RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumour immunity.

Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity, specifically in the context of CD8+ T-cell antitumour immunity, remains unclear. Here, we demonstrate that RIG-I is upregulated in tumour-infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T-cell function and limit antitumour immunity. Mechanistically, the upregulation of RIG-I in CD8+ T cells is induced by activated T cells, and directly inhibits the AKT/glycolysis signalling pathway. In addition, knocking out RIG-I enhances the efficacy of adoptively transferred T cells against solid tumours, and inhibiting RIG-I enhances the response to PD-1 blockade. Overall, our study identifies RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with an immune checkpoint inhibitor.

The sperm-specific K+ channel Slo3 is inhibited by albumin and steroids contained in reproductive fluids.

To locate and fertilize the egg, sperm probe the varying microenvironment prevailing at different stages during their journey across the female genital tract. To this end, they are equipped with a unique repertoire of mostly sperm-specific proteins. In particular, the flagellar Ca2+ channel CatSper has come into focus as a polymodal sensor used by human sperm to register ligands released into the female genital tract. Here, we provide the first comprehensive study on the pharmacology of the sperm-specific human Slo3 channel, shedding light on its modulation by reproductive fluids and their constituents. We show that seminal fluid and contained prostaglandins and Zn2+ do not affect the channel, whereas human Slo3 is inhibited in a non-genomic fashion by diverse steroids as well as by albumin, which are released into the oviduct along with the egg. This indicates that not only CatSper but also Slo3 harbours promiscuous ligand-binding sites that can accommodate structurally diverse molecules, suggesting that Slo3 is involved in chemosensory signalling in human sperm.

Bryophyllum pinnatum (Lam.) Oken: unravelling therapeutic potential and navigating toxicity.

Bryophyllum pinnatum (Lam.) Oken, a multipurpose medicinal herb, has drawn much interest for its therapeutic qualities from both traditional and modern medicine systems. Many active secondary metabolites, such as bufadienolides, triterpenes, phenols, alkaloids, glycosides, lipids, flavonoids, and organic acids, are responsible for the plant's curative properties. B. pinnatum exhibits a noteworthy significance in oncological research by exhibiting its ability to modify numerous pathways, which may suggest a potential anticancer impact. The herb is recommended for treating lithiasis, a common cause of renal failure, due to its effectiveness in dissolving stones and avoiding crystal formation. The plant has a major impact on diabetes, especially type II diabetes. Moreover, the versatility of B. pinnatum extends to its examination in connection to COVID-19. However, caution is warranted, as B. pinnatum has been reported to possess toxicity attributed to the presence of bufadienolides in its metabolic profile. A comprehensive investigation is essential to thoroughly understand and confirm the synthesis of potentially hazardous compounds. This is crucial for minimizing their presence and ensuring the safe consumption of B. pinnatum among diverse populations of organisms. This review highlights the various medical uses of B. pinnatum, including its ability to effectively treat kidney and liver diseases, as well as its anti-leishmanial, neuropharmacological, antibacterial, immunosuppressive, anti-tumour, and cytotoxic effects. While extensively employed in both traditional and scientific domains, the plant's complete medicinal potential, molecular mechanisms, safety profile, and pharmacodynamics remain ambiguous, rendering it an ideal candidate for pioneering research endeavours.

Unconscious Drivers of Consumer Behavior: An Examination of the Effect of Nature-Nurture Interactions on Product Desire.

Both biological and environmental factors can affect consumer behavior. Consumer behavior can also be a product of an interaction between one's evolved biology and environmental factors. If marketers aim to increase healthy consumption behavior and decrease unhealthy behavior, they need to identify whether the behavior is a product of one's evolved biology or environmental factors acting in isolation, or if the behavior is a product of a biology-environment interaction. Therefore, the purpose of this study is to examine the effect of biology-environment interactions on product desire. This study comprises two experiments that used a repeated-measures design. The first experiment included 315 females and examined the effect of perceived physical safety, economic well-being, and social support on the desire for beautifying and wealth-signalling products. The second experiment included 314 men and examined the effect of perceived physical safety, economic well-being, and social support on the desire for products that are used to signal wealth and toughness. The results showed that under harsh economic conditions, product desire generally decreased. However, there were significant differences in the amount of decrease between product categories in different environmental conditions.

