Role Of Signaling Research Articles

A Glutamate Receptor‐Like Gene AtGLR25 With Its Unusual Splice Variant Has a Role in Mediating Glutamate‐Elicited Changes in Arabidopsis Root Architecture

ABSTRACTThe occurrence of external L‐glutamate at the Arabidopsis root tip triggers major changes in root architecture, but the mechanism of ‐L‐Glu sensing is unknown. Members of the family of GLUTAMATE RECEPTOR‐LIKE (GLR) proteins are known to act as amino acid‐gated Ca2+‐permeable channels and to have signalling roles in diverse plant processes. To investigate the possible role of GLRs in the root architectural response to L‐Glu, we screened a collection of mutants with T‐DNA insertions in each of the 20 AtGLR genes. Reduced sensitivity of root growth to L‐Glu was found in mutants of one gene, GLR2.5. Interestingly, GLR2.5 was found to apparently produce four transcript variants encoding hypothetical proteins of 169–720 amino acids. One of these transcripts, GLR2.5c, encodes a truncated GLR protein lacking both the conserved amino‐terminal domain and part of the ligand‐binding domain. When a glr2.5 mutant was transformed with a construct constitutively expressing GLR2.5c, both L‐Glu sensitivity of root growth and L‐Glu‐elicited Ca2+ currents in root tip protoplasts were restored. These results, along with homology modelling of the truncated ligand‐binding domain of GLR2.5c, suggest that GLR2.5c has a regulatory or scaffolding role in heteromeric GLR complex(es) that may involve triggering the root architectural response to L‐Glu.

The Role of Bioelectric Signals in Cancer Genome Regulation and Potential Therapeutic Implication: An Overview

Bioelectrical signals which are directed by ion channels and membrane potential (V_mem), play a crucial role in many cellular processes including proliferation and differentiation. It has also been known to influence processes such as gene expression, epigenetics, and tumor progression which are key aspects of cancer development. This study explores the role of bioelectric signaling in oncogenesis, highlighting possible therapeutic implications. An inferential review of existing literature was done to understand the possible outcomes of integrating Tumor-Treating Fields (TTFields) with traditional therapies like chemotherapy and immunotherapy. Relevant sources were analyzed to gain mechanistic insights from clinical and non-clinical studies to deduce potential therapeutic implications. Dysregulated ion channel activity and abnormal cellular membrane potential are hallmark findings of cancer cells. Deviant bioelectric signals seen in tumors promote oncogene activation and tumor suppressor silencing. These bioelectric changes affect chromatin remodeling through pathways involving calcium signaling, histone modifications, and DNA methylation. Therapeutically, targeting ion channels, such as potassium and sodium-proton exchangers may offer a novel strategy to disrupt tumor growth. Bioelectric stimulation, using techniques like optogenetics, can also help reprogram cancer cells to induce differentiation or apoptosis. There are also potential diagnostic advancements that leverage bioelectric markers, such as depolarized membrane potential, for early cancer detection through electrophysiological imaging and wearable sensors. Bioelectric modulation can enhance drug uptake, improve immune responses by normalizing the tumor microenvironment, and enable targeted delivery using electroporation. Bioelectrical signals influence genome regulation and offer significant therapeutic and diagnostic potential. Further studies are recommended to provide essential insights into the potential of harnessing bioelectricity for advanced cancer management and improved patient outcomes.

Deciphering the Role of Calcium Signaling Pathway‐Associated Single Nucleotide Variants in Susceptibility to Hypertension

ABSTRACTBackgroundAs a complex disease, hypertension (HTN) is influenced by both genetic and environmental factors and their interaction. The calcium signaling pathway is known to be involved in the regulation of blood pressure, and dysfunction in this pathway may contribute to the development of hypertension. Genome‐wide association studies (GWAS) have identified several genes in the calcium signaling pathway associated with susceptibility to HTN, including PLCB1, ATP2B1, and ADRB1. The aim of this study was to investigate the possible association between single nucleotide variants (SNVs) in the calcium signaling pathway and HTN.MethodsWe genotyped three SNVs: rs1801253 (ADRB1), rs6108168 (PLCB1), and rs17249754 (ATP2B1) in a population of 131 patients with hypertension and 115 healthy controls from Kermanshah province, Iran.ResultsOur results showed a strong and significant association between the G allele and the GG and CG genotypes of the rs1801253 variant in the ADRB1 gene and susceptibility to hypertension. However, no significant association was found for the other two SNVs. In addition, the presence of the GCG haplotype (alleles from left to right: rs1801253, rs6108168, and rs17249754) appeared to confer a protective role against HTN.ConclusionThis study has made a significant contribution towards enhancing the comprehension of hypertension development, as well as the early identification of individuals who are at risk.

