Components Of Signaling Pathway Research Articles

Glycogen Synthase Kinase 3 beta confers refractoriness to the microRNA-210-elicited exacerbation of hypoxia-reoxygenation stress-induced apoptotic cell death

Abstract Introduction Apoptotic cell death is a detrimental signatory molecular hallmark of Ischemia / Reperfusion (I/R) injury. Despite the exhaustive findings and significant advancements in the realm of I/R research, there is a paucity of viable molecular strategies that could be targeted to combat the underlying deleterious biochemical pathways that precipitate Hypoxia-Reoxygenation (H-R) stress, the cellular manifestation of I/R injury. The master hypoxamiR, microRNA-210 (miR-210), is an indispensable molecular component of the protective cellular adaptive response to hypoxia stress that paradoxically exacerbates apoptotic cell death during the cellular reoxygenation phase. While the entire repertoire of molecular entities mediating this paradoxical deleterious impact of miR-210 on H-R stress induced apoptotic cell death are largely unknown, recent studies have unveiled and posited, the evolutionary conserved serine/threonine kinase, Glycogen Synthase Kinase 3 beta (GSK3β) as a pivotal molecular focal point of the convergent and divergent signaling cascades that modulate the miR-210-regulated apoptotic cell death during the cellular reoxygenation phase. Purpose In this study, we elucidated and delineated the role of GSK3β (in)activation in the miR-210-induced exacerbation of the H-R stress-induced apoptotic cell death in AC-16 cardiomyocytes. Methods Using transient overexpression vectors and decoy / inhibition vectors to modulate miR-210 expression concomitant with the ectopic expression of the constitutive active GSK3β S9A (ca-GSK3β S9A) and the catalytically-dead dominant negative GSK3β K85A (dn-GSK3β K85A) mutants, we performed exhaustive biochemical and molecular assays determining apoptotic cell death in AC-16 cardiomyocytes subjected H-R stress. Results Caspase-3 activity analysis coupled with DNA fragmentation assays demonstrated that the H-R driven augmented GSK3β kinase activity significantly attenuates the miR-210-induced exacerbation of H-R evoked apoptotic cell death during the cellular reoxygenation phase. Resolution of the multimodal components of the apoptotic signaling pathway, unveiled that the H-R driven augmented GSK3β kinase activity modestly increases the miR-210-driven exacerbation of the intrinsic apoptotic pathway during the cellular reoxygenation phase, as molecularly inferred by the levels of the release of Cytochrome C from the mitochondria into the cytosol. However, in a stark contrast, H-R driven augmented GSK3β kinase activity concomitantly overwhelmingly attenuated the flux through the extrinsic apoptotic pathway during the cellular reoxygenation phase, as molecularly inferred by caspase-8 activity analysis. Conclusion Our study is the first to unveil that the H-R driven augmented GSK3β kinase activity during the cellular reoxygenation phase, is an inherent protective cellular adaptive response that mitigates the miR-210-orchestrated exacerbation of the cellular reoxygenation-elicited apoptotic cell death.

Food deprivation reduces sensitivity of liver Igf1 synthesis pathways to growth hormone in juvenile gopher rockfish (Sebastes carnatus)

