaccines and antibody-based therapeutics. Here, we describe those representative categories of broadly neutralizing antibodies (bnAbs) that retain prominent effectiveness against emerging variants including Omicron sub-lineages. The molecular characteristics, epitope conservation, and resistance mechanisms of these antibodies are further detailed, aiming to offer suggestion or direction for the development of therapeutic antibodies, and facilitate the vaccine design with broad-spectrum potential.

In Cameroon, Aedes mosquitoes transmit various arboviruses, posing significant health risks. We aimed to characterize the Aedes virome in southwestern Cameroon and identify potential core viruses which might be associated with vector competence. A total of 398 Aedes mosquitoes were collected from four locations (Bafoussam, Buea, Edea and Yaounde). Aedes albopictus dominated all sites except for Bafoussam where Aedes africanus prevailed. Metagenomic analyses of mosquitoes grouped per species into 54 pools revealed notable differences in eukaryotic viromes between Ae. africanus and Ae. albopictus, with the former exhibiting greater richness and diversity. Thirty-seven eukaryotic virus species from 16 families were identified, including six novel viruses with near complete genome sequences. Seven viruses were further quantified in individual mosquitoes via qRT-PCR. Although none of them could be identified as core viruses, Guangzhou sobemo-like virus and Bafoussam mosquito solemovirus virus were highly prevalent regionally in Ae. albopictus and Ae. africanus, respectively. This study highlights the diverse eukaryotic virome of Aedes species in southwestern Cameroon. Despite their shared Genus, Aedes species exhibit limited viral sharing, with varying viral abundance and prevalence across locations. Ae. africanus, an understudied vector, harbors a rich and diverse virome, suggesting potential implications for arbovirus vector competence.

In bacteria, enzymes usually comprise of enzymatic domains only. In eukaryotes/mammals, and here particularly in context of signal transduction, proteins with enzymatic functions contain additional modules promoting interactions with cooperating signaling proteins. Often such protein-protein interaction domains, such as SH2- and SH3-domains, help to localize the enzymatic function (e.g. kinase, phosphatase) to another protein, cellular compartment, or membrane nanodomain. In such cases, the interaction domain(s) serve(s) the enzymatic function. However, there are molecular situations in which an interaction domain fulfills its task completely independent of the protein´s enzymatic function and in this review, we call such function the adapter function of an enzyme. Though many stories can be told, we will concentrate on several proteins playing crucial roles in cells of the immune system, such as BTK, PI3K, and SHIP1, as well as in cancer cells, such as proteins of the RAS/ERK MAPK pathway. We will also discuss how these adaptor functions of enzymes determine or even undermine the efficacy of targeted therapy compounds, such as ATP-competitive kinase inhibitors, thereby highlighting the need to develop pharmacological approaches, such as PROTACs, that eliminate the entire protein. We also review how genetic kock-out and knock-in approaches can be leveraged to identify adaptor functions of signaling proteins.

Silencing of the fragile X mental retardation 1 (FMR1) gene and consequently lack of synthesis of FMR protein (FMRP) are associated with fragile X syndrome, which is one of the most prevalent inherited intellectual disabilities. FMRP is a multifunctional protein involved in many cellular functions in nearly all subcellular compartments under normal conditions and under conditions of cellular stress in both neuronal and non-neuronal cell types. This is achieved through its trafficking signals, nuclear localization signal (NLS), nuclear export signal (NES), and nucleolar localization signal (NoLS), as well as its RNA and protein binding domains, and is modulated by various post-translational modifications such as phosphorylation, ubiquitination, sumoylation, and methylation. This review summarizes recent advances in understanding the interaction networks of FMRP with a special focus on FMRP stress-related functions, including stress granule formation, mitochondrion and endoplasmic reticulum plasticity, ribosome biogenesis, cell cycle control, and DNA damage response.

A large diversity of epigenetic factors, such as microRNAs and histones modifications, are known to be capable of regulating gene expression without altering DNA sequence itself. In particular, miR-1 is considered the first essential microRNA in cardiac development. In this study, miR-1 potential role in early cardiac chamber differentiation is analyzed through specific signaling pathways. For this, we performed in chick embryos functional experiments by means of miR-1 microinjections into the posterior cardiac precursors -of both primitive endocardial tubes- committed to sinoatrial region fates. Subsequently, embryos were subjected to whole mount in situ hybridization, immunohistochemistry and RT-qPCR analysis. As a relevant nov-elty, our results revealed that miR-1 increases Tbx5, Gata4 and AMHC1, while this microRNA diminishes Mef2c expression, during early differentiation of cardiac sinoatrial region. Further-more, we observed in this developmental context that miR-1 upregulates CRABPII and RARß, and downregulates CRABPI, which are three crucial factors in retinoic acid signaling pathway. Interestingly, we also noticed that miR-1 directly interacts with HDAC4 and Calmodulin, as well as with Erk2/MAPK1, which are three key factors actively involved in Mef2c regulation. Our study shows, for the first time, a key role of miR-1 as an epigenetic regulator in early differenti-ation of cardiac sinoatrial region through orchestrating opposite actions between retinoic acid and Mef2c, fundamental to properly assign cardiac cells to their respective heart chambers. A better understanding of those molecular mechanisms modulated by miR-1 will definitely help in fields applied to therapy and cardiac regeneration and repair.

Viral contamination in the aquaculture industry is a significant challenge that requires further research. Emerging evidence suggests that long noncoding RNAs (lncRNAs) play a role in regulating various biological processes, including immunity. However, most studies have focused on model organisms, and little is known about non-coding RNAs in the immune response to viral hemorrhagic septicemia (VHS) in rainbow trout. In this study, we investigated the listing of non-coding RNAs (ncRNAs) in rainbow trout challenged with VHS virus. We explored their potential role in defense-like responses based on transcriptomic analysis of the virus-treated and control groups. As a result of this research, 4207 lncRNAs were identified, of which 182 lncRNAs were differentially expressed between treated and untreated samples. Among 7753 lncRNA transcripts, 1920 were novel intergenic (class code “u”), and 3748 transcripts were potentially novel isoform of lncRNAs. Gene ontology analysis revealed biological pathways associated with the stress response and immune signaling. Pairs of genes such as TP63-MSTRG.62, IL10-MSTRG.9783, IL10-MSTRG.9784, TK1-MSTRG.22826, and MSTRG.17881-GLI1 showed cis interactions, while DOCK10-MSTRG.30015, MSTRG.36357-LOC101268921, and MSTRG.34190-ENPP2 showed trans interactions. In this study, the role of lncRNAs in regulating the expression of the target genes was clearly identified. This finding is consistent with the regulatory processes of immune system responses mediated by cytokines, as well as the regulation of oxygen levels in response to viral infection. The information presented here highlights the various regulatory mechanisms of lncRNAs in the expression of immune system genes in fish treated with VHS virus.

Global warming and the associated increasing frequency of heatwaves are on the rise leading to numerous health complications. Diabetic patients are more vulnerable to heat exposure than healthy individuals, owing to their impaired sweating ability, however, little is known about how heat exposure may impact the function of skin cells, commonly keratinocytes. Our recent report provided the first proof-of-concept revealing that the metabolic composition of sweat EVs is associated with metabolic changes in healthy individuals and type 2 diabetes patients. Given this and the shared cellular proprieties of eccrine sweat glands with keratinocytes, we questioned whether the metabolic changes in sweat EVs may mirror the responses of keratinocytes upon heat exposure. To this, we exposed HaCat, which were maintained in low (mimicking healthy condition) and high glucose (mimicking diabetes condition) to acute (90 min), chronic (48 h), and repetitive heat exposure at 40 ⁰C. Through conducting a set of experiments including a targeted metabolomics approach, Greiss assay, western blotting analysis, and electron microscopy studies. The data demonstrate that heat exposure results in substantial changes of metabolite levels belonging to amino acids, pyrimidine metabolism, and glycolysis pathways in high glucose maintained HaCat cells when compared to those noted in low glucose condition. Exploring the molecular mechanisms through which heat exposure may impact the metabolic composition in keratinocytes, our discoveries highlight nitric oxide (NO) as a novel biomarker that the level is correlated with heat duration and frequency. Furthermore, data reveal that the HSP-70 protein levels and mitochondrial morphology are consequently altered. This study provides evidence of shared metabolic alterations in keratinocytes and sweat EVs collected from clinical study and proposes, for the first time, NO as a novel biomarker for monitoring changes in health and diabetes upon heat exposure.