Cytochromes P450 evolution in the plant terrestrialization context.

Plants started to colonize land around 500 million years ago. It meant dealing with new challenges like absence of buoyancy, water and nutrients shortage, increased light radiation, reproduction on land, and interaction with new microorganisms. This obviously required the acquisition of novel functions and metabolic capacities. Cytochrome P450 (CYP) monooxygenases form the largest superfamily of enzymes and are present to catalyse critical and rate-limiting steps in most plant-specific pathways. The different families of CYP enzymes are typically associated with specific functions. CYP family emergence and evolution in the green lineage thus offer the opportunity to obtain a glimpse into the timing of the evolution of the critical functions that were required (or became dispensable) for the plant transition to land. Based on the analysis of currently available genomic data, this review provides an evolutionary history of plant CYPs in the context of plant terrestrialization and describes the associated functions in the different lineages. Without surprise it highlights the relevance of the biosynthesis of antioxidants and UV screens, biopolymers, and critical signalling pathways. It also points to important unsolved questions that would deserve to be answered to improve our understanding of plant adaptation to challenging environments and the management of agricultural traits. This article is part of the theme issue 'The evolution of plant metabolism'.

Grb7, Grb10 and Grb14, encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism.

BACKGROUND: The growth factor receptor bound protein 7 (Grb7) family of signalling adaptor proteins comprises Grb7, Grb10 and Grb14. Each can interact with the insulin receptor and other receptor tyrosine kinases, where Grb10 and Grb14 inhibit insulin receptor activity. In cell culture studies they mediate functions including cell survival, proliferation, and migration. Mouse knockout (KO) studies have revealed physiological roles for Grb10 and Grb14 in glucose-regulated energy homeostasis. Both Grb10 KO and Grb14 KO mice exhibit increased insulin signalling in peripheral tissues, with increased glucose and insulin sensitivity and a modestly increased ability to clear a glucose load. In addition, Grb10 strongly inhibits fetal growth such that at birth Grb10 KO mice are 30% larger by weight than wild type littermates. RESULTS: Here, we generate a Grb7 KO mouse model. We show that during fetal development the expression patterns of Grb7 and Grb14 each overlap with that of Grb10. Despite this, Grb7 and Grb14 did not have a major role in influencing fetal growth, either alone or in combination with Grb10. At birth, in most respects both Grb7 KO and Grb14 KO single mutants were indistinguishable from wild type, while Grb7:Grb10 double knockout (DKO) were near identical to Grb10 KO single mutants and Grb10:Grb14 DKO mutants were slightly smaller than Grb10 KO single mutants. In the developing kidney Grb7 had a subtle positive influence on growth. An initial characterisation of Grb7 KO adult mice revealed sexually dimorphic effects on energy homeostasis, with females having a significantly smaller renal white adipose tissue depot and an enhanced ability to clear glucose from the circulation, compared to wild type littermates. Males had elevated fasted glucose levels with a trend towards smaller white adipose depots, without improved glucose clearance. CONCLUSIONS: Grb7 and Grb14 do not have significant roles as inhibitors of fetal growth, unlike Grb10, and instead Grb7 may promote growth of the developing kidney. In adulthood, Grb7 contributes subtly to glucose mediated energy homeostasis, raising the possibility of redundancy between all three adaptors in physiological regulation of insulin signalling and glucose handling.

IFIT3 mediates TBK1 phosphorylation to promote activation of pDCs and exacerbate systemic sclerosis in mice.