Growth hormone (Gh) regulates growth in part by stimulating the liver to synthesize and release insulin-like growth factor-1 (Igf1), which then promotes somatic growth. However, for fish experiencing food limitation, elevated blood Gh can occur even with low circulating Igf1 and slow growth, suggesting that nutritional stress can alter the sensitivity of liver Igf1 synthesis pathways to Gh. Here, we examined how recent feeding experience affected Gh regulation of liver Igf1 synthesis pathways in juvenile gopher rockfish (Sebastes carnatus) to illuminate mechanisms underlying the nutritional modulation of Igf1 production. Juvenile gopher rockfish were maintained under conditions of feeding or complete food deprivation (fasting) for 14 d and then treated with recombinant sea bream (Sparus aurata) Gh or saline control. Gh upregulated hepatic igf1 mRNA levels in fed fish but not in fasted fish. The liver of fasted rockfish also showed a lower relative abundance of gene transcripts encoding teleost Gh receptors 1 (ghr1) and 2 (ghr2), as well as reduced protein levels of phosphorylated janus tyrosine kinase 2 (pJak2) and signal transducer and activator of transcription 5 (pStat5), which function to induce igf1 gene transcription following Gh binding to Gh receptors. Relative hepatic mRNA levels for suppressors of cytokine signaling (Socs) genes socs2, socs3a, and socs3b were also lower in fasted rockfish. Socs2 can suppress Gh activation of Jak2/Stat5, and fasting-related variation in socs expression may reflect modulated inhibitory control of igf1 gene transcription. Fasted rockfish also had elevated liver mRNA abundances for lipolytic hormone-sensitive lipase 1 (hsl1) and Igf binding proteins igfbp1a, -1b and –3a, reduced liver mRNAs encoding igfbp2b and an Igfbp acid labile subunit-like (igfals) gene, and higher transcript abundances for Igf1 receptors igf1ra and igf1rb in skeletal muscle. Together, these findings suggest that food deprivation impacts liver Igf1 responsiveness to Gh via multiple mechanisms that include a downregulation of hepatic Gh receptors, modulation of the intracellular Jak2/Stat5 transduction pathway, and possible shifts in Socs-inhibitory control of igf1 gene transcription, while also demonstrating that these changes occur in concert with shifts in liver Igfbp expression and muscle Gh/Igf1 signaling pathway components.

Absence of the primary cilia formation gene Talpid3 impairs muscle stem cell function

Skeletal muscle stem cells (MuSC) are crucial for tissue homoeostasis and repair after injury. Following activation, they proliferate to generate differentiating myoblasts. A proportion of cells self-renew, re-enter the MuSC niche under the basal lamina outside the myofiber and become quiescent. Quiescent MuSC have a primary cilium, which is disassembled upon cell cycle entry. Ex vivo experiments suggest cilia are important for MuSC self-renewal, however, their requirement for muscle regeneration in vivo remains poorly understood. Talpid3 (TA3) is essential for primary cilia formation and Hedgehog (Hh) signalling. Here we use tamoxifen-inducible conditional deletion of TA3 in MuSC (iSC-KO) and show that regeneration is impaired in response to cytotoxic injury. Depletion of MuSC after regeneration suggests impaired self-renewal, also consistent with an exacerbated phenotype in TA3iSC-KO mice after repeat injury. Single cell transcriptomics of MuSC progeny isolated from myofibers identifies components of several signalling pathways, which are deregulated in absence of TA3, including Hh and Wnt. Pharmacological activation of Wnt restores muscle regeneration, while purmorphamine, an activator of the Smoothened (Smo) co-receptor in the Hh pathway, has no effect. Together, our data show that TA3 and primary cilia are important for MuSC self-renewal and pharmacological treatment can efficiently restore muscle regeneration.

ASO Visual Abstract: Expression of Wnt5a and ROR2, Components of the Noncanonical Wnt Signaling Pathway, is Associated with Tumor Differentiation in Hepatocellular Carcinoma.

ASO Visual Abstract: Expression of Wnt5a and ROR2, Components of the Noncanonical Wnt Signaling Pathway, is Associated with Tumor Differentiation in Hepatocellular Carcinoma.

Identification of MicroRNAs Associated with Prediabetic Status in Obese Women.

