Role Of Signaling Research Articles

ENZYMES AND METABOLITES OF ENDOGENOUS CARBON MONOXIDE IN THE FETOPLACENTAL SYSTEM DURING PHYSIOLOGICAL GESTATION AND PLACENTAL DYSFUNCTION

Introduction. Prenatal ontogenesis largely depends on the functional and metabolic viability of the placenta and the entire fetoplacental complex. That is why the dysfunction of the placenta due to the changes in cellular regulation processes will lead to pregnancy complications and impaired fetal develop-ment. An important component of the system of intra- and intercellular regulators is the gas transmitter – carbon monoxide. Its role in cellular signaling and communication reactions, and at the same time, insufficient data of its metabolism, justifies the need to conduct research on this gas transmitter during complicated pregnancy. The aim of the work. To study the features of the metabolism of the active cellular mediator - the gas transmitter carbon monoxide in different objects of the fetoplacental system during physiological pregnancy and placental dysfunction. Material and methods. The research materials included placental tissue, amnion and amniotic fluid. The work uses spectrophotometric methods, enzyme immunoassay, and ion exchange chromatography. Results. Multidirectional changes in the activity of the studied enzymes (heme oxygenase and histidine decarboxylase), the content of the substrate of His-tidine reaction and the product of reaction of Histamine are established in case of placental disfunction. There is a certain correlation between the discov-ered studied components. Indicators of carbon monoxide metabolism can be markers for predicting postnatal damage – cerebral disorders in newborns. Conclusions. The identified injuries are obviously important links in the chain of disorders accompanied by the development of placental dysfunction.

Dynamics of Hydrogen Peroxide Accumulation During Tip Growth of Infection Thread in Nodules and Cell Differentiation in Pea (Pisum sativum L.) Symbiotic Nodules.

Hydrogen peroxide (H2O2) in plants is produced in relatively large amounts and plays a universal role in plant defense and physiological responses, including the regulation of growth and development. In the Rhizobium-legume symbiosis, hydrogen peroxide plays an important signaling role throughout the development of this interaction. In the functioning nodule, H2O2 has been shown to be involved in bacterial differentiation into the symbiotic form and in nodule senescence. In this study, the pattern of H2O2 accumulation in pea (Pisum sativum L.) wild-type and mutant nodules blocked at different stages of the infection process was analyzed using a cytochemical reaction with cerium chloride. The observed dynamics of H2O2 deposition in the infection thread walls indicated that the distribution of H2O2 was apparently related to the stiffness of the infection thread wall. The dynamics of H2O2 accumulation was traced, and its patterns in different nodule zones were determined in order to investigate the relationship of H2O2 localization and distribution with the stages of symbiotic nodule development in P. sativum. The patterns of H2O2 localization in different zones of the indeterminate nodule have been partially confirmed by comparative analysis on mutant genotypes.

Unveiling the critical role of androgen receptor signaling in avian sexual development

Gonadal hormone activities mediated by androgen and estrogen receptors, along with cell-autonomous mechanisms arising from the absence of sex-chromosome dosage compensation, are key factors in avian sexual development. In this study, we generate androgen receptor (AR) knockout chickens (AR−/−) to explore the role of androgen signaling in avian sexual development. Despite developing sex-typical gonads and gonadal hormone production, AR−/− males and females are infertile. While few somatic sex-specific traits persist (body size, spurs, and tail feathers), crucial sexual attributes such as comb, wattles and sexual behaviors remain underdeveloped in both sexes. Testosterone treatment of young AR−/− males fails to induce crow behavior, comb development, or regression of the bursa of Fabricius, which are testosterone-dependent phenotypes. These findings highlight the significance of androgen receptor mechanisms in fertility and sex-specific traits in chickens, challenging the concept of a default sex in birds and emphasizing the dominance of androgen signaling in avian sexual development.

An increase in reactive oxygen species underlies neonatal cerebellum repair.