Some peptide-based drugs including oxytocin, vasopressin, ziconotide, pramlintide, nesiritide, and octreotide, contain one intramolecular disulfide bonds. A novel and reusable monodispersed silica nanosphere-supported Pt(IV) complex (SiO2@TPEA@Pt(IV)) was synthesized via a four-step procedure and used for formation of intramolecular disulfide bonds in peptides. TEM and chemical mapping results for the Pt(II) intermediates and for SiO2@TPEA@Pt(IV) show that the silica nanospheres possess a monodisperse spherical structure and contain uniformly distributed Si, O, C, N, Cl, and Pt. The valence state of Pt on the silica nanospheres was characterized by XPS. The Pt(IV) loaded on SiO2@TPEA@Pt(IV) was 0.15 mmol/g, as determined by UV-vis spectrometry. Formation of intramolecular disulfides in six dithiol-containing peptides of variable lengths by use of SiO2@TPEA@Pt(IV) was investigated and the relative oxidation yields were determined by HPLC. In addition, peptide 1 (Ac-CPFC-NH2) was utilized to study the reusability of SiO2@TPEA@Pt(IV). No significant decrease in the relative oxidation yield was observed after ten reaction cycles. Moreover, the structure of SiO2@TPEA@Pt(IV) after being used ten cycles was determined to be similar to its initial one, demonstrating the cycling stability of the complex.

Many fundamental molecular techniques (PCR, Microarray, Southern and northern hybridization, siRNA, CRISPR/Cas9 etc.) developed so far shows errors. I wish to highlight these molecular techniques are developed on basis of Watson-Crick DNA model, ignoring the concept of parallel stranded DNA. Through this opinion article, I wish to highlight specificity and accuracy of these molecular techniques can be enhanced by considering both parallel and anti parallel hybridization of DNA. Hopefully my views will also solve issue of irreproducibility in life science research.

Even with 100% certainty of a complete cure for breast cancer (BC), there is still a long way to go toward more efficient treatment. This requires sensitive and timely detection and accurate pre/post-clinical characterizations. Despite the availability of advanced diagnostic tools, many cancer patients lack access to efficient diagnostics that are both highly reliable and affordable. The fluorescence-based optical technique aims to make another significant leap forward in improving patient safety. It offers a convenient operation that reduces healthcare costs compared to visual examination tools (VETs). The primary and metastatic stages of BC consider different cancerous cell lines (MDAs), meaning the highest number of cells in this research (up to 300,000) represents the metastatic stages of BC, and 50,000 represents the primary level of BC developments have been studied based on fluorescence-enhanced photodynamic characterizations. The ability to characterize the fluorescence caused by MDA with 50,000 cells compared to the dominant radiation of MDA with 300,000 cells is emphatic proof of the high potential of fluorescence technique in timely BC detections, specifically before it spreads to the axillary lymph nodes. The specific cell numbers of 50,000 and 300,000 were chosen arbitrarily based on the cultivation of common biological limitations. Comparing the outcomes between 50,000 and 300,000 cells allows for evaluating the fluorescence technique’s diagnostic capability across various stages of breast cancer. This assessment provides valuable insights into the effectiveness of the fluorescence-based characterizing approach in detecting cancerous cells at different stages of the disease. Here, we have assessed fluorescence’s spectral shift and intensity difference as a diagnostic approach to distinguish between cancerous and normal breast cells. This study also presents a two-way structure of the 5-aminolevulinic acid (5-ALA) prodrug and Fluorescein Sodium (FS) effect in BC cell characterization from the perspective of photodynamical procedures and the detection side. 5-ALA induces an accumulation of protoporphyrin IX (PpIX) photosensitizer through a biosynthetic pathway, leading to red radiation of fluorescence measurements depending on different factors, such as temperature, incubation time, added glucose of the culturing medium, as well as photosynthesis processes. The presence and progression of breast cancer can be indicated by elevated levels of Reactive Oxygen Species (ROS), which are associated with the production of PpIX in cells following the administration of 5-ALA. Also, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) fluorophores are recognized as the main factors for fluorescence emissions at around 420-580 nm emission intervals. Considering the MDA’s high metastatic potential, the impact of 5-ALA on MDA’s cellular morphology and viability has been investigated. The molecular fluorophores are the primary probes to MDA’s cellular photodynamic considerations, allowing this widespread pre/post-clinical approach. The fluorescence signal reduction due to decreased cell viability and increased MDA’s cellular death rate after 24 hours of the 5-ALA-induced staining corresponds to the changes in lipid metabolism enzymes of MDAs cultured at different doses, which could be known as a cell death inducer function. Furthermore, statistical concerns have been studied using PCA multivariate component analysis to differentiate MDA cell lines administrated by 5-ALA.

The development of a rapid, sensitive, specific method for detecting foodborne pathogens is paramount in supplying safe food to enhance public health safety. Despite the significant improvement in pathogen detection methods, key issues are still associated with rapid methods, such as distinguishing living cells from dead, pathogenic potential or health risk of the analyte at the time of consumption, detection limit, and sample-to-result. The mammalian cell-based assays analyze pathogens' interaction with the host cells and are responsive to only live pathogens or active toxins. In this study, a human embryonic kidney (HEK293) cell line expressing Toll-Like Receptor 5 (TLR-5) and chromogenic reporter system (HEK dual hTLR5) was used for the detection of viable Salmonella in a 96-well tissue culture plate. This cell line responds to low concentrations of TLR5 agonist flagellin. Stimulation of TLR5 ligand activates nuclear factor-kB (NF-κB) - linked alkaline phosphatase (AP-1) signaling cascade inducing the production of secreted embryonic alkaline phosphatase (SEAP). With the addition of a ρ-nitrophenyl phosphate as a substrate, a colored end product representing a positive signal is quantified. The assay's specificity was validated with the top 20 Salmonella enterica serovars and 19 non-Salmonella spp. The performance of the assay was also validated with spiked food samples. The total detection time (sample-to-result), including shortened pre-enrichment (4 h) and selective enrichment (4 h) steps with artificially inoculated outbreak-implicated food samples (chicken, peanut kernel, peanut butter, black pepper, mayonnaise, and peach) was 15 h when inoculated at 1–100 CFU/25 g sample. These results show the potential of HEK-DualTM hTLR5 cell-based functional biosensors for rapid screening of Salmonella.

The p53 tumor suppressor protein is an activator of transcription. Diverse stress factors lead to various sets of posttranslational modifications of p53 what results in different sets of upregulat-ed genes. We noticed that actinomycin D and nutlin-3a (A+N) synergize in inducing activating phosphorylations of p53 and upregulation of selected p53-target genes. Here we found that one of these genes is DUSP13, which codes for poorly-studied, dual-specificity phosphatase having at least two isoforms, one expressed in testis and the other in skeletal muscles. In cancer cells ex-posed to A+N, DUSP13 is expressed from an alternative promoter in intron, what results in ex-pression of isoform named TMDP-L1. The luciferase reporter tests demonstrated that this pro-moter is activated by both endogenous and ectopically expressed p53. We showed for the first time that mRNA expressed from this promoter actually produces the protein, which can be de-tected by Western blotting in all examined cancer cell lines with wild-type p53 exposed to A+N. In some cell lines it is also induced by clinically relevant camptothecin or by nutlin-3a acting alone. This isoform, fused with green fluorescent protein localizes in perinuclear region of cells. Thus, TMDP-L1 isoform may be an important element of p53-regulated stress response system.

We identified six natural "control knobs" for global weather and climate, which clearly regulate, increase and decrease global temperatures, thus performing a true temperature "control" on Earth. Identified control knobs act as Earth's orbital forcing. We present a detailed Earth orbital model, from where the analysis proceeds. Based on our orbital model, we compare meteorological data from all over the globe, in order to detect orbital forcing fingerprints. Ninety temperature graphs and bar charts demonstrate the results. Empirical meteorological data covers the Pacific ocean, the Atlantic ocean, Arctic and Antarctic sea ice extent, and presents land based meteorological measurements from all continents for the year 2020, as well as multi-decadal data from global daily temperature datasets. A supplementary file provides another 100 additional graphs of weather data and temperature charts. The global orbital "temperature control" is clearly observable in all graphs and charts. Until today, orbital forcing has not been integrated in weather models and CMIP6 climate models.It is concluded that the proposed new orbital forcing should be part of weather and climate forecasting models.

Human serum albumin (HSA) corona formation at polymer microparticles of a spheroidal shape was studied using dynamic light scattering and laser Doppler velocimetry (LDV). Physicochemical characteristics of the albumin comprising, the zeta potential and the isoelectric point were determined as a function of pH for various ionic strengths. Analogous characteristics of the polymer particles were carried out. The adsorption of albumin on the particles was monitored by electrophoretic mobility measurements (LDV). The stability of the HSA functionalized particle suspensions under various pHs and their electrokinetic properties were determined. The deposition kinetics of the particles on mica, silica and gold sensors were determined in situ by optical microscopy, AFM and by the quartz microbalance (QCM) under diffusion and flow conditions. The obtained results were interpreted in terms of the coarse-grained random sequential adsorption model that allowed to estimate the range of applicability of QCM for determining deposition kinetics of virus and bacteria at abiotic surfaces.