A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer

Copper is an essential nutrient for sustaining vital cellular processes spanning respiration, metabolism, and proliferation. However, loss of copper homeostasis, particularly misregulation of loosely bound copper ions which are defined as the labile copper pool, occurs in major diseases such as cancer, where tumor growth and metastasis have a heightened requirement for this metal. To help decipher the role of copper in the etiology of cancer, we report a histochemical activity-based sensing approach that enables systematic, high-throughput profiling of labile copper status across many cell lines in parallel. Coppermycin-1 reacts selectively with Cu(I) to release puromycin, which is then incorporated into nascent peptides during protein translation, thus leaving a permanent and dose-dependent marker for labile copper that can be visualized with standard immunofluorescence assays. We showcase the utility of this platform for screening labile Cu(I) pools across the National Cancer Institute’s 60 (NCI-60) human tumor cell line panel, identifying cell types with elevated basal levels of labile copper. Moreover, we use Coppermycin-1 to show that lung cancer cells with heightened activation of nuclear factor-erythroid 2-related factor 2 (NRF2) possess lower resting labile Cu(I) levels and, as a result, have reduced viability when treated with a copper chelator. This work establishes that methods for labile copper detection can be used to assess cuproplasia, an emerging form of copper-dependent cell growth and proliferation, providing a starting point for broader investigations into the roles of transition metal signaling in biology and medicine.

Lack of TLR9 exacerbates ocular impairment and visual loss during systemic Cryptococcus gattii infection

Abstract Cryptococcus gattii is a saprophytic basidiomycete that grows in the environment and can cause systemic cryptococcosis. Ocular cryptococcosis causes blindness and is commonly associated with central nervous system (CNS) infection. Toll-like receptor 9 (TLR9) can control cryptococcosis and another mycosis. Here, using C57BL/6 TLR9 knockout mice (TLR9-/-), we evaluated the role of TLR9 signaling in ocular involvement during systemic C. gattii-infection. We observed ocular impairment and found a high fungal burden in the retina, vitreous humor (VH), and optic nerve (ON) of TLR9-/- mice three weeks after infection. Capsular polysaccharide glucuronoxylomannan (GXM) deposition, astrogliosis and morphological alterations in retina lead to progressive blindness of TLR9-/- mice. The phenomenon observed in our work has not yet been explored in a murine model. These results contribute to the understanding of the role of TLR9 during ocular cryptococcosis. Therapies using TLR9 agonists may be important for the treatment of ocular cryptococcosis.

The TRP Channels Serving as Chemical-to-Electrical Signal Converter

Biology uses many signaling mechanisms. Among them, calcium and membrane potential are two prominent mediators for cellular signaling. TRPM4 and TRPM5, two calcium-activated monovalent cation-conducting ion channels, offer a direct linkage between these two signals. Their activities convert a rise in the intracellular calcium level—a chemical signal—into depolarization of membrane potential—an electrical signal. Interestingly, membrane depolarization can in turn alter the electrical driving force or membrane permeability for calcium entry, hence offers feedback mechanisms for regulating calcium signaling. By converging two powerful cellular signals, TRPM4 and TRPM5 are capable of contributing to many fundamental biological processes including cardiovascular biology, immunology, insulin release, chemo-sensation, and others. Numerous mutations in TRPM4 are linked to human hereditary cardiac and skin diseases, whereas knocking out TRPM5 in mice abolishes perception of sweet, umami and bitter tastes. This review summarizes what are currently known about the signaling roles of these unique TRP channels, and what remain mysterious.

Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests. We identify 9 genes; 5 with fetal-only effects on birth weight, 1 with maternal-only effects, 3 with both, and observe directionally concordant associations in an independent sample. Four of the genes were previously implicated by GWAS of birth weight. IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (fetal-acting) are involved in adipose tissue regulation, and the latter two also show associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG (fetal-acting) in adipocyte differentiation and placental angiogenesis. NOS3 (fetal and maternal-acting), NRK (fetal), and ADAMTS8 (maternal-acting) have been implicated in placental function and hypertension. To conclude, our analysis of rare coding variants identifies regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, and further evidence for the role of insulin-like growth factors.

Upregulated astrocyte HDAC7 induces Alzheimer-like tau pathologies via deacetylating transcription factor-EB and inhibiting lysosome biogenesis

BackgroundAstrocytes, the most abundant glial cell type in the brain, will convert into the reactive state in response to proteotoxic stress such as tau accumulation, a characteristic feature of Alzheimer's disease (AD) and other tauopathies. The formation of reactive astrocytes is partially attributed to the disruption of autophagy lysosomal signaling, and inhibiting of some histone deacetylases (HDACs) has been demonstrated to reduce the molecular and functional characteristics of reactive astrocytes. However, the precise role of autophagy lysosomal signaling in astrocytes that regulates tau pathology remains unclear.MethodsWe investigated the expression of class IIa HDAC7 in astrocytes from AD patients and PS19 mice. PS19 mice were treated with AAVs expressing shRNA for HDAC7 with astrocyte-specific promoter and with a selective class IIa HDAC inhibitor, TMP195, and the effects on tau pathology, gliosis, synaptic plasticity and cognition-related behavioral performance were measured. Tau uptake and degradation assays in cultured astrocytes were utilized to investigate the role of HDAC7 on astrocyte-mediated tau clearance. Immunoprecipitation, immunofluorescence, western blotting, RT-qPCR, mass spectrometric, and luciferase reporter assay were used to identify HDAC7 substrates, modification site and related signaling pathways in astrocyte-tau clearance. We generated a new antibody to clarify the role of HDAC7-mediated signaling in AD patients and PS19 mice.ResultsHere, we found that the level of histone deacetylase 7 (HDAC7) was remarkably increased in the astrocytes of AD patients and P301S tau transgenic (PS19) mice. Genetic or pharmacological inhibition of HDAC7 effectively enhanced astrocytic clearance of tau with improved cognitive functions in PS19 mice. HDAC7 could modulate astrocytic uptake and lysosomal degradation of tau proteins through a transcriptional factor EB (TFEB) acetylation-dependent manner. Specifically, deacetylation of TFEB at K310 site by HDAC7 prevented TFEB nuclear translocation with reduced lysosomal biogenesis and tau clearance in astrocytes, whereas inhibiting HDAC7 restored astrocytic TFEB acetylation level at K310 with improved tau pathology and cognitive functions in PS19 mice.ConclusionsOur findings suggest that upregulation of HDAC7 induces AD-like tau pathologies via deacetylating TFEB and inhibiting lysosomal biogenesis in astrocytes, and downregulating HDAC7-TFEB signaling is promising for arresting AD and other tauopathies.

The ER protein CANX (calnexin)-mediated autophagy protects against alzheimer disease

ABSTRACT Although the relationship between macroautophagy/autophagy and Alzheimer disease (AD) is widely studied, the underlying mechanisms are poorly understood, especially the regulatory role of the initiation signaling of autophagy on AD. Here, we find that the ER transmembrane protein CANX (calnexin) is a novel interaction partner of the autophagy-inducing kinase ULK1 and is required for ULK1 recruitment to the ER under basal or starved conditions. Loss of CANX results in the inactivity of ULK1 kinase and inhibits autophagy flux. In the brains of people with AD and APP-PSEN1 mice, the interaction of CANX and ULK1 declines. In mice, the lack of CANX in hippocampal neurons causes the accumulation of autophagy receptors and neuron damage, which affects the cognitive function of C57BL/6 mice. Conversely, overexpression of CANX in hippocampal neurons enhances autophagy flux and partially contributes to improving cognitive function of APP-PSEN1 mice, but not the CANX variant lacking the interaction domain with ULK1. These findings reveal a novel role of CANX in autophagy activity and cognitive function by cooperating with ULK1. Abbreviation: AD: Alzheimer disease; APEX: ascorbate peroxidase; APP: amyloid beta precursor protein; APP-PSEN1 mice: amyloid beta precursor protein-presenilin 1 transgenic mice; ATG: autophagy related; Aβ: amyloid-β; BiFC: bimolecular fluorescence complementation; CANX: calnexin; EBSS: Earle’s balanced salt solution; EM: electron microscopy; IP: immunopurification; KO: knockout; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MWM: Morris water maze; PLA: proximity ligation assay; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62, sequestosome 1.