MicroRNAs (miRNAs) recently emerged as means of communication between insulin-sensitive tissues to mediate diabetes development and progression, and as such they present a valuable proxy for epigenetic alterations associated with type 2 diabetes. In order to identify miRNA markers for the precursor of diabetes called prediabetes, we applied a translational approach encompassing analysis of human plasma samples, mouse tissues and an in vitro validation system. MiR-652-3p, miR-877-5p, miR-93-5p, miR-130a-3p, miR-152-3p and let-7i-5p were increased in plasma of women with impaired fasting glucose levels (IFG) compared to those with normal fasting glucose and normal glucose tolerance (NGT). Among these, let-7i-5p and miR-93-5p correlated with fasting blood glucose levels. Human data were then compared to miRNome data obtained from islets of Langerhans and adipose tissue of 10-week-old female New Zealand Obese mice, which differ in their degree of hyperglycemia and liver fat content. Similar to human plasma, let-7i-5p was increased in adipose tissue and islets of Langerhans of diabetes-prone mice. As predicted by the in silico analysis, overexpression of let-7i-5p in the rat β-cell line INS-1 832/12 resulted in downregulation of insulin signaling pathway components (Insr, Rictor, Prkcb, Clock, Sos1 and Kcnma1). Taken together, our integrated approach highlighted let-7i-5p as a potential regulator of whole-body insulin sensitivity and a novel marker of prediabetes in women.

PKCζ phosphorylates VASP to mediate chemotaxis in breast cancer cells

Breast carcinoma (BC) is one of the most common malignant cancers in females, and metastasis remains the leading cause of death in these patients. Chemotaxis plays an important role in cancer cell metastasis and the mechanism of breast cancer chemotaxis has become a central issue in contemporary research. PKCζ, a member of the atypical PKC family, has been reported to be an essential component of the EGF-stimulated chemotactic signaling pathway. However, the molecular mechanism through which PKCζ regulates chemotaxis remains unclear. Here, we used a proteomic approach to identify PKCζ-interacting proteins in breast cancer cells and identified VASP as a potential binding partner. Intriguingly, stimulation with EGF enhanced this interaction and induced the translocalization of PKCζ and VASP to the cell membrane. Further experiments showed that PKCζ catalyzes the phosphorylation of VASP at Ser157, which is critical for the biological function of VASP in regulating chemotaxis and actin polymerization in breast cancer cells. Furthermore, in PKCζ knockdown BC cells, the enrichment of VASP at the leading edge was reduced, and its interaction with profilin1 was attenuated, thereby reducing the chemotaxis and overall motility of breast cancer cells after EGF treatment. In functional assays, PKCζ promoted chemotaxis and motility of BC cells through VASP. Our findings demonstrate that PKCζ, a new kinase of VASP, plays an important role in promoting breast cancer metastasis and provides a theoretical basis for expanding new approaches to tumor biotherapy.

DDX20: A Multifunctional Complex Protein.

DEAD-box decapping enzyme 20 (DDX20) is a putative RNA-decapping enzyme that can be identified by the conserved motif Asp-Glu-Ala-Asp (DEAD). Cellular processes involve numerous RNA secondary structure alterations, including translation initiation, nuclear and mitochondrial splicing, and assembly of ribosomes and spliceosomes. DDX20 reportedly plays an important role in cellular transcription and post-transcriptional modifications. On the one hand, DDX20 can interact with various transcription factors and repress the transcriptional process. On the other hand, DDX20 forms the survival motor neuron complex and participates in the assembly of snRNP, ultimately affecting the RNA splicing process. Finally, DDX20 can potentially rely on its RNA-unwinding enzyme function to participate in microRNA (miRNA) maturation and act as a component of the RNA-induced silencing complex. In addition, although DDX20 is not a key component in the innate immune system signaling pathway, it can affect the nuclear factor kappa B (NF-κB) and p53 signaling pathways. In particular, DDX20 plays different roles in tumorigenesis development through the NF-κB signaling pathway. This process is regulated by various factors such as miRNA. DDX20 can influence processes such as viral replication in cells by interacting with two proteins in Epstein-Barr virus and can regulate the replication process of several viruses through the innate immune system, indicating that DDX20 plays an important role in the innate immune system. Herein, we review the effects of DDX20 on the innate immune system and its role in transcriptional and post-transcriptional modification processes, based on which we provide an outlook on the future of DDX20 research in innate immunity and viral infections.