The neonatal mouse cerebellum shows remarkable regenerative potential upon injury at birth, wherein a subset of Nestin-expressing progenitors (NEPs) undergoes adaptive reprogramming to replenish granule cell progenitors that die. Here, we investigate how the microenvironment of the injured cerebellum changes upon injury and contributes to the regenerative potential of normally gliogenic-NEPs and their adaptive reprogramming. Single cell transcriptomic and bulk chromatin accessibility analyses of the NEPs from injured neonatal cerebella compared to controls show a temporary increase in cellular processes involved in responding to reactive oxygen species (ROS), a known damage-associated molecular pattern. Analysis of ROS levels in cerebellar tissue confirm a transient increased one day after injury at postanal day 1, overlapping with the peak cell death in the cerebellum. In a transgenic mouse line that ubiquitously overexpresses human mitochondrial catalase (mCAT), ROS is reduced 1 day after injury to the granule cell progenitors, and we demonstrate that several steps in the regenerative process of NEPs are curtailed leading to reduced cerebellar growth. We also provide evidence that microglia are involved in one step of adaptive reprogramming by regulating NEP replenishment of the granule cell precursors. Collectively, our results highlight that changes in the tissue microenvironment regulate multiple steps in adaptative reprogramming of NEPs upon death of cerebellar granule cell progenitors at birth, highlighting the instructive roles of microenvironmental signals during regeneration of the neonatal brain.

Hippo pathway in cancer cells induces NCAM1+αSMA+ fibroblasts to modulate tumor microenvironment

Cancer cells adeptly manipulate the tumor microenvironment (TME) to evade host antitumor immunity. However, the role of cancer cell-intrinsic signaling in shaping the immunosuppressive TME remains unclear. Here, we found that the Hippo pathway in cancer cells orchestrates the TME by influencing the composition of cancer-associated fibroblasts (CAFs). In a 4T1 mouse breast cancer model, Hippo pathway kinases, large tumor suppressor 1 and 2 (LATS1/2), promoted the formation of neural cell adhesion molecule 1 (NCAM1)+alpha-smooth muscle actin (αSMA)+ CAFs expressing the transforming growth factor-β, which is associated with T cell inactivation and dysfunction. Depletion of LATS1/2 in cancer cells resulted in a less immunosuppressive TME, indicated by the reduced proportions of NCAM1+αSMA+ CAFs and dysfunctional T cells. Notably, similar Hippo pathway-induced NCAM1+αSMA+ CAFs were observed in human breast cancer, highlighting the potential of TME-manipulating strategies to reduce immunosuppression in cancer immunotherapy.

CD30 influences germinal center B-cell dynamics and the expansion of IgG1-switched B cells.

Initially, identified as a Hodgkin lymphoma marker, CD30 was subsequently detected on a subset of human B cells within and around germinal centers (GCs). While CD30 expression is typically restricted to a few B cells, expansion of CD30-expressing B cells occurs in certain immune disorders and during viral infections. The role of CD30 in B cells remains largely unclear. To address this gap in knowledge, we established a conditional CD30-knockinmouse strain. In these mice, B-cell-specific CD30 expression led to a normal B-cell phenotype in young mice, but most aged mice exhibited significant expansion of B cells, T cells and myeloid cells and increased percentages of GC B cells and IgG1-switched cells. This may be driven by the expansion of CD4+ senescence-associated T cells and T follicular helper cells, which partially express CD30-L (CD153) and may stimulate CD30-expressing B cells. Inducing CD30 expression in antigen-activated B cells accelerates the GC reaction and augments plasma cell differentiation, possibly through the posttranscriptional upregulation of CXCR4. Furthermore, CD30 expression in GC B cells promoted the expansion of IgG1-switched cells, which displayed either a GC or memory-like B-cell phenotype, with abnormally high IgG1 levels compared with those in controls. These findings shed light on the role of CD30 signaling in GC B cells and suggest that elevated CD30+ B-cell numbers lead to pathological lymphocyte activation and proliferation.

T-2 Toxin Induces Immunosenescence in RAW264.7 Macrophages by Activating the HIF-1α/cGAS-STING Pathway.