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing in-creased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play im-portant roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB de-pendence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima-media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of exposure of guinea pigs to CIH (FiO2, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter en-dothelial function or the contractile response to phenylephrine in these arteries. In contrast, CIH exposure increased the systemic arterial pressure, and enhanced the contractile response to phenylephrine while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta, without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH.

The process of oxygenic photosynthesis is primarily driven by two multiprotein complexes known as photosystem II (PSII) and photosystem I (PSI). PSII facilitates the light–induced reactions of water–splitting and plastoquinone reduction, while PSI functions as the light–driven plastocyanin-ferredoxin oxidoreductase. In contrast to the highly conserved structure of PSII among all oxygen–evolving photosynthetic organisms, the structures of PSI exhibit remarkable variations, especially for photosynthetic organisms that grow in special environments. In this review, we make a concise overview of the recent investigations of PSI from photosynthetic microorganisms including prokaryotic cyanobacteria and eukaryotic algae from the perspective of structural biology. All known PSI complexes contain a highly conserved heterodimeric core; however, their pigment compositions and peripheral light-harvesting proteins are substantially flexible. This structural plasticity of PSI reveals the dynamic adaptation to environmental changes for photosynthetic organisms.

Biohydrogen is a versatile energy carrier for the generation of electric energy from renewable sources. Hydrogenases can be used in enzymatic fuel cells to oxidize dihydrogen. The rate of electron transfer (ET) at the anodic side between the [NiFe]-hydrogenase enzyme distal iron-sulfur cluster and the electrode surface can be described by the Marcus equation. All parameters for the Marcus equation are accessible from DFT calculations. The distal cubane FeS-cluster has a three cysteine and one histidine coordination [Fe₄S₄](His)(Cys)₃ first ligation sphere. The reorganization energy (inner- and outer-sphere) is almost unchanged upon a histidine-to-cysteine substitution. Differences in rates of electron transfer between the wild-type enzyme and the all-cysteine mutant can be rationalized by a diminished electronic coupling between the donor and acceptor molecules in the [Fe₄S₄](Cys)₄ case. The fast and efficient electron transfer from the distal iron-sulfur cluster is realized by a fine-tuned protein environment which facilitates the flow of electrons. This study enables the design and control of electron transfer rates and pathways by protein engineering.

High systolic blood pressure and increased blood pressure variability after the onset of ischemic stroke are associated with poor clinical outcomes. One of the key determinants of blood pressure is arteriolar size, determined by vascular smooth muscle tone and vasodilatory and vasoconstrictor substances that are released by the endothelium. The aim of this study is to outline alterations in vasomotor function in isolated peripheral arteries following ischemic stroke. The reactivity of thoracic aortic segments from male C57BL/6 mice to dilators and constrictors was quantified using wire myography. Acetylcholine induced endothelium-dependent vasodilation was impaired after ischemic stroke (LogIC50 Sham=-7.499, LogIC50 Stroke=-7.350, P=0.0132, n= 19, 31 respectively). Vasodilatory responses to SNP were identical in isolated aortas in sham and stroke groups. Phenylephrine induced vasoconstriction was impaired in aortas isolated from stroke animals in comparison to sham counterparts (Sham LogEC50= -6.652 vs Stroke LogEC50=-6.475, P< 0.001). Our study demonstrates that 24 hours post-ischemic stroke, peripheral vascular responses are impaired in remote arteries. Aortas from stroke animals exhibited reduced vasoconstrictor and endothelium-dependent vasodilator responses, while endothelium-independent vasodilatory responses were preserved. Since both vasodilatory and vasoconstrictor responses of peripheral arteries are impaired following ischemic stroke, our findings might explain increased blood pressure variability following ischemic stroke.

The study of the change in entropy during the formation of stars in collapsing molecular clouds is an important area of research in astrophysics. As the cloud decreases in size, the presence of gases leads to an increase in entropy. However, the extent of this change in entropy is influenced by the amount of space available for the gases. In this scientific investigation, I conduct a detailed analysis of entropy on a small scale within the contracting cloud, following the principles of the second law of thermodynamics. Initially, my focus is on a turbulent cloud composed of N particles with a mass of M, which collapses under the force of gravity. It becomes clear that in order for the collapse to occur, gravitational energy must overcome other pressure forces that oppose it. This process results in the rapid movement of particles within the cloud, ultimately leading to a change in entropy

Liver fibrosis, a consequence of chronic liver damage or inflammation, is characterized by the excessive buildup of extracellular matrix components. This progressive condition significantly raises the risk of severe liver diseases like cirrhosis and hepatocellular carcinoma. The lack of approved therapeutics underscores the urgent need for novel anti-fibrotic drugs. Hepatic stellate cells (HSCs), key players in fibrogenesis, are promising targets for drug discovery. This study investigated the anti-fibrotic potential of Citrus hystrix DC. (KL) and its bioactive compound, β-citronellol (β-CIT), in a human HSC cell line (LX-2). Cells exposed to TGF-β1 to induce fibrogenesis were co-treated with crude KL extract and β-CIT. Gene expression was analyzed by Real-Time qRT-PCR to assess fibrosis-associated genes (ACTA2, COL1A1, TIMP1, SMAD2). The releasing of matrix metalloproteinase 9 (MMP-9) was measured by ELISA. Proteomic analysis and molecular docking identified potential signaling proteins and modeled protein-ligand interactions. Results showed that both crude KL extract and β-CIT suppressed HSC activation genes and MMP-9 levels. The MAPK signaling pathway emerged as a potential target of β-CIT. This study demonstrates the ability of KL extract and β-CIT to inhibit HSC activation during TGF-β1-induced fibrogenesis, suggesting a promising role of β-CIT in anti-hepatic fibrosis therapies.

Transition-metal-free synthesis of 4-pyrones via TfOH-promoted nucleophilic addition/cyclization of diynones and water has been developed. This transformation is simple, atom economical and environmentally benign, providing rapid and efficient access to substituted 4-pyrones.

Nose mask is a fomite and its usage was mandatory during the COVID-19 outbreak. Its effectiveness has been established; however, as a fomite, it can harbor opportunistic respiratory pathogens such as Streptococcus spp., which could complicate COVID-19 infections. This study profiled Streptococcus species resident on nose masks obtained from consenting participants. Phenotypic assays and 16S rRNA sequencing were used to identify Streptococcus spp. resident on the interior and exterior of 100 nose masks analyzed. Antibiotic resistance (AMR) was determined with disc diffusion and broth microdilution assays. AMR and virulence makers were profiled with primer-specific PCR amplification. 23% of the analyzed samples had Streptococcus isolates. The isolates were highly resistant to the antimicrobials, including conventional, last-resort antibiotics, disinfectants and antiseptics. All the isolates are multidrug resistant with 80-100% levels of AMR to the 16 antibiotics tested with a Multiple-Antibiotic Resistance index greater than 0.2, indicative of potential pathogens. The isolates harbored tetB, ermB, pbp2B, pbp2b1 (resistance) and lytA, lytA1, ply1, cbpA, lytA, pavA (virulence) markers, which might constitute a serious public health risk. Overall, the study emphasizes the need to assess mask usage and the risks associated with opportunistic pathogens that are resident on frequently used nose masks in the COVID-19 era.

. Protein cysteine S-glycosylation is a relatively rare and less well characterized post-translational modification (PTM). Creating reliable model proteins that carry this modification is challenging. The lack of available model or natural S-glycosylated proteins significantly hampers the development of MS-based methodologies for detecting protein cysteine S-glycosylation in real-world proteomic studies. There is also limited MS-sequencing data describing easier to create synthetic S-glycopeptides. Here, we present the results of an in-depth manual analysis of automatically annotated CID/HCD spectra for model S-glucopeptides. The CID spectra show a long series of y/b-fragment ions with retained S-glucosylation, regardless of the dominant m/z signals corresponding to neutral loss of 1,2-anhydroglucose from the precursor ions. In addition, the spectra show signals manifesting glucosyl transfer from the cysteine position onto Lys, Arg side chains, and a peptide N-terminus. Other spectral evidence indicates that the N-glucosylated initial products of transfer are converted into N-furanosylated (i.e., glycated) structures due to Amadori rearrangement. We discuss the peculiar transfer of the glucose oxocarbenium ion (Glc+) to positively charged guanidinium residue (ArgH+) and propose a mechanism for the gas-phase Amadori rearrangement involving a hydride ion shift.