OBJECTIVE: To assess the impact of the IFIT3/TBK1 signalling pathway in activating plasmacytoid dendritic cells (pDCs) and its role in the development of SSc. METHODS: Utilized single-cell RNA sequencing (scRNA-seq) and high-throughput transcriptome RNA sequencing to reveal the differential abundance of pDCs and the role of the key gene IFIT3 in SSc. Conducted in vitro cell experiments to evaluate the effect of IFIT3/TBK1 signalling pathway intervention on pDC activation cytokine release and fibroblast function. Constructed an IFIT3-/- mouse model using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing to assess the potential benefits of intervening in the IFIT3/TBK1 signalling pathway on skin and lung fibrosis in the SSc mouse model. RESULTS: The IFIT3/TBK1 signalling pathway plays a crucial role in activating pDCs, with IFIT3 acting as an upstream regulator of TBK1. Intervention in the IFIT3/TBK1 signalling pathway can inhibit pDC activation cytokine release and impact fibroblast function. The IFIT3-/- mouse model shows potential benefits of targeting the IFIT3/TBK1 signalling pathway in reducing skin and lung fibrosis in the SSc mouse model. CONCLUSION: This study provides new insights into potential therapeutic targets for SSc, highlighting the critical role of the IFIT3/TBK1 signalling pathway in SSc development. HIGHLIGHTS: This study elucidates the pivotal role of plasmacytoid dendritic cells (pDCs) in systemic sclerosis (SSc). This study identified the key regulatory gene involved in systemic sclerosis (SSc) as IFIT3. This study has found that IFIT3 functions as an upstream regulatory factor, activating TBK1. This study provides Evidence of the regulatory effects of the IFIT3/TBK1 pathway on plasmacytoid dendritic cells (pDCs). This study validated the therapeutic potential using the IFIT3-/- mouse model.

Photoexcited Cryptochrome 1 Interacts With SPCHLESS to Regulate Stomatal Development in Arabidopsis.

Stomata are epidermal openings that facilitate plant-atmosphere gas and water exchange during photosynthesis, respiration and water evaporation. SPEECHLESS (SPCH) is a master basic helix-loop-helix (bHLH) transcription factor that determines the initiation of stomatal development. It is known that blue light promotes stomatal development through the blue light photoreceptor cryptochromes (CRYs, CRY1 and CRY2). Whether CRYs regulate stomatal development through directly modulating SPCH is unknown. Here, we demonstrate by biochemical studies that CRY1 physically interacts with SPCH in a blue light-dependent manner. Genetic studies show that SPCH acts downstream of CRY1 to promote stomatal development in blue light. Furthermore, we show that CRY1 enhances the DNA-binding activity of SPCH and promotes the expression of its target genes in blue light. These results suggest that the mechanism by which CRY1 promotes stomatal development involves positive regulation of the DNA-binding activity of SPCH, which is likely mediated by blue light-induced CRY1-SPCH interaction. The precise regulation of SPCH DNA-binding activity by CRY1 may allow plants to optimize stomatal density and pattern according to ambient light conditions.

Higher levels of AKT-interacting protein in the frontal pole from people with schizophrenia are limited to a sub-group who have a marked deficit in cortical muscarinic M1 receptors.

We are studying the molecular pathology of a sub-group within schizophrenia (∼ 25 %: termed Muscarinic Receptor Deficit subgroup of Schizophrenia (MRDS)) who can be separated because they have very low levels of cortical muscarinic M1 receptors (CHRM1). Based on our transcriptomic data from Brodmann's area ((BA) 9, 10 and 33 (controls, schizophrenia and mood disorders) and the cortex of the CHRM1-/- mouse (a molecular model of aberrant CHRM1 signaling), we predicted levels of AKT interacting protein (AKTIP), but not tubulin alpha 1b (TUBA1B) or AKT serine/threonine kinase 1 (AKT1) and pyruvate dehydrogenase kinase 1 (PDK1) (two AKTIP-functionally associated proteins), would be changed in MRDS. Hence, we used Western blotting to measure AKTIP (BA 10: controls, schizophrenia and mood disorders; BA 9: controls and schizophrenia) plus TUBA1B, AKT1 and PDK1 (BA 10: controls and schizophrenia) proteins. The only significant change with diagnosis was higher levels of AKTIP protein in BA 10 (Cohen's d = 0.73; p = 0.02) in schizophrenia compared to controls due to higher levels of AKTIP only in people with MRDS (Cohen's d = 0.80; p = 0.03). As AKTIP is involved in AKT1 signaling, our data suggests that signaling pathway is particularly disturbed in BA 10 in MRDS.

Unravelling bisphenol A-induced hepatotoxicity: Insights into oxidative stress, inflammation, and energy dysregulation.