T-2 toxin induces cell immunotoxicity by triggering an intracellular hypoxic microenvironment and activates hypoxia-inducible factor-1α (HIF-1α), which exerts cellular protective effects. Mycotoxins can also induce senescence. The aging of immune function, termed "immunosenescence," is an important factor in the decline of biological immunity and accelerates senescence. However, the mechanism underlying T-2 toxin-induced immunosenescence remains unclear. This study aimed to elucidate the roles of HIF-1α and cGAS-STING signaling in this process and uncover the mechanisms through which T-2 toxin impacts cytoskeletal integrity and cellular senescence using a RAW264.7 macrophage model. The cells were treated with T-2 toxin (14 nM) for 1-24 h. We revealed that T-2 toxin-induced immunosenescence in RAW264.7 cells by activating the HIF-1α/cGAS-STING axis. The cGAS-STING pathway promotes cell senescence and apoptosis; however, we revealed that HIF-1α negatively regulated this pathway, thereby inhibiting cellular senescence and apoptosis. However, PARP 1 cleavage by caspase 3/9 inhibited DNA repair and accelerated the transition from senescence to apoptosis. At the late stages of T-2 toxin exposure (12 h), HIF-1α accelerated cellular senescence by disrupting the dynamic balance of cytoskeletal α-tubulin and F-actin and destabilizing the cytoskeletal structure. Our research demonstrates that T-2 toxin induces immunosenescence in RAW264.7 cells by activating the cGAS-STING pathway, with HIF-1α signaling serving as a negative regulator. This study provides a deeper understanding of T-2 toxin-induced immunosenescence.

Brain-Region-Specific Differences in Protein Citrullination/Deimination in a Pre-Motor Parkinson's Disease Rat Model.

The detection of early molecular mechanisms and potential biomarkers in Parkinson's disease (PD) remains a challenge. Recent research has pointed to novel roles for post-translational citrullination/deimination caused by peptidylarginine deiminases (PADs), a family of calcium-activated enzymes, in the early stages of the disease. The current study assessed brain-region-specific citrullinated protein targets and their associated protein-protein interaction networks alongside PAD isozymes in the 6-hydroxydopamine (6-OHDA) induced rat model of pre-motor PD. Six brain regions (cortex, hippocampus, striatum, midbrain, cerebellum and olfactory bulb) were compared between controls/shams and the pre-motor PD model. For all brain regions, there was a significant difference in citrullinated protein IDs between the PD model and the controls. Citrullinated protein hits were most abundant in cortex and hippocampus, followed by cerebellum, midbrain, olfactory bulb and striatum. Citrullinome-associated pathway enrichment analysis showed correspondingly considerable differences between the six brain regions; some were overlapping for controls and PD, some were identified for the PD model only, and some were identified in control brains only. The KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways identified in PD brains only were associated with neurological, metabolic, immune and hormonal functions and included the following: "Axon guidance"; "Spinocerebellar ataxia"; "Hippo signalling pathway"; "NOD-like receptor signalling pathway"; "Phosphatidylinositol signalling system"; "Rap1 signalling pathway"; "Platelet activation"; "Yersinia infection"; "Fc gamma R-mediated phagocytosis"; "Human cytomegalovirus infection"; "Inositol phosphate metabolism"; "Thyroid hormone signalling pathway"; "Progesterone-mediated oocyte maturation"; "Oocyte meiosis"; and "Choline metabolism in cancer". Some brain-region-specific differences were furthermore observed for the five PAD isozymes (PADs 1, 2, 3, 4 and 6), with most changes in PAD 2, 3 and 4 when comparing control and PD brain regions. Our findings indicate that PAD-mediated protein citrullination plays roles in metabolic, immune, cell signalling and neurodegenerative disease-related pathways across brain regions in early pre-motor stages of PD, highlighting PADs as targets for future therapeutic avenues.

Unveiling the impact of antibiotic stress on biofilm formation and expression of toxin-antitoxin system genes in Clostridium difficile clinical isolates.

The study investigates how antibiotics affect biofilm formation and toxin gene expression in Clostridium difficile, which is essential for its survival and persistence. The study confirmed 25 strains of C. difficile and assessed biofilm formation. The MIC of metronidazole and vancomycin was determined through agar dilution, and the impact of sub-MIC levels on biofilm formation and eradication was investigated. Additionally, Real-time PCR was used to analyze the expression levels of target genes related to antibiotic treatment. We found that certain genes, such as the ImmA/IrrE system, were associated with increased biofilm formation in isolates. Sub-MIC antibiotic levels influenced gene expression related to biofilm activities, particularly emphasizing the importance of toxin-antitoxin systems. The results suggest that antibiotics at sub-MIC levels may play a signaling role in promoting biofilm formation and gene expression in C. difficile. Our study suggests that toxin and antitoxin genes may impact C. difficile biofilm formation, while antibiotics could signal biofilm strengthening and gene expression increase.