Clustered regularly interspaced short palindromic repeats (CRISPR) based gene-editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single guide RNA (sgRNA)-based gene-editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, instructive, and inspiring for future advances. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent beta thalassemia has renewed hope for treating other hematologic diseases, including patients with germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-based gene therapies. The purpose of this manuscript is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy; and third, the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards developing these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with germline predisposition to hematologic malignancies.

This study focuses on the potential medicinal properties of Campsis radicans L. extracts and its aim is to investigate the antioxidant and antiproliferative effects of these extracts on the human colon adenocarcinoma cell line (HT-29). Cytotoxic activity in the HT-29 cell line was evaluated, and the 3-dimensional structures of phenolic compounds were obtained using the GC-MS method. Docking simulations were performed with AutoDock Vina, targeting proteins that are crucial in the apoptotic pathway (Bax, Bcl-2, and Caspase-3). Drug similarities and ADMET estimates of the phenolic compounds were obtained from databases. The highest antioxidant activity of Campsis radicans L. plant was observed in ethanol and water extracts, with notable inhibition capacities. While the total phenolic content was highest in ethanol, water, and ether extracts respectively the total flavonoid content was highest in ethanol, then ether, and water extracts. Certain elements were undetectable in mineral determination, and others exceeded the toxic doses for plants. The water extract exhibited dose-dependent cytotoxic activity in the HT-29 cell line, with an IC50 value of 4.47 mg/mL. Molecular docking results revealed the binding of phenolic molecules to the active sites of apoptotic pathway proteins. The findings suggest that Campsis radicans L. plant possesses cytotoxic properties, significant phenolic and flavonoid content, and a high antioxidant capacity. These properties make it a potential candidate for treatment use, emphasizing its potential therapeutic value in the HT-29 cell line. Further research and exploration on the identified phenolic compounds could contribute to the development of novel therapeutic agents.

Chronic kidney disease patients treated by hemodialysis present a high cardio-vascular morbidity and mortality. There is an imperative need for novel biomarkers in identifying and to offer possible therapeutically intervention in these patients. We performed a prospective observational cohort study on 77 patients in the period October 2021 – October 2023. We measured serum plasma levels of Interleukin 1-Beta, Galectin 3, human suppression of tumorigenicity factor 2, bone morphogenetic protein 2 and fibroblastic growth factor 23 at the inclusion. We evaluated the correlations of these biomarkers with cardiac function and structure evaluated by echocardiography. Mean age was 61.02 (±11.81) years, 45 (56.2%) males and with a dialysis vintage of 4.95 (2.4-7.8) years. Median ejection fraction was 51 (43-54 %) and more than two thirds of the patients presented valvular calcifications. Overall mortality was 22%. Interleukin 1-Beta correlated positively with ejection fraction and global longitudinal strain and negatively with left atrium diameter and left ventricle tele systolic diameter. Galectin 3 values negatively correlated with aortic valve fibrosis and mitral valve calcifications and human suppression tumorigenity factor 2 negatively correlated with mitral valve calcifications. Some of these novel biomarkers could be used to better asses the cardio-vascular disease in patients on maintenance hemodialysis.

Recurrent pregnancy loss (RPL) affects around 2 % of women of reproductive age. Primary RPL is defined by ≥2 pregnancy losses and no normal birth delivery. In secondary RPL, the losses are after a normal pregnancy and delivery. Most cases have no clear aetiology, although primary cases are the most complex. Several gene polymorphisms have been associated with RPL. Some polymorphisms are increased in women of Asian or Caucasian race. In admixed RPL populations, the information on possible genetic links is scarce and contradictory. The study aimed to assess the frequency of two SNP in different enzymes involved in medical conditions observed during pregnancy. Microsomal epoxy hydrolase (mEPH) is involved in detoxifying xenobiotics. It is present in ovaries, and it is hormonally regulated. The endothelial nitric oxide synthase forms nitric oxide from arginine and is involved in vascular tone. Two SNPs, rs1051740 and rs1799983, were assessed. The study included 26 controls and 63 primary RPL patients. Significant differences were observed in the frequencies of both SNP (p<0.05). The frequency of mutated alleles was higher in patients. Double mutated homozygotes were encountered only in RLP patients (p<0.05). Genetic polymorphisms rs1051740 and rs1799983 may be involved in primary RPL in the Venezuelan admix population. Genetic studies could provide crucial information on the aetiology of primary RPL.

The African continent has the highest prevalence of hypertension globally, with South Africa reporting the highest prevalence in Southern Africa. While the influence of genetic variability in the pathogenesis of hypertension is well described internationally, limited reports are available for African populations. This study aimed to assess the association of genetic variants and essential hypertension in a cohort of two ethnic South African population groups. Two hundred and seventy-seven hypertensive and one hundred and seventy-six normotensive individuals were genotyped for 79 variants. Genotyping was performed using the Illumina GoldenGate Assay and allele-specific polymerase chain reaction. The association of variants was assessed using the Fisher Exact test under the additive and allelic genetic models, while multivariate logistic regression was used to predict the development of hypertension. Five variants (CYP11B2 rs179998, AGT rs5051 and rs699, AGTR1 rs5186 and ACE rs4646994) were significantly associated with essential hypertension in the cohort under study. Furthermore, AGTR1 rs5186 and AGT rs699 were identified as risk factors for the development of hypertension in both ethnic groups. In two ethnic South African populations an association was observed between Renin-Angiotensin-Aldosterone System (RAAS) related genes and the development of hypertension.

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

Background : Newly generated cardiomyocytes (NGC) concur to recovery of human myocarditis. However, Methods: We retrospectively assessed NGC in 213 consecutive patients with endomyocardial biopsy denoting acute myocarditis, with normal coronaries and valves. Tissue samples were processed for histology (H&E), immunohistochemistry for the evaluation of inflammatory infiltrates, immunostaining for alpha-sarcomeric-actin, junctional connexin-43, Ki-67, phosphorylated STAT3 (p-STAT3) and Western Blot (WB) for HMGB1. Frozen samples were analyzed with polymerase chain reaction (PCR) for cardiotropic viruses. Controls included 20 normal surgical biopsies. Results: NGCs were defined as small myocytes (diameter < 10 µm) with nuclear positivity to Ki-67 and p-STAT3, positive immunostaining for cytoplasmic α-sarcomeric actin and connexin 43. Their number/mm2 in relation with age and pathway of integration were evaluated. NGCs crossed the membrane and grew integrated within the empty necrotic myocytes. NGC mean diameter was 6.6 ± 3.34 vs 22.5 ± 3.11 µm adult cells; their number, in comparable LVEF, was 86.3 ± 10.3/mm2 in patients between 10 and 40 years; 50.4 ±13.8/mm2 in those between 41 and 60; 15.1 ± 5.7/ mm2 in those between 61 and 80; control NGC mean diameter was 0.2± 0.2/mm2. PCR was positive for viral genomes in 16% of cases; NGCs were not statistically different in viral and non-viral myocarditis. WB analysis revealed a higher expression of HMGB1 in myocarditis compared to myocardial controls. Conclusions: NGCs are constantly recognizable in acute human myocarditis. Their number declines with age. Their integration within necrotic myocytes consents preservation of cardiac structure and function.

Darier disease (DD) is an autosomal dominant disorder due to mutation of ATP2A2 gene causing an isolated skin manifestation based on keratinocyte disconnection and apoptosis. Systemic manifestations of DD have not been demonstrated so far although a high incidence of neuropsychiatric syndromes suggest an involvement of central nervous system. A Novel ATP2A2 Gene Mutation c.118G>A, causing keratinocyte and cardiomyocyte disconnection in Darier disease, is reported. Their common pathologic pathway, still unreported, was documented by both skin and left ventricular endomyocardial biopsy because of cardiac dilatation and dysfunction appeared several decades after skin manifestations.Keratinocyte disconnection was paralleled by cardiomyocyte separation at lateral junction. Cardiomyocyte separation was associated to cell disarray, sarcoplasmic reticulum dilatation and increased myocyte apoptosis. Clinically, hyperkeratotic skin papules were associated to chest pain, severe muscle exhaustion and ventricular arrhythmias that improved following administration of aminophylline, a phosphodiesterase inhibitor enhancing SERCA2 protein phosphorylation.Specific mutations of ATP2A2 gene may cause cardiac involvement in patients with DD. Cardiac pathologic changes are similar to those documented in the skin including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias. Phosphodiesterase inhibitors, enhancing SERCA2 protein phosphorylation may substantially attenuate the symptoms.