Role of the Psi Packaging Signal and Dimerization Initiation Sequence in the Organization of Rous Sarcoma Virus Gag-gRNA Co-Condensates

Retroviral genome selection and virion assembly remain promising targets for novel therapeutic intervention. Recent studies have demonstrated that the Gag proteins of Rous sarcoma virus (RSV) and human immunodeficiency virus type-1 (HIV-1) undergo nuclear trafficking, colocalize with nascent genomic viral RNA (gRNA) at transcription sites, may interact with host transcription factors, and display biophysical properties characteristic of biomolecular condensates. In the present work, we utilized a controlled in vitro condensate assay and advanced imaging approaches to investigate the effects of interactions between RSV Gag condensates and viral and nonviral RNAs on condensate abundance and organization. We observed that the psi (Ψ) packaging signal and the dimerization initiation sequence (DIS) had stabilizing effects on RSV Gag condensates, while RNAs lacking these features promoted or antagonized condensation, depending on local protein concentration and condensate architecture. An RNA containing Ψ, DIS, and the dimerization linkage structure (DLS) that is capable of stable dimer formation was observed to act as a bridge between RSV Gag condensates. These observations suggest additional, condensate-related roles for Gag-Ψ binding, gRNA dimerization, and Gag dimerization/multimerization in gRNA selection and packaging, representing a significant step forward in our understanding of how these interactions collectively facilitate efficient genome packaging.

The Signaling Effect of Biophilic Job Posts: Do Applicants Trade Green for Green?

ABSTRACTContemporary job postings increasingly rely on visual content to attract applicants through social media platforms, calling for scholarly attention to organizational aesthetics in recruitment. This study accordingly examines the signaling function of biophilic workspace design conveyed in job posts. We integrate theorizing on organizational aesthetics and biophilia with signaling theory to posit that biophilic job posts serve a dual signaling role as both a stimulus of signal attention by eliciting a visceral response and as a signaled source of credible information by evoking an evolutionary disposed cognitive interpretation. More specifically, we model pleasure and arousal as an indicator of stimulated attention, organizational attraction and the willingness to trade pay as evaluated responses to the signal, and attributions of communal organizational traits as an intervening interpretation of the signal—consistent with the role of symbolic attributes in prospective applicant evaluation of organizations. Three primary experiments largely support our predictions. Overall, this research extends the function of aesthetic signals to organizational signaling, validates organizational aesthetics as a stimulus of directed evaluation, and expands the scope of biophilic theory in organizational research. Findings also inform the practical question of whether biophilic job posts function as a non‐pecuniary differentiator in recruitment.

Methionine-Derived Fluorescent Probes Targeting Mitochondria: A Tool for Real-Time Oxidative Stress Monitoring in Live Cells.

Reactive oxygen species (ROS) play crucial roles in both cell signaling and defense mechanisms. Hypochlorous acid (HOCl), a strong oxidant, aids the immune response by damaging pathogens. In this study, we developed two pyridinium-based fluorophores PSSM and PSSE for selective hypochlorite detection. Out of these two fluorescent probes, PSSM shows a strong turn-on emission via a photoinduced electron transfer (PeT) mechanism, excellent mitochondrial localization, and rapid response to HOCl with high selectivity among reactive oxygen species by achieving a detection limit of 2.41 μM. It successfully detects both exogenous and endogenous HOCl in live cells, enabling the study of HOCl's role at the organelle level. Structural analysis of PSSM via thioether oxidation confirmed by HPLC, NMR and HRMS further supports its specificity. Confocal imaging and flow cytometry studies further highlights its utility in investigating oxidative stress, positioning this fluorophore as a valuable tool for monitoring HOCl imbalances in biological systems.

Sequence termination cues drive habits via dopamine-mediated credit assignment.