Mucosal sugars delineate pyrazine vs pyrazinone autoinducer signaling in Klebsiella oxytoca

Virulent Klebsiella oxytoca strains are associated with gut and lung pathologies, yet our understanding of the molecular signals governing pathogenesis remains limited. Here, we characterized a family of K. oxytoca pyrazine and pyrazinone autoinducers and explored their roles in microbial and host signaling. We identified the human mucin capping sugar Neu5Ac as a selective elicitor of leupeptin, a protease inhibitor prevalent in clinical lung isolates of K. oxytoca, and leupeptin-derived pyrazinone biosynthesis. Additionally, we uncovered a separate pyrazine pathway, regulated by general carbohydrate metabolism, derived from a broadly conserved PLP-dependent enzyme. While both pyrazine and pyrazinone signaling induce iron acquisition responses, including enterobactin biosynthesis, pyrazinone signaling enhances yersiniabactin virulence factor production and selectively activates the proinflammatory human histamine receptor H4 (HRH4). Our findings suggest that the availability of specific carbohydrates delineates distinct autoinducer pathways in K. oxytoca that may have differential effects on bacterial virulence and host immune responses.

Thermal proteome profiling reveals fructose-1,6-bisphosphate as a phosphate donor to activate phosphoglycerate mutase 1

Deep understanding of sugar metabolite-protein interactions should provide implications on sugar metabolic reprogramming in human physiopathology. Although tremendous efforts have been made for determining individual event, global profiling of such interactome remains challenging. Here we describe thermal proteome profiling of glycolytic metabolite fructose-1,6-bisphosphate (FBP)-interacting proteins. Our results reveal a chemical signaling role of FBP which acts as a phosphate donor to activate phosphoglycerate mutase 1 (PGAM1) and contribute an intrapathway feedback for glycolysis and cell proliferation. At molecular level, FBP donates either C1-O-phosphate or C6-O-phosphate to the catalytic histidine of PGAM1 to form 3-phosphate histidine (3-pHis) modification. Importantly, structure-activity relationship studies facilitate the discovery of PGAM1 orthostatic inhibitors which can potentially restrain cancer cell proliferation. Collectively we have profiled a spectrum of FBP interactome, and discovered a unique covalent signaling function of FBP that supports Warburg effect via histidine phosphorylation which inspires the development of pharmacological tools targeting sugar metabolism.

TGF-β signaling in the cranial neural crest affects late-stage mandibular bone resorption and length.

Malocclusions are common craniofacial malformations that cause quality of life and health problems if left untreated. Unfortunately, the current treatment for severe skeletal malocclusion is invasive surgery. Developing improved therapeutic options requires a deeper understanding of the cellular mechanisms responsible for determining jaw bone length. We have recently shown that neural crest mesenchyme (NCM) can alter jaw length by controlling the recruitment and function of mesoderm-derived osteoclasts. Transforming growth factor beta (TGF-β) signaling is critical to craniofacial development by directing bone resorption and formation, and heterozygous mutations in the TGF-β type I receptor (TGFBR1) are associated with micrognathia in humans. To identify the role of TGF-β signaling in NCM in controlling osteoclasts during mandibular development, the mandibles of mouse embryos deficient in the gene encoding Tgfbr1, specifically in NCM, were analyzed. Our laboratory and others have demonstrated that Tgfbr1 fl/fl ;Wnt1-Cre mice display significantly shorter mandibles with no condylar, coronoid, or angular processes. We hypothesize that TGF-β signaling in NCM can also direct late bone remodeling and further regulate late embryonic jaw bone length. Interestingly, analysis of mandibular bone based on micro-computed tomography and Masson's trichrome revealed no significant difference in bone quality between the Tgfbr1 fl/fl ;Wnt1-Cre mice and controls, as measured by the bone perimeter/bone area, trabecular rod-like diameter, number and separation, and gene expression of collagen type 1 alpha 1 (Col1α1) and matrix metalloproteinase 13 (Mmp13). Although there was not a difference in localization of bone resorption within the mandible indicated by tartrate-resistant acid phosphatase (TRAP) staining, Tgfbr1 fl/fl ;Wnt1-Cre mice had approximately three-fold less osteoclast number and perimeter than controls. Gene expression of receptor activator of nuclear factor kappa-β (Rank) and Mmp9, markers of osteoclasts and their activity, also showed a three-fold decrease in Tgfbr1 fl/fl ;Wnt1-Cre mandibles. Evaluation of osteoblast-to-osteoclast signaling revealed no significant difference between Tgfbr1 fl/fl ;Wnt1-Cre mandibles and controls, leaving the specific mechanism unresolved. Finally, pharmacological inhibition of Tgfbr1 signaling during the initiation of bone mineralization and resorption significantly shortened jaw length in embryos. We conclude that TGF-β signaling in NCM decreases mesoderm-derived osteoclast number, that TGF-β signaling in NCM impacts jaw length late in development, and that this osteoblast-to-osteoclast communication may be occurring through an undescribed mechanism.