Bisphenol A (BPA), a prevalent plastic monomer and endocrine disruptor, negatively impacts metabolic functions. This study examines the chronic effects of eco-relevant BPA concentrations on hepatotoxicity, focusing on redox balance, inflammatory response, cellular energy sensors, and metabolic homeostasis in male Swiss albino mice. Chronic BPA exposure resulted in reactive oxygen species (ROS) accumulation, altered hepatic antioxidant defense, lipid peroxidation, and NOX4 expression, leading to reduced cell viability. Additionally, BPA exposure significantly upregulated hepatic pro-inflammatory cytokine genes (Tnf-α, Il-1ß, Il-6), NOS2, and arginase II, correlating with increased TLR4 expression, NF-κB phosphorylation, and a dose-dependent decrease in IκBα levels. BPA-induced NF-κB nuclear localization and inflammasome activation (NLRP3, cleaved caspase-1, IL-1ß) established an inflammatory milieu. Perturbations in hepatic AMPKα phosphorylation, SIRT1, and PGC-1α, along with elevated p38 MAPK phosphorylation and ERα expression, indicated BPA-induced energy dysregulation. Furthermore, increased PLA2G4A, COX1, COX2, and PTGES2 expression in BPA-treated liver correlated with hyperlipidemia, hepatic FASN expression, steatosis, and visceral adiposity, likely due to disrupted energy sensors, oxidative stress, and inflammasome activation. Elevated liver enzymes (ALP, AST, ALT) and apoptotic markers indicated liver damage. Notably, N-acetylcysteine (NAC) priming reversed BPA-induced hepatocellular ROS accumulation, NF-κB-inflammasome activation, and intracellular lipid accumulation, while upregulating cellular energy sensors and attenuating ERα expression, suggesting NAC's protective effects against BPA-induced hepatotoxicity. Pharmacological inhibition of the NF-κB/NLRP3 cascade in BAY11-7082 pretreated, or NLRP3 immunodepleted hepatocytes reversed BPA's negative impact on SIRT1/p-AMPKα/PGC-1α and intracellular lipid accumulation, providing mechanistic insights into BPA-induced metabolic disruption.

The KDR Gene rs2071559 and the VEGF Gene rs6921438 May Be Associated with Diabetic Nephropathy in Caucasians with Type 2 Diabetes Mellitus.

The aim of our study was to investigate an association between polymorphisms of either the VEGF (vascular endothelial growth factor) gene (rs6921438) or the KDR (kinase insert domain receptor) gene (rs2071559, rs2305948) and DN (diabetic nephropathy) in Caucasians with T2DM (type 2 diabetes mellitus). The second aim was to investigate the effect of either the VEGF gene (rs6921438) or the KDR gene (rs2071559, rs2305948) on the immune expression of either VEGF or KDR in the renal tissues of T2DM subjects (to test the functional significance of tested polymorphisms). The study included 897 Caucasians with T2DM for at least ten years (344 patients with DN and 553 patients without DN). Each subject was genotyped and analyzed for KDR (rs1617640, rs2305948) and VEGF (rs6921438) polymorphisms. Kidney tissue samples taken from 15 subjects with T2DM (autopsy material) were immunohistochemically stained for the expression of VEGF and KDR. We found that the rs2071559 KDR gene was associated with an increased risk of DN. In addition, the GG genotype of the rs6921438 VEGF gene had a protective effect. We found a significantly higher numerical area density of VEGF-positive cells in T2DM subjects with the A allele of the rs6921438-VEGF compared to the homozygotes for wild type G allele (7.0 ± 2.4/0.1 mm2 vs. 1.24 ± 0.5/0.1 mm2, respectively; p < 0.001). Moreover, a significantly higher numerical area density of KDR-positive cells was found in T2DM subjects with the C allele of rs2071559 (CC + CT genotypes) compared to the homozygotes for wild type T allele (9.7± 3.2/0.1 mm2 vs. 1.14 ± 0.5/0.1 mm2, respectively; p < 0.001) To conclude, our study showed that the presence of the C allele of the rs2071559 KDR gene was associated with a higher risk of DN, while the G allele of the rs6921438-VEGF conferred protection against DN in Slovenian T2DM subjects.

Cancer-associated fibroblasts barrier breaking via TGF-ß blockade paved way for docetaxel micelles delivery to treat pancreatic cancer.