Mesolimbic dopamine (DA) neurons are central to sequence learning and habit formation. Yet, the mechanisms by which cue-induced DA neural activity drives goal-directed or habitual sequence execution remain unknown. We designed two novel tasks to investigate how sequence initiation and termination cues influence DA-driven behavioral strategies and learning. We found that sequence initiation and termination cues differentially affect reward expectation during action sequences, with only the termination cue contributing to greater outcome devaluation insensitivity, automaticity and behavioral chunking. Mesolimbic fiber photometry recording revealed that this habit-like behavior was associated with a rapid backpropagation in DA signals from the reward to the immediately preceding cue and with attenuated DA reward prediction error signals, which reflected greater behavioral inflexibility. Finally, in absence of external cues, brief optogenetic stimulation of VTA DA neurons at sequence termination was sufficient to drive automaticity and behavioral chunking. Our results highlight the critical role of cue-evoked DA signals at sequence termination in mediating credit assignment and driving the development of habitual action sequence execution.

The contribution of cutaneous thermal signals to bodily self-awareness

Thermosensory signals may contribute to the sense of body ownership, but their role remains highly debated. We test this assumption within the framework of pathological body ownership, hypothesising that skin temperature and thermoception differ between right-hemisphere stroke patients with and without Disturbed Sensation of Ownership (DSO) for the contralesional plegic upper limb. Patients with DSO exhibit lower basal hand temperatures bilaterally and impaired perception of cold and warm stimuli. Lesion mapping reveals associations in the right Rolandic Operculum and Insula, with these regions linked to lower skin temperature located posterior to those associated with thermoception deficits. Disconnections in bilateral parietal regions are associated with lower hand temperature, while disconnections in a right-lateralized thalamus-parietal hub correlate with thermoception deficits. We discuss the theoretical implications of these findings in the context of the ongoing debate on the role of homeostatic signals in shaping a coherent sense of body ownership.

Computational screening and molecular dynamics of natural compounds targeting the SH2 domain of STAT3: a multitarget approach using network pharmacology.

SH2 (Src Homology 2) domains play a crucial role in phosphotyrosine-mediated signaling and have emerged as promising drug targets, particularly in cancer therapy. STAT3 (Signal Transducer and Activator of Transcription 3), which contains an SH2 domain, plays a pivotal role in cancer progression and immune evasion because it facilitates the dimerization of STAT3, which is essential for their activation and subsequent nuclear translocation. SH2 domain-mediated STAT3 inhibition disrupts this binding, reduces phosphorylation of STAT3, and impairs dimerization. This study employed an in silico approach to screen potential natural compounds that could target the SH2 domain of STAT3 and inhibit its function. The phytomolecules (182455) were retrieved from the ZINC 15 database and were docked using various modes like HTVS, SP, and XP. The phytomolecules exhibiting higher binding affinity were selected. MM-GBSA was performed to determine binding free energy, and the QikProp tool was utilized to assess the pharmacokinetic properties of potential hit compounds, narrowing down the list of candidates. Molecular dynamics simulations, thermal MM-GBSA, and WaterMap analysis were performed on compounds that exhibited favorable binding affinities and pharmacokinetic characteristics. Based on docking scores and binding interactions, ZINC255200449, ZINC299817570, ZINC31167114, and ZINC67910988 were identified as potential STAT3 inhibitors. ZINC67910988 demonstrated superior stability in molecular dynamics simulation and WaterMap analysis. Furthermore, DFT was performed to determine energetic and electronic properties, and HOMO and LUMO sites were predicted for electronic structure calculation. Additionally, network pharmacology was performed to map the compounds' interactions within biological networks, highlighting their multitarget potential. Compound-target networks elucidate the relationships between compounds and multiple targets, along with their associated pathways and help to minimize off-target effects. The identified lead compound showed strong potential as a STAT3 inhibitor, warranting further validation through in vitro and in vivo studies.

Sonic Hedgehog signaling regulates the optimal differentiation pace from early-stage mesoderm to cardiogenic mesoderm in mice.