Shigella and Salmonella have been implicated in neonatal sepsis, food poisoning, and bacteremia. Their increasing resistance to antibiotics has undermined treatment options, constituting a public health crisis. Also, the scarcity of new antibiotics in the development pipeline compounds multidrug-resistance (MDR). Hence, there is a need to potentiate antibiotics to mitigate resistance. This study leveraged riboflavin to re-sensitize fluoroquinolones and carbapenems against MDR Shigella and Salmonella spp. Disk diffusion, microbroth-dilution, chequerboard, and time-kill assays were used to determine resistance profiles and riboflavin-antibiotic activity. Biofilm-formation and bacterial viability (after riboflavin-antibiotic challenge) was determined with crystal-violet and Macrophage infection assays, respectively. Strains exhibited &gt;80% resistance to fluoroquinolones and carbapenems, with 160–320 µg MIC ranges and 0.5–2 FIC, indicating no synergy. At 40–80 µg riboflavin, there was two-fold reduction in bacterial survival, with meropenem-riboflavin exhibiting significant reduction and FIC of 0.075 indicating high synergistic activity. Biofilm-formation was altered (from strong to weak phenotype) with 40 µg riboflavin-antibiotic treatment. There was a 40–70% reduction in bacterial survival in THP-1 cells treated with meropenem-riboflavin after 3 hours, and complete clearance between 24-48 hpi. Riboflavin potentiated fluoroquinolones and meropenem, leading to modulation of the host immune response for the clearance of the strains.

Obstructive sleep apnea (OSA) is a common sleep disorder that is associated with a wide variety of health conditions, including cardiovascular, cerebrovascular, metabolic, neoplastic, and neurocognitive manifestations. OSA as a chronic condition is mainly characterized by repeated upper airway obstructions during sleep that cause episodes of intermittent hypoxia (IH), resulting in tissue hypoxia-reoxygenation cycles. Decreased arterial oxygen pressure (PaO₂) and hemoglobin saturation (SatO₂) stimulate reflex responses to overcome the obstruction. The prevalence of OSA is significant worldwide, and an underrated problem when focusing on women during pregnancy. The physiological changes associated with pregnancy, especially during its latest stages, are related with a higher prevalence of OSA events in pregnant mothers, and associated with an increased risk of hypertension, pre-eclampsia and diabetes, among other deleterious consequences. Furthermore, OSA during pregnancy can interfere with normal fetal development and is associated with growth retardation, preterm birth, or low term weight. Carotid body overstimulation and hypoxia-reoxygenation episodes contribute to cardiovascular disease and oxidative stress, which can harm both mother and fetus and have long-lasting effects that can reach into adulthood. Because IH is the hallmark of OSA, this review examines the literature available about the impact of gestational intermittent hypoxia (GIH) on the respiratory system at maternal, fetal, and offspring levels. Offering the latest scientific data about OSA during pregnancy, we may help to tackle this condition with lifestyle changes and therapeutic approaches, that could influence the mothers, but also impact adult health problems, mostly unknown, inherited from these hypoxic episodes in the uterus.

This article develops a multi-perspective view on motivations and methods for tobamovirus purification through the ages, and presents a novel efficient, easy-to-use approach that can be well-adapted to different species of native and functionalized virions. We survey the various driving forces prompting researchers to enrich tobamoviruses: from the search for the causative agents of mosaic diseases in plants to their increasing recognition as versatile nanocarriers in biomedical and engineering applications. Best practice and also rarely applied options for the serial processing steps required for successful isolation of tobamoviruses are then reviewed. Adaptations for distinct particle species, pitfalls and 'forgotten' or underrepresented technologies are considered as well. The article is topped off with our own development of a method for virion preparation, rooted in historical protocols. It combines selective re-solubilization of polyethylene glycol (PEG) virion raw precipitates with density step gradient centrifugation in biocompatible iodixanol formulations, yielding ready-to-use particle suspensions. This newly established protocol and some considerations for perhaps worthwile further developments could serve as putative stepping stones towards preparation procedures appropriate for routine practical uses of the multivalent soft-matter nanorods.

A numerical method has been presented to simulate hypervelocity impacts into metal targets. The target is a rectangular prism and positioned at various inclined angles relative to the impact direc-tion, while four different projectile such as square prism, triangular prism, truncated cone and ogival shape are chosen. With this numerical model we aim to evaluate the risk of orbital debris impacting space structures in the design of shield systems for protection against hypervelocity impacts in space. To explore the geometric influences on hypervelocity impact, various projec-tile/target configurations are simulated using the Material Point Method. The Johnson–Cook plas-ticity model with a failure criterion is employed alongside Mie-Grüneisen's equation of state. Our analysis results reveal that the structure of debris cloud formations, scattering behavior of the ejected particle from both front and rear faces and penetration depth measures are significantly influenced by the projectile shape and impact angles.

Ground-based high-power lasers enable to, in principle, deorbit any kind of space debris object from the low Earth orbit (LEO) by remotely inducing laser-ablative momentum. However, the assessment of efficiency and operational safety depends on many factors like atmospheric constraints or the risk of debris disintegration during irradiation. We analyze laser momentum for a great variety of target geometries and sizes, and – for the first time in a large-scale simulation – include thermal constraints for laser irradiation configuration. Using a coherently coupled 100 kJ laser system at 1030 nm wavelength, 5 ns pulse duration in an optimized pointing elevation angle range, the pulse frequency should amount to less than 10 Hz to prevent fragment meltdown. For mechanically intact payloads or rocket bodies, repetition rates should be even lower. Small debris fragments sized between 10 and 40 cm can be de-orbited by around 100 to 400 station passes with head-on irradiation while objects exceeding 2 m typically require far more than 1000 irradiations for deorbit. Hence, laser-based debris removal cannot be considered a prime space sustainability measure tackling the top-risk large debris, yet it can provide for remediation of a multitude of small-sized debris using small networks of globally distributed laser sites.

Based on measured astronomical position data of heavenly objects in the Solar System and other planetary systems, all bodies in space seem to move in some kind of elliptical motion with respect to each other. According to Kepler’s 1^st Law, “orbit of a planet with respect to the Sun is an ellipse, with the Sun at one of the two foci.” Orbit of the Moon with respect to Earth is also distinctly elliptical, but this ellipse has a varying eccentricity as the Moon comes closer to and goes farther away from the Earth in a harmonic style along a full cycle of this ellipse. In this paper, our research results are summarized, where it is first mathematically shown that the “distance between points around any two different circles in three dimensional space” is equivalent to the “distance of points around a vector ellipse to another fixed or moving point, as in two dimensional space”. What is done is equivalent to showing that bodies moving on two different circular orbits in space vector wise behave as if moving on an elliptical path with respect to each other, and virtually seeing each other as positioned at an instantaneously stationary point in space on their relative ecliptic plane, whether they are moving with the same angular velocity, or different but fixed angular velocities, or even with different and changing angular velocities with respect to their own centers of revolution. This mathematical revelation has the potential to lead to far reaching discoveries in physics, enabling more insight into forces of nature, with a formulation of a new fundamental model regarding the motions of bodies in the Universe, including the Sun, Planets, and Satellites in the Solar System and elsewhere, as well as at particle and subatomic level. Based on the demonstrated mathematical analysis, as they exhibit almost fixed elliptic orbits relative to one another over time, the assertion is made that the Sun, the Earth, and the Moon must each be revolving in their individual circular orbits of revolution in space. With this expectation, individual orbital parameters of the Sun, the Earth, and the Moon are calculated based on observed Earth to Sun and Earth to Moon distance data, also using analytical methods developed as part of this research to an approximation. This calculation and analysis process have revealed additional results aligned with observation, and this also supports our assertion that the Sun, the Earth, and the Moon must actually be revolving in individual circular orbits.

Respiratory Syncytial Virus is a common respiratory pathogen known for causing respiratory illnesses, ranging from mild symptoms to severe lower respiratory tract infections in infants and the elderly. This virus is responsible for one-third of pneumonia deaths in the pediatric population, but there are currently only a few effective vaccines and pharmacological treatments. The frac-talkine (CX3CL1) receptor (CX3CR1) is a co-receptor for RSV expressed by airway epithelial cells and a diversity of immune cells. Recent research has highlighted the role of CX3CR1 in the host immune response to RSV infection, and its potential role in the development of an efficient vaccine and novel treatments.