A novel role for the chloride intracellular channel protein Clic5 in ciliary function

CLIC5 belongs to a family of ion channels with six members reported so far. In vertebrates, the CLIC5 gene encodes two different isoforms, CLIC5A and CLIC5B. In addition to its ion channel activity, there is evidence for further functions of CLIC5A, such as the remodeling of the actin cytoskeleton during the formation of a functional glomerulus in the vertebrate kidney. However, its specific role is still incompletely understood and a specific functional role for CLIC5B has not been described yet. Here we report our findings on the differential expression and functions of Clic5a and Clic5b during zebrafish kidney development. Whole-mount in situ hybridization studies revealed specific expression of clic5a in the eye and pronephric glomerulus, and clic5b is expressed in the gut, liver and the pronephric tubules. Clic5 immunostainings revealed that Clic5b is localized in the cilia. Whereas knockdown of Clic5a resulted in leakiness of the glomerular filtration barrier, Clic5b deficient embryos displayed defective ciliogenesis, leading to ciliopathy-associated phenotypes such as ventral body curvature, otolith deposition defects, altered left–right asymmetry and formation of hydrocephalus and pronephric cysts. In addition, Clic5 deficiency resulted in dysregulation of cilia-dependent Wnt signalling pathway components. Mechanistically, we identified a Clic5-dependent activation of the membrane-cytoskeletal linker proteins Ezrin/Radixin/Moesin (ERM) in the pronephric tubules of zebrafish. In conclusion, our in vivo data demonstrates a novel role for Clic5 in regulating essential ciliary functions and identified Clic5 as a positive regulator of ERM phosphorylation.

Genome wide identification and expression profiling of PYL genes in barley

PYLs (pyrabactin resistance1/PYR1-like) sense ABA, an essential phytohormone that regulates plant growth and stress responses. PYLs act as the main controllers of ABA stress signaling in plants. In this study, a total of 10 HvPYLs were discovered in the barley genome using an in silico genome search technique. These HvPYLs were then grouped into 3 subfamilies based on a phylogenetic analysis that compared them to the genomes of Arabidopsis, Brachypodium, rice, and maize. These HvPYLs demonstrated conserved motif compositions and identical protein structures across clades. Additionally, this study includes detailed investigations of gene structure variations, chromosomal distributions, cis-regulatory elements, protein-protein interactions, expression profiles in different tissues, and stress responses. We identified various cis-elements in the HvPYL promoter regions related to plant development and stresses indicating their potential roles in development and stress management. Our analysis of the interaction network has identified that HvPYLs can interact with key components of the ABA signaling pathway, demonstrating the critical regulatory functions of HvPYL genes in managing stress and growth in barley. These findings provide a basis for future research aimed at exploring the functions of PYL genes, with the ultimate goal of enhancing stress tolerance in barley and other related species.

Angelica sinensis polysaccharide inhibits inflammation of collagen-induced arthritis rat fibroblast-like synoviocytes by inhibiting JAK2/STAT3 and MAPK signaling

A. sinensis polysaccharide (ASP), one of the effective components of A. sinensis, has been used to treat inflammatory diseases in China. However, its effect on rheumatoid arthritis (RA) is unknown. The purpose of this study was to explore the anti-inflammatory effects and mechanisms of ASP on RA using a rat model of collagen-induced arthritis (CIA). For evaluation of the therapeutic effects of ASP in vitro, the CIA model was used. Our study showed that ASP (100 and 200 μg/mL) dose-dependently inhibited tumor necrosis factor (TNF)-α-induced (10 ng/mL) proliferation, migration, and invasion of fibroblast-like synovial (FLS) cells, promoted apoptosis, and arrested the cell cycle in G0/G1 phase (P < 0.05). In vivo, ASP increased body weight in CIA rats while decreasing paw swelling, arthritis score, and synovial tissue proliferation (P < 0.05). ASP also reduced the expression of pro-inflammatory cytokines (interleukin (IL) −6, IL-1β, inducible nitric oxide synthetase (iNOS), matrix metalloproteinase (MMP)-1 and MMP-3) (P < 0.05). ASP inhibited the phosphorylation of JAK2/STAT3 and MAPK signaling pathway components (P < 0.05) induced by TNF-α in CIA-FLS cells. Using JAK and p38 inhibitors, we found that JAK2/STAT3 might be an upstream pathway of MAPK. In conclusion, our study investigated the therapeutic effects of ASP in RA in vitro and in vivo. Our research suggests that ASP can inhibit the invasiveness and secretion of inflammatory cytokines of FLS cells in CIA rats via JAK2/STAT3 and MAPK signaling. Elucidation of the underlying mechanism will provide a theoretical basis for clinical application of ASP.