Sonic Hedgehog (Shh), encoding an extracellular signaling molecule, is vital for heart development. Shh null mutants show congenital heart disease due to left-right asymmetry defects stemming from functional anomaly in the midline structure in mice. Shh signaling is also known to affect cardiomyocyte differentiation, endocardium development, and heart morphogenesis, particularly in second heart field (SHF) cardiac progenitor cells that contribute to the right ventricle, outflow tract, and parts of the atrium. Despite extensive studies, our understanding remains incomplete. Notably, Shh signaling is suggested to promote cardiac differentiation, while paradoxically preventing premature differentiation of SHF progenitors. In this study, we elucidate the role of Shh signaling in the earliest phase of cardiac differentiation. Our meta-analysis of single-cell RNA sequencing suggests that cardiogenic nascent mesoderm cells expressing the bHLH transcription factor Mesp1 interact with axial mesoderm via Hh signaling. Activation of Hh signaling using a Smoothened agonist delayed or suppressed the differentiation of primitive streak cells expressing T-box transcription factor T to Mesp1+ nascent mesoderm cells both in vitro and ex vivo. Conversely, inhibition of Hh signaling by cyclopamine facilitated cardiac differentiation. The reduction of Eomes, an inducer of Mesp1, by Hh signaling appears to be the underlying mechanism of this phenomenon. Our data suggest that SHH secreted from axial mesoderm inhibits premature differentiation of T+ cells to Mesp1+ nascent mesoderm cells, thereby regulating the pace of cardiac differentiation. These findings enhance our comprehension of Shh signaling in cardiac development, underscoring its crucial role in early cardiac differentiation.

Neuroprotective Effects of Sodium Nitroprusside on CKD-Induced Cognitive Dysfunction in Rats: Role of CBS and Nrf2/HO-1 Pathway.

Chronic kidney disease (CKD) is a conceivable new risk factor for cognitive disorder and dementia. Uremic toxicity, oxidative stress, and peripheral-central inflammation have been considered important mediators of CKD-induced nervous disorders. Nitric oxide (NO) is a retrograde neurotransmitter in synapses, and has vital roles in intracellular signaling in neurons. This research aims to determine the effectiveness of NO in CKD-induced cognitive deficits by considering the nuclear factor-erythroid factor 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling pathway and the important roles of cystathionine beta-synthase (CBS, H2S producing enzyme). Forty rats were divided into four experimental groups: sham, five-sixth (5/6) nephrectomy (5/6Nx, CKD), CKD + NO donor (Sodium nitroprusside, SNP), CKD + SNP and a CBS inhibitor (amino-oxy acetic acid, AOAA). To assess the neurocognitive abilities, eleven weeks after 5/6Nx, behavioral tests (Novel object recognition test, Passive avoidance test, and Barnes maze test) were done. Twelfth week after 5/6Nx, blood urea nitrogen (BUN) and serum creatinine (sCr) levels, as well as the nuclear factor-erythroid factor 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) expression levels and neuronal injury in the hippocampus and prefrontal cortex were assessed. As predicted, the levels of BUN and sCr (both P < 0.001) and neuronal injury in the hippocampus (P < 0.001 for CA1; CA3; DG) and prefrontal cortex (P < 0.001) increased in CKD rats as well as 5/6Nx induced reduction of Nrf2 (both P < 0.001) /HO-1(P < 0.001; P < 0.01 respectively) pathway activity in the hippocampus and prefrontal cortex in CKD rats. Moreover, CKD leads to cognitive disorder and memory loss (Novel object recognition test (NOR) (P < 0.001), Passive avoidance test (PA) (P < 0.001) and Barnes maze (BA) (Escape latency (P < 0.001); Error (P < 0.001)). SNP treatment significantly improved Nrf2 (both P < 0.001) /HO-1 (P < 0.001; P < 0.05 respectively) pathways and neuronal injury (P < 0.001 for CA1; CA3; DG) in the hippocampus and prefrontal cortex in CKD rats as well as enhanced learning and memory ability in CKD rats. However, ameliorating effects of SNP on cognitive disorder (NOR (P < 0.05), PA (P < 0.001) and BA (Escape latency (P < 0.05); Error (P < 0.001)) and Nrf2 (P < 0.01; P < 0.001 in the hippocampus and prefrontal cortex respectively) /HO-1 (P < 0.05 in both) signaling pathway activity were nullified by CBS inhibitor and H2S reduction. In conclusion, this study demonstrated that NO improved CKD-induced cognitive impairment and neuronal death which is may be depended to CBS activity and endogenous H2S levels.