Thalassemia syndromes are common monogenic disorders that represent a significant global health issue. No systematic epidemiological and molecular investigations on thalassemias in Croatian population have been reported to date. This prospective study included 70 children with a presumptive diagnosis of thalassemia, and their 42 first-degree relatives. Molecular characterization was performed using direct sequencing and gap-PCR methods. We identified 46 (30 children and 16 first-degree relatives) β-thalassemia heterozygous carriers from 24 unrelated families, carrying eight different mutations and one hemoglobin variant. Five variants account for approximately 85% of all affected β-globin alleles: Hb Lepore-Boston-Washington (32,6%), HBB: c.93-21G&gt;A (19,6%), HBB:c.315+1G&gt;A (13,1%), HBB:c.92+1G&gt;A (10,9%), and HBB:c.92+6T&gt;C variant (8,7%). A need for more detailed genetic profiling of β-thalassemia carriers is emphasized since genetic modifiers can significantly impact their phenotype. Our study provides important new insights into the relevance of β-thalassemia heterozygosity in the pediatric clinical practice.

Gestational trophoblastic diseases (GTDs) encompass a spectrum of conditions characterized by abnormal trophoblastic cell growth, ranging from benign molar pregnancies to malignant trophoblastic neoplasms. This systematic review explores the molecular underpinnings of GTDs, focusing on genetic and epigenetic factors that influence disease progression and clinical outcomes. Based on 65 studies identified through systematic search and selection criteria, key findings include dysregulations in tumor suppressor genes such as p53, aberrant apoptotic pathways involving BCL-2, and altered expression of growth factor receptors and microRNAs. These molecular alterations not only differentiate molar pregnancies from normal placental development but also contribute to their clinical behavior, from benign moles to potentially malignant forms. The review synthesizes insights from immunohistochemical studies and molecular analyses to provide a comprehensive understanding of GTD pathogenesis and implications for personalized care strategies.

Social biases may concentrate attention of researchers on a small number of well-known molecules/mechanisms leaving others underexplored. In accordance with this view, central to mechanistic toxicology is a narrow range of molecular pathways that are assumed to be involved in significant part of responses to toxicity. It is unclear, however, if there are other molecular mechanisms which play important role in toxicity events but are overlooked by toxicology. To identify overlooked genes sensitive to chemical exposures we used publicly available databases. First, we used data on published chemical-gene interactions for 17,338 genes to estimate their sensitivity to chemical exposures. Next, we extracted data on publication numbers per gene for 19,243 human genes from Find My Understudied Genes database. Threshold were applied to both datasets using our algorithm to identify chemically sensitive and chemically insensitive genes and well-studied and underexplored genes. 1,110 underexplored genes highly sensitive to chemical exposures were used in GSEA and Shiny GO analyses to identify enriched biological categories. Metabolism of fatty acids, amino acids, and glucose were identified as underexplored molecular mechanisms sensitive to chemical exposures. These findings suggest that future effort is needed to uncover the role of xenobiotics in the current epidemics of metabolic diseases.

This study evaluated the presence of Human Papillomavirus (HPV) and Bovine Leukemia Virus (BLV) DNA in breast cancer (BC) samples from women in Northeastern Brazil. We analyzed 186 formalin-fixed, paraffin-embedded tissue block samples using PCR and qPCR to detect HPV and BLV DNA. BLV DNA was not detected in any BC patients. However, HPV DNA was found in 46.2\% of the BC samples: 44.6\% were positive for HPV16, 3.5\% for HPV31, and 2\% were coinfected with HPV16 and HPV31. Additionally, we found an association between HPV-positive BC and Ki-67 expression (P=0.03, OR=1.85; CI=1.02-3.34), as well as between HPV31-positive BC and mitotic index (P=0.047). Although BLV was not detected in BC patients from Northeastern Brazil, the association between HPV and cell proliferation markers warrants further investigation, as HPV may contribute to the aggressiveness of BC in these patients.

Carotid atherosclerotic lesions are a major cause of cerebrovascular disease (CVD). Identification and quantification of carotid plaques are important for categorizing the vulnerability of plaques for rupture and assessing the impact of treatments. The irregularity of plaque surface is associated with previous plaque rupture and plays an important role in the risk of stroke. Thus, the aim of this study is to develop and validate novel vulnerability biomarkers from three-dimensional ultrasound (3DUS) images by analyzing the surface morphological characterization of carotid plaque using fractal geometry features. 3D box-counting and 3D blanket are the two types of 3D fractal dimension that were employed to describe the smoothness of plaques. This fractal dimension analysis tool was used to evaluate the effect of atorvastatin using 3DUS carotid images, which were acquired from 6 patients treated with atorvastatin with 80 mg daily and 5 patients with placebo. The Student's T Test results showed that those two fractal features were effective for detecting the statin-related changes in carotid atherosclerosis with p<0.0068 and p<0.015 respectively, suggesting that 3D fractal dimension measurements can be used effectively to analyze the surface characteristics of carotid plaques, especially for evaluating the impact of the treatment.

Salinity stress emerges as an important menace to global food security, particularly affecting susceptible crops such as common bean plants (Phaseolus vulgaris L.). The disruption of ion balances caused by salt stress withing plants cells reduces water and nutrient absorption, and hampers growth and productivity. Sacchorhiza polyschides, a brown macroalga rich in essential elements, and macrominerals, has drawn attention as a natural biostimulant, being a potential remedy to bolster crop resilience against salt stress. This study delves into the effect of water extracts of Sacchorhiza polyschides (SPE) across varying concentrations (1%, 2%, and 5%) in common bean plants under salt stress (68.4 mM NaCl) conditions. Two different methods of application were used: by spraying the aerial part of the plant or by irrigation together with the watering solution. The effects of both systems of application were studied on the aerial parts of the plants. SPE exhibited significant enhancements in morphological parameters, chlorophyll content, carbon-nitrogen activities, and antioxidant enzymatic system activities, alongside increasing osmolyte accumulation, compared to salt-stressed plants without biostimulation. Moreover, SPE reduced reactive oxygen species (ROS) levels caused by salt stress, mitigating lipid peroxidation. The concentrations of 2% and 5% SPE applied by spraying showed the most significant results in most of the parameters analyzed. By shedding light on the underlying science behind this biostimulant effect, this research underscores the potential of SPE to enhance crop resilience and augment food production in salt-challenged environments.

At present, magnetic selection of genetically modified cells is mainly performed with surface markers naturally expressed by cells such as LNGFR, CD4 and H-2Kk. The disadvantage of such markers is the possibility of their undesired and poorly predictable expression by unmodified cells before or after cell manipulation, which makes it essential to develop new surface markers that would not have such a drawback. Earlier, modified CD52 surface protein variants with embedded HA and FLAG epitope tags (CD52/FLAG and CD52/HA) were developed by the group of Dr. Mazurov for selection of CRISPR-modified cells using FACS. In the current study, we tested whether these markers can be used for magnetic selection of transduced cells. For this purpose, appropriate constructs were created in MigR1-based bicistronic retroviral vectors containing EGFP and DsRedExpress2 as fluorescent reporters. Cytometric analysis of the transduced NIH 3T3 cell populations after magnetic selection evaluated the efficiency of isolation and purity of the obtained populations, as well as the change in the median fluorescence intensity (MFI). The results of this study demonstrate that the surface markers CD52/FLAG and CD52/HA can be effectively used for magnetic cell selection, and their efficiencies are comparable to that of the commonly used LNGFR marker. At the same time, the significant advantage of these markers is the absence of HA and FLAG epitope sequences in cellular proteins, which rules out spurious co-isolation of negative cells.

The occurrence of ovarian dysfunction is often due to the imbalance between the formation of reactive oxygen species (ROS) and the (in)effectiveness of the antioxidative defense mechanisms. Primary sources of ROS are the respiratory electron transfer and the activity of NADPH oxidases (NOX), while Superoxide dismutases (SOD) are the main key reg-ulators that control the levels of ROS and reactive nitrogen species intra- and extracel-lularly. Because of their central role, SODs are the subject of research on human ovarian dysfunction, but the sample acquisition is low. The high degree of cellular and molecular similarity between Drosophila melanogaster ovaries and human ovaries provides this model organism with the best conditions for analyzing the role of ROS during ovarian function. In this study, we clarify the localization of the ROS producing enzyme dNox within ovaries of Drosophila melanogaster and by a tissue specific knockdown, we show that dNox derived ROS are involved in the chorion hardening process. Furthermore, we analyze the dSod3 localization and show that reduced activity of dSod3 impacts egg laying behavior, but not the chorion hardening process.