Cables1 links Slit/Robo and Wnt/Frizzled signaling in commissural axon guidance.

During neural circuit formation, axons navigate from one intermediate target to the next, until they reach their final target. At intermediate targets, axons switch from being attracted to being repelled by changing the guidance receptors on the growth cone surface. For smooth navigation of the intermediate target and the continuation of their journey, the switch in receptor expression has to be orchestrated in a precisely timed manner. As an alternative to changes in expression, receptor function could be regulated by phosphorylation of receptors or components of signaling pathways. We identified Cables1 as a linker between floor-plate exit of commissural axons, regulated by Slit/Robo signaling, and the rostral turn of post-crossing axons, regulated by Wnt/Frizzled signaling. Cables1 localizes β-catenin, phosphorylated at tyrosine 489 by Abelson kinase, to the distal axon, which in turn is necessary for the correct navigation of post-crossing commissural axons in the developing chicken spinal cord.

Deciphering mitogen activated protein kinase pathway activated during insect attack in Nicotiana attenuata

Plant yields are compromised due to abiotic and biotic stresses. A crucial biotic stress instigated by insect attack, is a major concern that limits crop production. To overcome the deleterious effect of herbivory, pesticides are used but long-term usage of pesticides can be harmful to the environment and human health. Understanding the plants’ inherent defense mechanism by interpreting the interaction pattern of defense-related proteins and signalling components and manipulating them to strengthen defense status, is one of the alternative approaches of green biotechnology. During insect attack, host plants initiate innumerable signalling pathways to activate defense response; Mitogen Activated Protein Kinase (MAPK) Pathway is a crucial component of signalling pathway that regulate the expression of downstream defense-related genes. MAPK pathway has three components: MAPKKK, MAPKK and MAPK. Earlier studies have shown participation of SIPK and WIPK (MAPKs) as well as MEK2 (MAPKK) during insect infestation and its association with plant defense. However, information on the third component and elucidation of the complete MAPK pathway are still elusive. Therefore, this study aims to identify the unknown component and decipher MAPK pathway in Nicotiana attenuata involved in plant defense against herbivory by identifying herbivory-inducible MAPKKKs and and their interaction with known partners of the MAPK pathway by docking and MD simulation. The possible pathway was predicted to be MAPKKK Na12134/Na04522-MEK2-SIPK/WIPK. Further, validation of the above interaction by in vitro and in vivo methods is highly recommended. Communicated by Ramaswamy H. Sarma

Optimized new Shengmai powder ameliorates myocardial fibrosis in rats with heart failure by inhibition of the MAPK signaling pathway