The molecular anatomy of cashmere goat hair follicle during cytodifferentiation stage

BackgroundCashmere, named as “soft gold”, derives from the secondary hair follicles (SHFs) of cashmere goat which is vital to Northwest China’s economy. The cytodifferentiation stage (E120), mirroring the complete hair follicle (HF) structure of adult goats and marking a critical phase in SHF development. Therefore, this study aims to enhance the understanding of SHF development and its impact on fiber quality, informing breeding strategies.ResultsFrom the scRNA-seq data analysis, the intricate processes and transcriptional dynamics of inner layer cell differentiation of HFs were unveiled in this study. we identified nine cell populations during cytodifferentiation and key structures such as the hair shaft and inner root sheath. And we discovered three main inner layer lineages and seven subpopulations, clarifying their roles in specialization and signaling. Pseudotime mapping analysis showed cell evolution from early stage to mature stages marked by unique gene expressions, and the intermediate stage on the differentiation of each lineage was revealed. The identification and spatial localization of specific transcription factors, such as GATA3, LEF1 and PRDM1, as well as keratin genes highlight regulatory pathways involved in HF development, which was further validated by immunofluorescence. These findings suggested the potential strategies to improve fiber quality, and the discovery of diverse cell types and their developmental molecular mechanisms, particularly in this species-specific context, offered a nuanced view of the regulatory mechanisms driving HF development in cashmere goats.ConclusionOverall, these findings provide a systematic molecular atlas of skin, defining three major branches and cell states of inner layer cells of HF, and determining how the branch-specific transcription factors, keratins, and signals coordinate HF morphogenesis during cytodifferentiation stage. This research not only advances skin tissue research in goats but also holds broader implications for the understanding of HF regeneration and development across various species.

FPR1 signaling aberrantly regulates S100A8/A9 production by CD14+FCN1hi macrophages and aggravates pulmonary pathology in severe COVID-19

Excessive alarmins S100A8/A9 escalate the inflammation and even exacerbate immune-driven thrombosis and multi-organ damage. However, the regulatory mechanisms of S100A8/A9 expression in infectious diseases remain unclear. In this study, high-dimensional transcriptomic data analyses revealed a high proportion of CD14+FCN1hi macrophages within the pulmonary niche post-severe SARS-CoV-2 infection. By constructing the S100-coexpression gene list and supervised module scoring, we found that CD14+FCN1hi macrophages presented the highest scores of alarmin S100, and possibly served as the trigger and amplifier of inflammation in severe COVID-19. These CD14+FCN1hi cells lacked the positive regulatory activity of transcription factor PPARγ, and lost their differentiation ability towards mature macrophages. Ex vivo experiments further validated that the epithelial cells with high ORF-3a expression promoted the expression and secretion of S100A8/A9 through ANXA1/SAA1-FPR1 signaling. S100A8/A9 heterodimers, as well as the co-localization of S100A8/A9 with microtubules, were both diminished by the FPR1 inhibitor. Phospho-kinase protein array indicated that STAT3 promoted transcription, and PLC-γ and ERK1/2 pathways were involved in the hetero-dimerization and unconventional secretion of S100A8/A9. Our study highlights the pivotal role of FPR1 signaling in the excessive production of S100A8/A9 and provides a promising target for the prevention and control of severe COVID-19 and post-acute COVID-19 sequelae.