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

During the last years there has been a high interest in the development of new purely-organic single-component conductors. Very recently, we have reported a new neutral radical conductor based on the perchlorotriphenylmethyl (PTM) radical moiety linked to a monopyrrolo-tetrathiafulvalene (MPTTF) unit by a -conjugated bridge (1). Interestingly, this system behaves as a semiconductor with high conductivity and small energy gap under high pressure. With the aim of developing a new material with improved conducting properties, we have designed and synthesized the radical dyad 2 which was functionalized with an ethylenedithio (EDT) group in order to improve the intermolecular interactions of the TTF subunits. The physical properties of the new radical dyad 2 were studied in detail in solution to further analyze its electronic structure as well as its potential use as radical conductor in the solid state.

The mosquito-borne zoonotic nematode parasites, Dirofilaria immitis and Dirofilaria repens, primarily affect dogs. In recent years, their distribution has expanded due to various factors influencing vector-borne pathogens. This study aimed to investigate the comparative prevalence of infection in dogs and humans within a hyperenzootic region of Europe and to estimate the proportional relationship between infection prevalence in dogs and humans, in the concept of “One Health”. To this end, 604 blood samples from dogs and 625 serum samples from humans living in the Thrace region of northeastern Greece were collected. Dog samples were examined using Kott’s test for Dirofilaria spp. microfilariae and a commercial serological test for D. immitis antigen. Human sera were analysed by western blot for both parasites. The overall prevalence of infection in dogs was 177 (29.3%), with 173 (28.6%) testing positive for D. immitis and 7 (1.3%) for D. repens, including 6 (1%) cases of mixed infection. Specific IgG antibodies were detected in 42 (6.7%) human samples, with 24 (3.8%) positive for D. immitis and 18 (2.9%) for D. repens. The infection proportion in humans was 23.4% of the corresponding canine infection, indicating a high risk of human infection in this hyperenzootic region.

Several studies with kaempferol (KP) and linearolactone (LL) have shown antiparasitic activities. However, the toxicity of treat-ments with both active principles is unknown. Therefore, this study aimed to evaluate the toxicological effects of treatments with KP and LL on the amoebic liver abscess (ALA) model in M. auratus administered intraperitoneally (i.p.). For this, ALA in-duction was carried out in male hamsters with 1.5 x105 E. histolytica trophozoites inoculated in the left hepatic lobe. The lesion evolved for four days and the i.p. of the treatments with KP (5 mg/kg body weight/day) and LL (10 mg/kg body weight/day) was carried out for four consecutive days. For histopathological evaluation, NMR studies, paraclinical analysis, and necropsy were performed. The results revealed that the inhibition of ALA by KP and LL were similar to that metronidazole (MTZ). Biochemical parameters revealed hepatic and renal alterations in all treatment groups, mainly for KP (AST and BUN). The lesions found in the organs were those that are directly linked to the pathology. In conclusion, KP and LL decrease ALA development but have few toxicological effects. Both compounds combined with MTZ could be therapeutic alternatives for amoebiasis caused by E. histolytica.

This study provides a comprehensive analysis of the conformational dynamics of pseudo-endocannabinoid receptors (p-CBRs) CB₁ and CB₂ in response to ligand binding. The ligands studied include N-arachidonoyl dopamine (NADA), Cannabidiol (CBD), known agonists (FUB-MDMB and E3R), and inverse agonists (Taranabant and AM630). Using homology models based on crystal structures (PDB ID: 5U09 for CB₁ and 5ZTY for CB₂), molecular docking, and molecular dynamics (MD) simulations, the research validates the structural integrity and dynamic behaviours of these pseudo-receptors. Induced-fit docking revealed NADA as having the highest binding affinity for both receptors, with docking scores of −13.92 kcal/mol for CB₁ and −13.32 kcal/mol for CB₂, facilitated by key hydrogen bond interactions. MD simulations over 250 ns at ~298 K showed successful equilibration, indicating the most stable interaction for NADA, thereby further validating the models. CB₁ and CB₂ exhibited distinct conformational responses to ligands, with Cα RMSD and Cα RMSF analyses suggesting a more rigid binding pocket for CB₁ and a flexible binding pocket for CB₂. These findings highlight the significance of receptor behaviour and dynamics in the development of cannabinoid-based therapeutics, supporting the potential of CBD and NADA as modulators for CB₁ and CB₂, respectively.

Plant transcriptomes are an extremely dynamic entities shaped spatially and temporally by many intracellular and environmental cues. In this review, we first summarize the complexity and diversity of plant genomes and transcriptomes as a start point for the multitude of transcriptomic responses. Numerous alterations within various tissue and organ-specific transcriptomes as well as the most relevant transcriptomic responses associated with plant acclimation to selected abiotic and biotic stress conditions, from the current studies employing high-throughput transcriptomic analysis are widely discussed. Understanding changes within plant transcriptomes, revealed by in silico functional analysis, allows for the characterization of stress-affected genes and stress acclimatory mechanisms, as well as allows to perform plant metabolic engineering. The latter allow cultivars to produce more secondary metabolites in the future, which are often desirable substances in the biomedical industry. Accordingly, in this review special attention was also paid to characterize the potential of transcriptomic analyses of medicinal species, particularly to search for new cultivars. Extensive characterization of transcriptomic responses in stress would also result in the development of new cultivars that display physiological and molecular mechanisms that allow them to cope with adverse environmental conditions more adequately.

Space-based gravitational wave detection is extremely sensitive to disturbances. The Keplerian configuration cannot accurately reflect the variations in spacecraft configuration. Planetary gravitational disturbances are one of the main sources. Numerical simulation is an effective method to investigate the impact of perturbation on spacecraft orbits. This study shows that, in the context of the Taiji project, Earth’s gravity is an essential factor in the change in heliocentric formation configuration, contributing to the relative acceleration between spacecrafts in the order of O(10−6)m·s−2. Considering 00:00:00 on October 27, 2032 as the initial orbiting moment, under the influence of Earth’s gravitational perturbation, the maximum relative change in armlengths and variation rates of armlengths for Taiji is 1.6×105km, 32m·s−1 respectively, compared with the unperturbed Keplerian orbit. Additionally, by considering the gravitational perturbations of Venus and Jupiter, the armlength and relative velocity for Taiji are reduced by 16.01% and 17.45%, respectively, compared with when only considering that of Earth. The maximum amplitude of the formation motion indicator changes with the orbit entry time. Results show that the relative velocity increase between the spacecrafts is minimal when the initial orbital moment occurs in July. Moreover, the numerical simulation results are inconsistent when using different ephemerises. The differences between ephemeris DE440 and DE430 are smaller than those between DE440 and DE421.

Recently it was found from Cassini data that the mean recession speed of Titan from Saturn is v = 11.3 ± 2.0 cm/yr which corresponds to a tidal quality factor of Saturn Q ≈ 100 while the standard estimate yields Q ≥ 6 · 10⁴ . It was assumed that such a large speed v is due to a resonance locking mechanism of five inner mid-sized moons of Saturn. In this paper, we show that an essential part of v may come from a local Hubble expansion, where the Hubble-Lemaˆıtre constant H0 recalculated to the Saturn-Titan distance D is 8.15 cm/(yrD). Our hypothesis is based on many other observations showing a slight expansion of the Solar system and also of our Galaxy at a rate comparable with H0. We demonstrate that the large disproportion in estimating the Q factor can be just caused by the local expansion effect. [Accepted for publication in "Gravitation and Cosmology". The paper is to appear in Vol. 28, Issue 2 (2022) of the journal Gravitation and Cosmology.]

The archival Rossi X-ray Timing Explorer (RXTE) Proportional Counter Array (PCA) observations of HZ Her/Her X-1 are analyzed here. The time periods for Anomalous Low States are refined. The 35-day X-ray lightcurve of Her X-1 is produced using 35-day phases determined with RXTE All-Sky Monitor (ASM) and Swift Burst Altert Telescope (BAT) data, with adjustments based on the RXTE/PCA data. The result is the highest sensitivity 35-day lightcurve of Her X-1. The RXTE/PCA data were separated into 8 differents states of the 35-day cycle: Main High (MH) turn-on, MH, MH decline, Low State (LS) 1, Short High (SH) turn-on, SH, SH decline, and LS2. Orbital lightcurves were created for each state, and the different states are compared. Eclipse data was extracted for each state to determine the changes of eclipse shape with 35-day phase. A scattering corona model was fit to the eclipses for the different 35-day states: this shows that the corona is present at all 35-day phases with similar intensity. We carried out a search for previously-reported dips with no absorption, but did not find any.