Ethnopharmacological relevanceOptimized New Shengmai Powder (ONSMP) is a traditional Chinese medicine (TCM) formula for heart failure treatment. MAPK signaling pathway is the key driver of myocardial fibrosis in heart failure. However, the mechanism of ONSMP on myocardial fibrosis and MAPK signaling pathway remains unclear. Aim of the studyTo evaluate the effect of ONSMP against myocardial fibrosis in heart failure and the underlying mechanisms. Materials and methodsFirstly, UHPLC-Q-Exactive-MS/MS was used to identify the active components in ONSMP. Secondly, a rat model of heart failure was established by ligating the left anterior descending branch of the coronary artery. After four weeks of intragastric administration of ONSMP, we used various classic tests, including echocardiography, exhaustive swimming, cardiopulmonary coefficient, heart failure markers, and cardiac pathological section, to assess the prescription's anti-myocardial fibrosis in heart failure properties. AGEs, Ang Ⅱ, VEGF, CTGF, and TGFβ levels in rat serum were quantified using ELISA. The positive expression of p-ERK1/2 and p-JNK1/2 of rat myocardium was determined immunohistochemical. The protein and mRNA levels of genes involved in the MAPK signaling pathway and myocardial fibrosis were measured using western blotting or real-time PCR. ResultsThe main components of ONSMP that regulate the MAPK signaling pathway are isorhamnetin, kaempferol, quercetin, and tanshinone ⅡA. ONSMP ameliorated cardiac function and exercise tolerance and reduced cardiopulmonary coefficient, heart failure marker levels, and myocardial fibrosis in the heart failure rats. In addition, ONSMP diminished the serum MAPK pathway activator levels, positive expression level of p-ERK1/2 and p-JNK1/2, protein and mRNA levels of components of the MAPK signaling pathway in the myocardial tissue of heart failure rat, indicating that it inhibits MAPK signaling pathway. ConclusionsONSMP delayed heart failure by inhibiting myocardial fibrosis via the MAPK signaling pathway.

The G protein-coupled receptor COLD1 promotes chilling tolerance in maize during germination

The geographic range and yield of the staple crop maize (Zea mays L.) are both strongly limited by low-temperature conditions. One of the most economical and effective measures for improvement of maize production is chilling tolerance enhancement. In this study, a chilling-tolerance gene in maize, ZmCOLD1, was cloned and characterized. This gene encodes a G protein-coupled receptor that is localized to the plasma membrane and the endoplasmic reticulum. A single nucleotide polymorphism (SNP) in ZmCOLD1, SNP2738, was found to confer chilling tolerance and to have promoted maize adaptations during speciation from teosinte. Overexpression of the excellent haplotype ZmCOLD1Hap11 significantly enhanced chilling tolerance, whereas knocking down ZmCOLD1 increased sensitivity to low temperatures during the germination and seedling stages. ZmCOLD1 was associated with an influx of extracellular Ca2+, increases in abscisic acid content, and decreases in gibberellic acid and indole-3-acetic acid content under low temperatures during the germination stage. ZmCOLD1 interacted with the G protein α subunit ZmCT2 at the plasma membrane, and ZmCT2 interacted with ZmLanCL in the nucleus. These proteins are components of the chilling tolerance signaling pathway in maize that are triggered by abscisic acid and photosynthesis. These results offer novel strategies for improvement of chilling tolerance in key crop species.

Diversification of plant SUPPRESSOR OF MAX2 1 (SMAX1)-like genes and genome-wide identification and characterization of cotton SMXL gene family

BackgroundStrigolactones (SLs) are a recently discovered class of plant hormones. SUPPRESSOR OF MAX2 1 (SMAX1)-like proteins, key component of the SL signaling pathway, have been studied extensively for their roles in regulating plant growth and development, such as plant branching. However, systematic identification and functional characterization of SMXL genes in cotton (Gossypium sp.), an important fiber and oil crop, has rarely been conducted.ResultsWe identified 210 SMXL genes from 21 plant genomes and examined their evolutionary relationships. The structural characteristics of the SMXL genes and their encoded proteins exhibited both consistency and diversity. All plant SMXL proteins possess a conserved Clp-N domain, P-loop NTPase, and EAR motif. We identified 63 SMXL genes in cotton and classified these into four evolutionary branches. Gene expression analysis revealed tissue-specific expression patterns of GhSMXL genes, with some upregulated in response to GR24 treatment. Protein co-expression network analysis showed that GhSMXL6, GhSMXL7-1, and GhSMXL7-2 mainly interact with proteins functioning in growth and development, while virus-induced gene silencing revealed that GhSMAX1-1 and GhSMAX1-2 suppress the growth and development of axillary buds.ConclusionsSMXL gene family members show evolutionary diversification through the green plant lineage. GhSMXL6/7–1/7–2 genes play critical roles in the SL signaling pathway, while GhSMXL1-1 and GhSMXL1-2 function redundantly in growth of axillary buds. Characterization of the cotton SMXL gene family provides new insights into their roles in responding to SL signals and in plant growth and development. Genes identified in this study could be used as the candidate genes for improvement of plant architecture and crop yield.