TGF-ß is a crucial regulator in tumor microenvironment (TME), especially for myofibroblastic cancer-associated fibroblasts (myCAFs). The myCAFs can be motivated by TGF-ß signaling to erect pro-tumor TME, meanwhile, myCAFs overexpress TGF-ß to mediate the crosstalk between tumor and stromal cells. The blockade of TGF-ß can break cancer-associated fibroblasts barrier, consequently opening the access for drugs into tumor. The TGF-ß is a promising target in anti-tumor therapy. Herein, we introduced a two-stage combination therapy (TC-Therapy), including TGF-ß receptor I inhibitor SB525334 (SB) and cytotoxicity agent docetaxel micelle (DTX-M). We found that SB and DTX-M synergistically inhibited myCAFs proliferation and elevated p53 protein expression in BxPC-3/3T3 mixed cells. Gene and protein tests demonstrated that SB cut off TGF-ß signaling via receptor blockade and it did not arouse TGF-ß legend compensated internal autocrine. On the contrary, two agents combined decreased TGF-ß secretion and inhibited myCAFs viability marked by α-SMA and FAPα. TC-Therapy was applied in BxPc-3/3T3 mixed tumor-bearing mice model. After TC-Therapy, the α-SMA+/ FAPα+ myCAFs faded increasingly and collagenous fibers mainly secreted by myCAFs decreased dramatically as well. More than that, the myCAFs barrier breaking helped to normalize micro-vessels and paved way for micelle penetration. The TGF-ß protein level of TC-Therapy in TME was much lower than that of simplex DTX-M, which might account for TME restoration. In conclusion, TGF-ß inhibitor acted as the pioneer before nano chemotherapeutic agents. The TC-Therapy of TGF-ß signaling inhibition and anti-tumor agent DTX-M is a promising regimen without arising metastasis risk to treat pancreatic cancer. The therapeutic regimen focused on TGF-ß related myCAFs reminds clinicians to have a comprehensive understanding of pancreatic cancer.

Targeting JNK kinase inhibitors via molecular docking: A promising strategy to address tumorigenesis and drug resistance.

Among members of the mitogen-activated protein kinase (MAPK) family, c-Jun N-terminal kinases (JNKs) are vital for cellular responses to stress, inflammation, and apoptosis. Recent advances have highlighted their important implications in cancer biology, where dysregulated JNK signalling plays a role in the growth, progression, and metastasis of tumors. The present understanding of JNK kinase and its function in the etiology of cancer is summarized in this review. By modifying a number of downstream targets, such as transcription factors, apoptotic regulators, and cell cycle proteins, JNKs exert diverse effects on cancer cells. Apoptosis avoidance, cell survival, and proliferation are all promoted by abnormal JNK activation in many types of cancer, which leads to tumor growth and resistance to treatment. JNKs also affect the tumour microenvironment by controlling the generation of inflammatory cytokines, angiogenesis, and immune cell activity. However, challenges remain in deciphering the context-specific roles of JNK isoforms and their intricate crosstalk with other signalling pathways within the complex tumor environment. Further research is warranted to delineate the precise mechanisms underlying JNK-mediated tumorigenesis and to develop tailored therapeutic strategies targeting JNK signalling to improve cancer management. The review emphasizes the role of JNK kinases in cancer biology, as well as their potential as pharmaceutical targets for precision oncology therapy and cancer resistance. Also, this review summarizes all the available promising JNK inhibitors that are suggested to promote the responsiveness of cancer cells to cancer treatment.

Chitosan stimulates root hair callose deposition, endomembrane dynamics, and inhibits root hair growth.

Although angiosperm plants generally react to immunity elicitors like chitin or chitosan by the cell wall callose deposition, this response in particular cell types, especially upon chitosan treatment, is not fully understood. Here we show that the growing root hairs (RHs) of Arabidopsis can respond to a mild (0.001%) chitosan treatment by the callose deposition and by a deceleration of the RH growth. We demonstrate that the glucan synthase-like 5/PMR4 is vital for chitosan-induced callose deposition but not for RH growth inhibition. Upon the higher chitosan concentration (0.01%) treatment, RHs do not deposit callose, while growth inhibition is prominent. To understand the molecular and cellular mechanisms underpinning the responses to two chitosan treatments, we analysed early Ca2+ and defence-related signalling, gene expression, cell wall and RH cellular endomembrane modifications. Chitosan-induced callose deposition is also present in the several other plant species, including functionally analogous and evolutionarily only distantly related RH-like structures such as rhizoids of bryophytes. Our results point to the RH callose deposition as a conserved strategy of soil-anchoring plant cells to cope with mild biotic stress. However, high chitosan concentration prominently disturbs RH intracellular dynamics, tip-localised endomembrane compartments, growth and viability, precluding callose deposition.

