Stress-responsive Factor Research Articles

Translational Regulation Promotes Oxidative Stress Resistance in the Human Fungal Pathogen Cryptococcus neoformans.

Cryptococcus neoformans is one of the few environmental fungi that can survive within a mammalian host and cause disease. Although many of the factors responsible for establishing virulence have been recognized, how they are expressed in response to certain host-derived cellular stresses is rarely addressed. Here, we characterize the temporal translational response of C. neoformans to oxidative stress. We find that translation is largely inhibited through the phosphorylation of the critical initiation factor eIF2α (α subunit of eukaryotic initiation factor 2) by a sole kinase. Preventing eIF2α-mediated translational suppression resulted in growth sensitivity to hydrogen peroxide (H2O2). Our work suggests that translational repression in response to H2O2 partly facilitates oxidative stress adaptation by accelerating the decay of abundant non-stress-related transcripts while facilitating the proper expression levels of select oxidative stress response factors. Our results illustrate translational suppression as a critical determinant of select mRNA decay, gene expression, and subsequent survival in response to oxidative stress.IMPORTANCE Fungal survival in a mammalian host requires the coordinated expression and downregulation of a large cohort of genes in response to cellular stresses. Initial infection with C. neoformans occurs in the lungs, where it interacts with host macrophages. Surviving macrophage-derived cellular stresses, such as the production of reactive oxygen and nitrogen species, is believed to promote dissemination into the central nervous system. Therefore, investigating how an oxidative stress-resistant phenotype is brought about in C. neoformans not only furthers our understanding of fungal pathogenesis but also unveils mechanisms of stress-induced gene reprogramming. We discovered that H2O2-derived oxidative stress resulted in severe translational suppression and that this suppression was necessary for the accelerated decay and expression of tested transcripts.

Growth Phase-Dependent Chromosome Condensation and Heat-Stable Nucleoid-Structuring Protein Redistribution in Escherichia coli under Osmotic Stress.

The heat-stable nucleoid-structuring (H-NS) protein is a global transcriptional regulator implicated in coordinating the expression of over 200 genes in Escherichia coli, including many involved in adaptation to osmotic stress. We have applied superresolved microscopy to quantify the intracellular and spatial reorganization of H-NS in response to a rapid osmotic shift. We found that H-NS showed growth phase-dependent relocalization in response to hyperosmotic shock. In stationary phase, H-NS detached from a tightly compacted bacterial chromosome and was excluded from the nucleoid volume over an extended period of time. This behavior was absent during rapid growth but was induced by exposing the osmotically stressed culture to a DNA gyrase inhibitor, coumermycin. This chromosomal compaction/H-NS exclusion phenomenon occurred in the presence of either potassium or sodium ions and was independent of the presence of stress-responsive sigma factor σS and of the H-NS paralog StpA.IMPORTANCE The heat-stable nucleoid-structuring (H-NS) protein coordinates the expression of over 200 genes in E. coli, with a large number involved in both bacterial virulence and drug resistance. We report on the novel observation of a dynamic compaction of the bacterial chromosome in response to exposure to high levels of salt. This stress response results in the detachment of H-NS proteins and their subsequent expulsion to the periphery of the cells. We found that this behavior is related to mechanical properties of the bacterial chromosome, in particular, to how tightly twisted and coiled is the chromosomal DNA. This behavior might act as a biomechanical response to stress that coordinates the expression of genes involved in adapting bacteria to a salty environment.

대학생의 스포츠동아리 참여가 대학생활 적응 및 스트레스 대처방식에 미치는 영향

Objective: This study aims to establish the relationship between college students" participation in sports clubs that affect how they adapt to college life and cope with stress. Method: Out of four college students in the competition, 80 questionnaires out of 700 respondents who responded to the survey were excluded from the data collection process. Therefore, 620 responses from actual studies used in this study were used for data processing. To verify the differences, T-test and ANOVA were performed, and correlation between each lower scale was performed. Result: sports club activity participation groups showed that they had a higher aspect of adapting to college life than non-participating groups, and that there was a significant correlation between factors in college life adaptation and stress response. In addition, the degree of participation in sports club activities has been shown to be significant in how people adapt to college life and cope with stress. Conclusion: Program development and government support should be made so that students can actively participate in physical activities and feel them directly through constant participation during college life, by promoting positive awareness of physical activities, encouraging more active participation and developing further development.