The association of Sirtuin1 (SIRT1) polymorphism and downregulation of STAT4 gene expression with increased susceptibility to COVID-19 infection

ABSTRACT Sirtuin1 (SIRT1) is an epigenetic modulator that belongs to sirtuins family and participates in many physiologic reactions, as genomic stabilization, apoptosis, proliferation, and inflammation. STAT4 (signal transducer and activator of transcription 4) gene is a component of JAK-STAT signaling pathway, which plays key role in activating cellular-mediated immune responses. The present study aimed to investigate the association between SIRT1 rs12778366 SNP, expression level of STAT4 gene and susceptibility to COVID-19 infections as well as their correlation to clinicopathological data. The present study included 100 ICU patients with severe COVID-19 infection and 100 age- and sex-matched healthy controls. DNA was extracted. Genotyping of SNP in SIRT1 (rs12778366) was performed, Total RNA was extracted from PBMCs. Reverse transcription was done. STAT4 gene expression levels were evaluated with GAPDH as internal control using real-time PCR. We found a significantly higher frequency of ‘C’ allele and C/T genotype in case vs. control. The association was of low strength (φ = 0.105 for alleles, and 0.154 for genotypes). This was associated with higher expression of STAT4 gene (P < 0.001) and increased tendency for lower respiratory complications. Median STAT4 (FC) (Median = 0.18, 95% CI = 0.15–0.27) was lower than normal control value of 1.0. This difference was statistically significant (Hodges-Lehmann location estimator = 0.217, P < 0.001). SIRT1 polymorphism and decreased expression of STAT4 gene are associated with increased susceptibility to COVID-19 infection and correlate to its phenotypic manifestations.

Aristaless-like homeobox-3 is wound induced and promotes a low-Wnt environment required for planarian head regeneration.

The planarian Schmidtea mediterranea is a well-established model of adult regeneration, which is dependent on a large population of adult stem cells called neoblasts. Upon amputation, planarians undergo transcriptional wounding programs and coordinated stem cell proliferation to give rise to missing tissues. Interestingly, the Wnt signaling pathway is key to guiding what tissues are regenerated, yet less known are the transcriptional regulators that ensure proper activation and timing of signaling pathway components. Here, we have identified an aristaless-like homeobox transcription factor, alx-3, that is enriched in a population of putative neural-fated progenitor cells at homeostasis, and is also upregulated in stem cells and muscle cells at anterior-facing wounds upon amputation. Knockdown of alx-3 results in failure of head regeneration and patterning defects in amputated tail fragments. alx-3 is required for the expression of several early wound-induced genes, including the Wnt inhibitor notum, which is required to establish anterior polarity during regeneration. Together, these findings reveal a role for alx-3 as an early wound-response transcriptional regulator in both muscle cells and stem cells that is required for anterior regeneration by promoting a low-Wnt environment.