Quantifying Gq Signaling Using the IP1 Homogenous Time-Resolved Fluorescence (HTRF) Assay.

G protein-coupled receptors (GPCRs) play pivotal roles in cellular signaling and can regulate several cellular functions such as proliferation, secretion, protein expression, and cellular metabolism. Coupling of GPCRs to members of the Gq/11 protein family results in activation of inositol trisphosphate (IP3) and accumulation of calcium intracellularly. This protocol chapter outlines a step-by-step guide for utilizing the inositol phosphate-1 (IP1) accumulation assay, a time-resolved fluorescence resonance energy transfer (TR-FRET) method, to investigate Gq-IP3 signaling. The assay serves as a valuable tool for those conducting pharmacological investigations and compound screening targeting this critical cellular pathway. This protocol chapter covers experimental setup, sample preparation, and data analysis, providing researchers with an in-depth guide to explore the pharmacology of Gq-coupled receptors.

Pterin-Based Red Coloration Predicts the Outcome of Male-Male Competition in Guinan Toad-Headed Lizard.

Animal coloration offers a unique opportunity to explore the evolutionary mechanisms underlying phenotypic diversity. Conspicuous coloration caused by pigments plays a crucial role in social signaling across multiple species by conveying information about individual quality, social ranks, or reproductive condition. Nevertheless, most previous studies have focused predominantly on colors produced by the exogenous pigments-carotenoids. Pterins are another prevalent group of conspicuous pigments, which can be produced endogenously and have received comparatively little attention. Whether pterin-based colors represent reliable signals remains elusive. The remarkable red ventrolateral coloration exhibited by males of the Guinan toad-headed lizard (Phrynocephalus guinanensis) in the Mugetan Desert presents an ideal model for investigating pterin-based coloration. Through electron microscopy and metabolomic identification, we discovered three types of pterin pigments within xanthophores. Integrating a series of morphological measurements and behavioral experiments, we found that this red coloration was not correlated with body size, bite force, and testosterone level, nor did females show a preference bias toward it. However, the red intensity predicted male-male competition outcomes, with deeper red males being more likely to emerge as winners. Our results indicated that the pterin-based coloration could convey information about male quality, suggesting its potential role in honest signaling, given the vital importance of pterin metabolism in physiological processes. This study provides a novel case into the understanding of pterin-based colors in animals.

Juvenile hormone signaling is indispensable for late embryogenesis in ametabolous and hemimetabolous insects

BackgroundJuvenile hormone (JH) is an insect-exclusive hormone involved in regulating diverse aspects of insect physiology, and the evolution of its diverse function is widely interesting. Studying embryogenesis in basal wingless insects is important to understand the functional evolution of JH; however, experimental studies in this regard are scarce. In this study, we conducted CRISPR/Cas9-mediated knockout (KO) of genes involved in JH biosynthesis and signaling cascades in the ametabolous firebrat, Thermobia domestica. Additionally, we investigated whether the primitive action of JH is conserved in the hemimetabolous cricket, Gryllus bimaculatus.ResultsWe observed that KO of JHAMT, CYP15A1, Met, and Kr-h1 resulted in embryonic lethality in T. domestica. Deprivation of JH or JH signaling arrested the progression of extraembryonic fluid resorption after dorsal closure and hatching, which is consistent with the gene expression pattern showing high Kr-h1 expression in the late embryos of T. domestica. The embryos deficient in JH signaling displayed wrinkled and weak legs. Comparative transcriptome analysis revealed that JH signaling promotes embryonic leg maturation through inducing energy supply and muscle activity, as validated by transmission electron microscopy (TEM). In addition, JH signaling exhibited similar embryonic effects in G. bimaculatus.ConclusionsThis study reveals the indispensable role of JH signaling in facilitating the maturation of terminal tissues during late embryogenesis, as demonstrated by the regulation of leg development, in ametabolous and hemimetabolous insects. These findings further indicate that the embryonic functions of JH evolved earlier than its anti-metamorphic functions during postembryonic development.