The Proteasome and Cul3-Dependent Protein Ubiquitination Is Required for Gli Protein-Mediated Activation of Gene Expression in the Hedgehog Pathway.

Many cellular processes are regulated by proteasome-mediated protein degradation, including regulation of signaling pathways and gene expression. Among the pathways regulated by the ubiquitin-proteasome system is the Hedgehog pathway and its downstream effectors, the Gli transcription factors. Here we provide evidence that proteasomal activity is necessary for maintaining the activation of the Hedgehog pathway, and this crucial event takes place at the level of Gli proteins. We undertook extensive work to demonstrate the specificity of the observed phenomenon by ruling out the involvement of primary cilium, impaired nuclear import, failed dissociation from Sufu, microtubule stabilization, and stabilization of Gli repressor forms. Moreover, we showed that proteasomal-inhibition-mediated Hedgehog pathway downregulation is not restricted to the NIH-3T3 cell line. We demonstrated, using CRISPR/Ca9 mutagenesis, that neither Gli1, Gli2, nor Gli3 are solely responsible for the Hedgehog pathway downregulation upon proteasome inhibitor treatment, and that Cul3 KO renders the same phenotype. Finally, we report two novel E3 ubiquitin ligases, Btbd9 and Kctd3, known Cul3 interactors, as positive Hedgehog pathway regulators. Our data pave the way for a better understanding of the regulation of gene expression and the Hedgehog signaling pathway.

Increased Expression of the Neuropeptides PACAP/VIP in the Brain of Mice with CNS Targeted Production of IL-6 Is Mediated in Part by Trans-Signalling.

Inflammation with expression of interleukin 6 (IL-6) in the central nervous system (CNS) occurs in several neurodegenerative/neuroinflammatory conditions and may cause neurochemical changes to endogenous neuroprotective systems. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two neuropeptides with well-established protective and anti-inflammatory properties. Yet, whether PACAP and VIP levels are altered in mice with CNS-restricted, astrocyte-targeted production of IL-6 (GFAP-IL6) remains unknown. In this study, PACAP/VIP levels were assessed in the brain of GFAP-IL6 mice. In addition, we utilised bi-genic GFAP-IL6 mice carrying the human sgp130-Fc transgene (termed GFAP-IL6/sgp130Fc mice) to determine whether trans-signalling inhibition rescued PACAP/VIP changes in the CNS. Transcripts and protein levels of PACAP and VIP, as well as their receptors PAC1, VPAC1 and VPAC2, were significantly increased in the cerebrum and cerebellum of GFAP-IL6 mice vs. wild type (WT) littermates. These results were paralleled by a robust activation of the JAK/STAT3, NF-κB and ERK1/2MAPK pathways in GFAP-IL6 mice. In contrast, co-expression of sgp130Fc in GFAP-IL6/sgp130Fc mice reduced VIP expression and activation of STAT3 and NF-κB pathways, but it failed to rescue PACAP, PACAP/VIP receptors and Erk1/2MAPK phosphorylation. We conclude that forced expression of IL-6 in astrocytes induces the activation of the PACAP/VIP neuropeptide system in the brain, which is only partly modulated upon IL-6 trans-signalling inhibition. Increased expression of PACAP/VIP neuropeptides and receptors may represent a homeostatic response of the CNS to an uncontrolled IL-6 synthesis and its neuroinflammatory consequences.

Decreased inter-hemispheric connectivity predicts a coherent retrieval of auditory symbolic material.

Investigating the transmission of information between individuals is essential to better understand how humans communicate. Coherent information transmission (i.e., transmission without significant modifications or loss of fidelity) helps preserving cultural traits and traditions over time, while innovation may lead to new cultural variants. Although much research has focused on the cognitive mechanisms underlying cultural transmission, little is known on the brain features which correlates with coherent transmission of information. To address this gap, we combined structural (from high-resolution diffusion imaging) and functional connectivity (from resting-state functional magnetic resonance imaging [fMRI]) with a laboratory model of cultural transmission, the signalling games, implemented outside the MRI scanner. We found that individuals who exhibited more coherence in the transmission of auditory symbolic information were characterized by lower levels of both structural and functional inter-hemispheric connectivity. Specifically, higher coherence negatively correlated with the strength of bilateral structural connections between frontal and subcortical, insular and temporal brain regions. Similarly, we observed increased inter-hemispheric functional connectivity between inferior frontal brain regions derived from structural connectivity analysis in individuals who exhibited lower transmission coherence. Our results suggest that lateralization of cognitive processes involved in semantic mappings in the brain may be related to the stability over time of auditory symbolic systems.