New insights on the regulators and inhibitors of RhoA-ROCK signalling in Parkinson's disease.

A multifaceted and widely prevalent neurodegenerative disease, Parkinson's disease (PD) is typified by the loss of dopaminergic neurons in the midbrain. The discovery of novel treatment(s) that can reverse or halt the course of the disease progression along with identifying the most reliable biomarker(s) in PD remains the crucial concern. RhoA in its active state has been demonstrated to interact with three distinct domains located in the central coiled-coil region of ROCK. RhoA appears to activate effectors most frequently by breaking the intramolecular autoinhibitory connections, which releases functional domains from the effector protein. Additionally, RhoA is highly expressed in the nervous system and it acts as a central molecule for its several downstream effector proteins in multiple signalling pathways both in neurons and glial cells. Mitochondrial dysfunction, vesicle transport malfunction and aggregation of α-Synuclein, a presynaptic neuronal protein genetically and neuropathologically associated with PD. While the RhoA-ROCK signalling pathway appears to have a significant role in PD symptoms, suggesting it could be a promising target for therapeutic interventions. Thus, this review article addresses the potential involvement of the RhoA-ROCK signalling system in the pathophysiology of neurodegenerative illnesses, with an emphasis on its biology and function. We also provide an overview of the state of research on RhoA regulation and its downstream biological activities, focusing on the role of RhoA signalling in neurodegenerative illnesses and the potential benefits of RhoA inhibition as a treatment for neurodegeneration.

Thyroid hormones reversibly inhibit metamorphic development in ophiuroid larvae.

The timing of metamorphosis and settlement is critical for the survival and reproductive success of marine animals with biphasic life cycles. Thyroid hormones (THs) regulate developmental timing in diverse groups of chordates, including the regulation of metamorphosis in amphibians, teleosts, lancelets, tunicates, and lampreys. Recent evidence suggests a role for TH regulation of metamorphosis outside of the chordates, including echinoderms, annelids, and molluscs. Among echinoderms, TH effects on development as well as underlying signaling mechanisms in early embryogenesis have been documented for echinoid (sea urchin) larvae, but we lack information on TH effects on metamorphic development in most other echinoderm groups, including the ophiuroids (brittle stars). Unexpectedly, we found that THs, principally 3,5,3',5'-Tetraiodo-L-thyronine (T4), reversibly inhibit metamorphic development and settlement in the brittle star (Ophiopholis aculeata; daisy brittle star). Exposure to thiourea, an inhibitor of TH synthesis, accelerated metamorphic development. We showed that these effects were highly stage specific, providing evidence for a developmental point-of-no-return in ophiuroid metamorphic development. Furthermore, starvation of O. aculeata accelerates juvenile morphogenesis and settlement. Starvation also prevents the inhibitory effect of thiourea on TH function, suggesting that TH synthesis may play a role in delaying metamorphosis under conditions of high food availability. These findings provide evidence for a function of TH signaling in ophiuroid metamorphic development and suggest that exogenous thyroid hormone sources may be involved in the regulation of metamorphic timing in O. aculeata. Together with new evidence of TH involvement in metamorphic development in a range of invertebrates, these findings further emphasize the versatile and central role of endocrine signaling in metamorphosis.

Accurate sequence-to-affinity models for SH2 domains from multi-round peptide binding assays coupled with free-energy regression.

Short linear peptide motifs play important roles in cell signaling. They can act as modification sites for enzymes and as recognition sites for peptide binding domains. SH2 domains bind specifically to tyrosine-phosphorylated proteins, with the affinity of the interaction depending strongly on the flanking sequence. Quantifying this sequence specificity is critical for deciphering phosphotyrosine-dependent signaling networks. In recent years, protein display technologies and deep sequencing have allowed researchers to profile SH2 domain binding across thousands of candidate ligands. Here, we present a concerted experimental and computational strategy that improves the predictive power of SH2 specificity profiling. Through multi-round affinity selection and deep sequencing with large randomized phosphopeptide libraries, we produce suitable data to train an additive binding free energy model that covers the full theoretical ligand sequence space. Our models can be used to predict signaling network connectivity and the impact of missense variants in phosphoproteins on SH2 binding.