Oxytocin/Oxytocin Receptor Signalling in the Gastrointestinal System: Mechanisms and Therapeutic Potential.

The neuropeptide hormone oxytocin (OT) is involved in various physiological and pathological processes via the oxytocin receptor (OTR). While OT is most widely known as a reproductive system hormone and a nervous system neurotransmitter, the OT/OTR system has gradually gained much attention for its role in the gastrointestinal (GI) system, such as the GI motility, secretion, and bowel inflammatory reactions. Its importance in GI cancers has also been reported in the past few decades. The promising clinical observations have revealed OT's anti-nociceptive effect, protective effect over gut injury, and the potential of using microbiota to naturally increase endogenous OT levels, which shed a light on the management of GI disorders with lower side effects. However, no current comprehensive review is available on the actions of OT/OTR in the GI tract. This review aims to present the lesser-known role of the OT/OTR system in the GI tract, and the most recent findings are discussed regarding the distribution and functional role of OTR signalling in regulating (patho)physiological functions of the GI tract. Special emphasis is placed on its therapeutic potential for clinical management of GI disorders, such as GI pain, inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS). The recent characterisation of the OTR's crystal structure has advanced research for designing and identifying new OTR-specific molecules. Future in-depth basic and clinical research is needed to further elucidate the involvement and detailed mechanism of OT/OTR in GI disorders, and the development of OTR-specific ligands.

Mechanistic insights on the role of Nrf-2 signalling in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder affecting individualsworldwide. It is characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances.The pathogenesis of HD involves oxidative stress, neuroinflammation, and mitochondrial dysfunction.Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating cellular responses to redox imbalance and inflammation, has emerged as a potential target for therapeutic intervention. Through the use of a number of different search engines like Scopus, PubMed, Elsevier and Bentham, aliterature review was carried out with the keywords 'Huntington's Disease, 'Pathology of HD' and 'Nrf2 signallingpathway'.Using the keywords that were given above, this review was carried out in order to collect the most recent publications and gain an understanding of the breadth of the extensive research that has been conducted on the role of Nrf2 in HD pathogenesis. Oxidative stress and neuroinflammation significantly contribute to HD progression. Activation of Nrf2 offers neuroprotection by enhancing anti-oxidant defense mechanisms.Furthermore, several signaling pathways, play crucial roles in HD pathophysiology.Pharmacological modulation of these pathways through selective inhibitors or agonists shows promise for the development of new therapeutic strategies. The various downstream pathways such as extracellular signal-related kinase (ERK), phosphoinositide3-Kinase (PI3-K), 5'-AMP-activated protein kinase (AMPK), Sirtuins, Mitogen-activated protein kinases (MAPK) plays a role in alleviating pathophysiology of HD.Diverse reports of these studies demonstrated PI3-K/AMPK/ERK/Sirtuins activators and MAPK inhibitors as encouraging targets in alleviating HD pathophysiology.

Artificial Intelligence and the Sustainability of the Signaling and Human Capital Roles of Higher Education

Over the last several decades, there has been an arms race to acquire credentials as higher education has shifted from an elitist system to mass education. From an individual perspective, given the higher education system and labor market conditions, it is rational to pursue advanced qualifications. However, whether the education system delivers improvements in human capital or is principally a signaling mechanism is questionable. Estimates of the proportion of labor market rewards due to signaling range as high as 80%, suggesting that education is not only expensive but inefficient. In an increasingly transactional environment in which education providers are highly motivated by financial considerations, this situation is only likely to be exacerbated by the rapid developments in artificial intelligence (AI). The use of AI has the potential to make learning more effective, but given that many students see credential acquisition as transactional, it may reduce both human capital and the value of the signaling effect. If the credibility of the credentials offered is further damaged, the higher education sector in its present form and scale may well be unsustainable. We examine the evidence on credential inflation, returns to education, and mismatch of graduates to jobs before analyzing how AI is likely to affect these trends. We then suggest possible responses of prospective students, education providers, and employers to the growing adoption of AI in both education and the workplace. We conclude that the current offerings of generalist degrees, as opposed to vocational qualifications, are not sustainable and that to survive, even in a downsized form, the sector must respond to this disruptive technology by changing both the nature of its offerings and its methods of ensuring that the credentials they offer reflect genuine student learning.