Unravelling differential Hes1 dynamics during axis elongation of mouse embryos through single-cell tracking.

The intricate dynamics of Hes expression across diverse cell types in the developing vertebrate embryonic tail have remained elusive. To address this, we have developed an endogenously tagged Hes1-Achilles mouse line, enabling precise quantification of dynamics at the single-cell resolution across various tissues. Our findings reveal striking disparities in Hes1 dynamics between presomitic mesoderm (PSM) and preneural tube (pre-NT) cells. While pre-NT cells display variable, low-amplitude oscillations, PSM cells exhibit synchronized, high-amplitude oscillations. Upon the induction of differentiation, the oscillation amplitude increases in pre-NT cells. Additionally, our study of Notch inhibition on Hes1 oscillations unveils distinct responses in PSM and pre-NT cells, corresponding to differential Notch ligand expression dynamics. These findings suggest the involvement of separate mechanisms driving Hes1 oscillations. Thus, Hes1 demonstrates dynamic behaviour across adjacent tissues of the embryonic tail, yet the varying oscillation parameters imply differences in the information that can be transmitted by these dynamics.

The role of NF-κB-SOX9 signalling pathway in osteoarthritis.

The nuclear factor-κB (NF-κB) signalling pathway exists in a variety of cells and is involved in the gene regulation of various physiological and pathological processes such as inflammation, immunity, cell proliferation and apoptosis. It has been shown that this signaling pathway is also involved in numerous events associated with osteoarthritis, including chondrocyte catabolism, chondrocyte survival, and synovial inflammation. SRY-related high mobility group-box 9(SOX9) is the "master regulator" of chondrocytes and one of the key transcription factors that maintain chondrocyte phenotype and cartilage homeostasis. NF-κB can positively regulate the expression of SOX9 by directly binding to its promoter region, and play a role in the formation and development of chondrocytes. This article reviews the regulatory effect of the NF-κB-SOX9 signaling axis on osteoarthritis.

Cytokine Storm-Induced Thyroid Dysfunction in COVID-19: Insights into Pathogenesis and Therapeutic Approaches.

Angiotensin-converting enzyme 2 receptors (ACE2R) are requisite to enter the host cells for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). ACE2R is constitutive and functions as a type I transmembrane metallo-carboxypeptidase in the renin-angiotensin system (RAS). On thyroid follicular cells, ACE2R allows SARS-CoV-2 to invade the thyroid gland, impose cytopathic effects and produce endocrine abnormalities, including stiff back, neck pain, muscle ache, lethargy, and enlarged, inflamed thyroid gland in COVID-19 patients. Further damage is perpetuated by the sudden bursts of pro-inflammatory cytokines, which is suggestive of a life-threatening syndrome known as a "cytokine storm". IL-1ß, IL-6, IFN-γ, and TNF-α are identified as the key orchestrators of the cytokine storm. These inflammatory mediators upregulate transcriptional turnover of nuclear factor-kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and mitogen-activated protein kinase (MAPK), paving the pathway for cytokine storm-induced thyroid dysfunctions including euthyroid sick syndrome, autoimmune thyroid diseases, and thyrotoxicosis in COVID-19 patients. Targeted therapies with corticosteroids (dexamethasone), JAK inhibitor (baricitinib), nucleotide analogue (remdesivir) and N-acetyl-cysteine have demonstrated effectiveness in terms of attenuating the severity and frequency of cytokine storm-induced thyroid dysfunctions, morbidity and mortality in severe COVID-19 patients. Here, we review the pathogenesis of cytokine storms and the mechanisms and pathways that establish the connection between thyroid disorder and COVID-19. Moreover, cross-talk interactions of signalling pathways and therapeutic strategies to address COVID-19-associated thyroid diseases are also discussed herein.