We examine here characteristics of electromagnetic waves that propagate through an unbounded space filled with a homogeneous isotropic chiral medium. Resulting characters are compared to those of the electromagnetic waves propagating through an achiral free space. To this goal, we form energy conservation laws for key bilinear parameters in a chiral case. Due to a nonzero medium chirality, conservation laws turn out to contain extra terms that are linked to the spin-orbit coupling, which is absent for an achiral case. As an example, we take a plane wave for achiral case to evaluate those bilinear parameters. Resultantly, the conservation laws for a chiral case are found to reveal inconsistencies among several bilinear parameters that constitute the con-servation laws , thereby prompting us to establish partial remedies for formulating proper wave-propagation problems.

ATTO 565, a Rhodamine-type dye, has garnered significant attention due to its remarkable optical properties, such as a high fluorescence quantum yield, it is a relatively stable structure, and has low biotoxicity. ATTO 565 has found extensive applications in combination with microscopy technology. In this review, the chemical and optical properties of ATTO 565 are introduced, along with the principles behind them. Then, the functionality of ATTO 565 in confocal microscopy, stimulated emission depletion (STED) microscopy, single-molecule tracking (SMT) techniques, and fluorescence correlation spectroscopy (FCS) is discussed. These studies demonstrate that ATTO 565 plays a crucial role in areas such as biological imaging and single-molecule localization, thus warranting further in-depth investigation. Finally, we present some prospects and concepts for the future applications of ATTO 565 in the fields of biocompatibility and metal ion detection.

Introduction: Acute rhinosinusitis (ASR) is a common condition in children, which can be burdened by orbital complication (OC) or intracranial complications (IC) that are rare but have potential for serious sequelae; therefore, it needs prompt diagnosis and treatment. The first line of treatment is intravenous antibiotic therapy. In case of failure of clinical improvement after 48 hours, hypovisus or negative prognostic factors (intracranial abscess, large orbital abscess or in intraconic or lateral localization, cavernous sinus thrombosis), surgical treatment is indicated. Objective: the purpose of this work is to describe the clinical profile, treatments and outcome of a series of patients undergoing surgical treatment for complications of ARS at a tertiary referral center. Material and methods: a retrospective analysis of clinical databases was conducted to identify all patients under 16 years of age who underwent surgical treatment for complications of ARS during the 20-year period 2000-2023. Demographic characteristics, clinical data, radiological investigations, surgical treatment, and follow-up performed were reported for each case. Results: 29 patients (20 males and 9 females), mean age 13 years, were included, 69% of whom had OC, 21% had IC, and 7% had both OC and IC. The main symptoms of OC were orbital edema, hypovisus and diplopia; while the main symptoms of IC were headache, fever, comitial seizures and focal neurological symptoms. Mean hospitalization time was 11.75 (± 9.2) days. The mean length of hospital stay (LOS) was 9.1 days for OC, 21 days for IC and 14 days for OC + IC. A single patient manifested a Potts Puffy Tumor, with a LOS of 10 days. Basal CT and gadolinium-enhanced MRI were performed in all cases. Intravenous antibiotic therapy and surgical clearance was undertaken. The majority of patients (76%) underwent endoscopic endonasal approach, 24% external transorbital approach, 1,16% orbital decompression and 0,58% superior eyelid approach. Any complications related to the surgical procedures were found. All patients with hypovisus and diplopia had complete recovery. During follow-up 7 patients (24%) had sinus recurrences, at a time range of 1 to 4 years after surgery. Conclusion: our experience, in agreement with the data reported in the literature, confirmed the importance of appropriate diagnostic-therapeutic management to avoid potentially serious sequelae of complicated ARS.

Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to examine whether treatment with the selective α7nAChR agonist PHA 568487 can dampen inflammation and thereby improve cardiac function after myocardial infarction in mice. The possible anti-inflammatory properties of α7nAChR agonist PHA 568487 were tested in vivo using the air pouch model and in a permanent occlusion model of acute myocardial infarction in mice. Hematology parameters and cytokine levels were determined. Infarct size and cardiac function were assessed via echocardiography 24 h and one week after the infarction. Treatment with α7nAChR agonist PHA 568487 decreased 12 (CCL27, CXCL5, IL6, CXCL10, CXCL11, CXCL1, CCL2, MIP1a, MIP2, CXCL16, CXCL12 and CCL25) out of 33 cytokines in the air pouch model of acute inflammation. However, α7nAChR agonist PHA 568487 did not alter infarct size, ejection fraction, cardiac output or stroke volume at 24 h nor at 7 days after the myocardial infarction compared with control mice. In conclusion, despite promising immunomodulatory effects in the acute inflammatory air pouch model, α7nAChR agonist PHA 568487 did not affect infarct size or cardiac function after a permanent occlusion model of acute myocardial infarction in mice. Consequently, this study does not strengthen the hypothesis that stimulation of the α7nAChR is a future treatment strategy for acute myocardial infarction when reperfusion is lacking. However, whether other agonists of the α7nAChR can have different effects remains to be investigated.

Evaluation of drug permeability using cell monolayers is an important in vitro assay in the process of drug development, to identify compounds with favourable pharmacokinetics that may proceed to in vivo studies. When allowed to differentiate on permeable filters for at least 21 days, monolayers of Caco-2 cells develop morphological and functional properties similar to those of the intestinal epithelium. Permeability through Caco-2 monolayers is thus particularly relevant to assess drug absorption after oral administration. The major drawback of this assay is its very low throughput, with the cell monolayers being used in a single permeability assay. We have previously proposed a protocol to allow the re-use of the Caco-2 monolayer on additional permeability assays during the stable period and shown that cell monolayer integrity is maintained. In this work we evaluate the effect of re-use on the permeability of several reference compounds that permeate through passive pathways and show that the cell monolayers can be re-used twice in additional permeability assays. Preliminary results were also obtained regarding active transport pathways, and a new methodology is proposed to quantify the contribution from passive and active transport. This is a major step towards the full validation of the re-use methodology proposed, which at least triplicates the throughput of this important in vitro assay.

We review recent progress in high-speed orbital angular momentum (OAM) multiplexed free-space optical communication systems. The outdoor atmospheric turbulence is emulated by an indoor turbulence emulator, which is based on split-step beam propagation method. Adaptive optics, channel coding, Huffman coding combined with LDPC coding, and spatial offset are used for turbulence mitigation; while OAM multiplexing and wavelength-division multiplexing (WDM) are applied to boost aggregate capacity.

Insulin resistance is a condition characterized by a reduced biological response to insulin. It is one of the most common metabolic diseases of modern civilization. Numerous naturally occurring substances have shown to have a positive effect in restoring the proper sensitivity to insulin. Mature 3T3-L1 adipocytes with artificially induced insulin resistance by palmitic acid (16:0) were used for the study. Cinnamic acid and 1,2-dicinnamoyl-sn-glycero-3-phosphocholin (1,2-diCA-PC) were tested at three concentrations: 25 μM, 50 μM, and 125 μM. The number of mitochondria and the expression of genes encoded by mtDNA were elucidated in control and experimental cells. In experimental cells treated with 1,2-diCA-PC, we displayed increased insulin-stimulated glucose uptake in a dose-dependent manner, accompanied by an increase in mtDNA copy number. Moreover, in experimental cells treated with 1,2-diCA-PC at the concentration of 125 μM, we observed a significant increase in the expression level of all analyzed genes encoded by mtDNA compared to control cells. Our study showed a relationship between improved cellular sensitivity to insulin by 1,2-diCA-PC and an increase in the number of mitochondria and expression levels of genes encoded by mtDNA. Summarizing, the results suggest a therapeutic potential of cinnamic acid derivative 1,2-diCA-PC in enhancing the insulin sensitivity of adipocytes.

Lynch syndrome (LS) is an inherited cancer predisposition disorder associated with an elevated risk of various epithelial cancers. Despite sharing the same pathogenic variant (PV), Lynch syn-drome variant heterozygotes (LSVH) exhibit considerable phenotypic variability in cancer risk. The role of Human Leukocyte Antigen (HLA) in modifying cancer risk prompted our investiga-tion into whether HLA variations act as genetic modifiers influencing age at cancer diagnosis in a unique cohort of LSVH carrying a PV in the hMLH1 gene in South Africa. Within our extensive LS cohort, 426 individuals carried the same hMLH1 PV (MLH1:c.1528C>T). We selected 100 indi-viduals with the greatest diversity in age at cancer diagnosis and the oldest unaffected individu-als for high-throughput HLA genotyping of 12 HLA class I and II loci using next-generation se-quencing. Statistical analyses employed Kaplan-Meier survival analyses with Logrank tests and Cox proportional hazards. Following the robust application of statistical correction methods, six HLA alleles (3.2%) were significantly associated with a young age at cancer diagnosis. Notably, HLA-B*15:17 and HLA-DPB1*55:01 correlated significantly with very young colorectal cancer (CRC) diagnosis (Mean age: 21y [17-25]; HR = 71.59; q