Genome-wide identification of ETHYLENE INSENSITIVE 2 in Triticeae species reveals that TaEIN2-4D.1 regulates cadmium tolerance in Triticum aestivum

ETHYLENE INSENSITIVE 2 (EIN2), as the core component of the ethylene signaling pathway, can widely regulate plant growth, development, and stress responses. However, the comprehensive study and function of EIN2 in wheat Cadmium (Cd) stress remain largely unexplored. Here, we identified 33 EIN2 genes and designated as TaEIN2-2B to TaEIN2-Un.3 in Triticum aestivum. The analysis of cis-regulatory elements in promoter regions and RNA-Seq showed that TaEIN2s were functionally related to plant growth and development, as well as the response to biotic and abiotic stress. qRT-PCR analysis of TaEIN2s indicated their sensitivity to Cd stress. Compared with WT plants, TaEIN2-4D.1-RNAi transgenic wheat lines showed enhanced shoot and root elongation, dry weight and chlorophyll accumulation, together with a reduced accumulation of Cd in wheat grain. In addition, TaEIN2-4D.1-RNAi transgenic wheat lines showed enhanced Reactive Oxygen Species (ROS) scavenging capacity compared with WT plants. In conclusion, our research indicates that TaEIN2 plays a key role in response to cadmium stress in wheat, which provides valuable information for crop improvement.

Tespa1 deficiency reduces the antitumour immune response by decreasing CD8+T cell activity in a mouse Lewis lung cancer model

Thymocyte-expressed, positive selection-associated 1 (Tespa1) is a key molecule in T-cell development and has been linked to immune diseases. However, its role in antitumour CD8+T cell immunity remains unclear. Here, we demonstrated that Tespa1 plays an important role in antitumour CD8+T cell immunity. First, compared with wild-type (WT) mice, Lewis lung cancer cells grew faster in Tespa1 knockout (Tespa1−/−) mice, with reduced apoptosis, and decreased CD8+T cells in peripheral blood and tumor tissues. Second, the proportion of CD8+T and Th1 cells in the splenocytes of Tespa1−/− mice was lower than that in WT mice. Third, Tespa1−/− CD8+ tumor-infiltrating lymphocytes (TILs) showed weakened proliferation, invasion, cytotoxicity, and protein expression of IL-2 signalling pathway components compared to WT CD8+TILs. Furthermore, PD-1 expression in CD8+TILs was higher in Tespa1−/− than in WT mice. Lastly, CD8+TILs in WT mice improved the antitumour ability of Tespa1−/− mice. In conclusion, these findings suggest that Tespa1 plays a critical role in the tumor immune system by regulating CD8+T cells.

The serine/threonine kinase Akt gene affects fecundity by reducing Juvenile hormone synthesis in Liposcelis entomophila (Enderlein)

The serine/threonine kinase Akt is an important component of the insulin signalling pathway (ISP) in regulating insect metabolism, growth, and reproduction. The psocid Liposcelis entomophila (Enderlein) is a distasteful stored products pest for its fecundity. However, the molecular mechanism of Akt that controls vitellogenesis and oviposition in L. entomophila remains obscure. In this study, the function of the Akt gene in the female reproduction of L. entomophila (designated as LeAkt) was characterized and investigated. LeAkt contains a 1587 bp open reading frame encoding a 529 amino acid protein that possesses a conserved Pleckstrin Homology domain (PH) and a Ser/Thr-type protein kinase (S_TKc) domain. The mRNA expression of LeAkt was the highest in female adult stages and peaked for 7-day female adults. In female adult tissues, LeAkt was highly expressed in the head and the ovary, indicating that LeAkt was closely correlated with female ovarian development. LeAkt transcription level was significantly suppressed by oral feeding on artificial diets mixed with dsRNA-LeAkt. RNAi-mediated silencing of LeAkt led to a severe inhibition of vitellogenein (Vg) expression and ovarian development, together with lower fecundity and hatchability compared to that of the normal feeding group, suggesting a critical role for LeAkt in L. entomophila reproduction. Further studies revealed that LeAkt silencing significantly decreased the mRNA levels of several signalling and biosynthetic genes in the juvenile hormone (JH) signalling pathway, such as methoprene-tolerant (LeMet), krüppel homolog 1 (LeKr-h1) and JH methyltransferase (LeJHAMT), leading to a severe inhibition of JH biosynthesis in L. entomophila female adults. These results suggested that LeAkt was affecting JH synthesis, thereby influencing Vg synthesis and ultimately L. entomophila reproduction.