左亚叶酸钙、5-氟尿嘧啶联合表柔比星对胃癌患者应激反应及VEGF水平的影响

Objective To investigate the effects of calcium levofolinate and 5-fluorouracil combined with epirubicin on stress response and vascular endothelial growth factor (VEGF) level in patients with gastric cancer. Methods A total of 160 patients with gastric cancer treated in Huxi Hospital Affiliated to Jining Medical College from April 2016 to March 2018 were selected as research objects. All the patients were divided into two groups according to the random number table method and each group consisted of 80 cases. The control group was treated with epirubicin, while the study group was treated with calcium levofolinate and 5-fluorouracil combined with epirubicin. The clinical efficacy and adverse reactions of the two groups were observed and compared. The levels of VEGF and quality of life were compared before and after the treatment. The stress response indexes such as cortisol (Cor), norepinephrine (NE) and total antioxidant capacity (TAC) were detected, and the stress levels of the two groups were compared. Results The total effective rate of the study group was 67.5% (54/80), which was significantly better than that of the control group [45.0% (36/80)], and the difference was statistically significant (χ2=8.229, P=0.004). The quality of life of the two groups after the treatment was significantly higher than that before the treatment, and the quality of life scores of the study group were significantly higher than those of the control group (all P<0.001). After the treatment, the levels of Cor, NE and TAC of the study group were (239.27±19.63) μg/L, (258.46±18.31) ng/L, (11.01±0.77) KIU/L, which were significantly lower than those of the control group [(286.35±20.63) μg/L, (294.18±21.95) ng/L, (12.73±1.58) KIU/L], and the differences were statistically significant (t=10.003, P<0.001; t=9.476, P<0.001; t=6.984, P<0.001). After the treatment, the VEGF levels of the two groups were lower than those before the treatment, and the VEGF level of the study group was significantly lower than that of the control group [(39.4±0.9) pg/ml vs. (42.3±1.1) pg/ml, t=18.251, P<0.001]. The total incidences of adverse reactions in the control group and the study group were 82.5% (66/80) and 48.8% (39/80), respectively. The incidence of adverse reactions in the control group was significantly higher than that in the study group, and the difference was statistically significant (χ2=20.197, P<0.001). Conclusion Calcium levofolinate and 5-fluorouracil combined with epirubicin has a good clinical effect in treating patients with gastric cancer. It can not only improve the level of VEGF in the serum of patients, but also can improve the quality of life of patients, reduce the incidence of adverse reactions and body stress response. It has broad application prospects and is worthy of further promotion and application in clinic. Key words: Stomach neoplasms; Vascular endothelial growth factors; Stress response; Epirubicin; Calcium levofolate

THE EFFECT OF PSYCHOLOGICAL STRESS ON MPF INTRAFOLLICULAR

Objective: The aim of the study is to investigate the influence of cortisol and Heat Shock Protein 70 (HSP70) on the stressed mice to maturationpromoting factor (MPF) expression intrafollicular.Methods: Experimental laboratory with Randomized Post Test Only Control Group Design was carried out on intrafollicular mice. Divided into twogroups, experimental and control groups. The experimental group was given a 95 dB 4 hours/day noisy exposure for 5 days which was analogous topsychological stress in humans and the control group was not given noisy exposure. Furthermore, both groups were examined for cortisol levels toensure stress in mice. Heat shock protein 70 (HSP70) expression was examined as the main regulatory protein for stress response and Maturationpromoting factor (MPF) expression which is a mediator for oocyte maturation.Results: Psychological stress by 95 dB/4 hours/day noisy exposure for 5 days significantly increased serum cortisol levels in experimental group(p=0.000) and HSP70 expression (p=0.000). The effect of Increased cortisol levels and HSP70 expression significantly decrease in MPF expression(p=0.000).Conclusion: The study concluded that psychological stress could be seen by increasing cortisol and HSP70 expression affected to decreasing MPFexpression intrafollicular

Alternative Oxidase (AOX) Senses Stress Levels to Coordinate Auxin-Induced Reprogramming From Seed Germination to Somatic Embryogenesis-A Role Relevant for Seed Vigor Prediction and Plant Robustness.

Somatic embryogenesis (SE) is the most striking and prominent example of plant plasticity upon severe stress. Inducing immature carrot seeds perform SE as substitute to germination by auxin treatment can be seen as switch between stress levels associated to morphophysiological plasticity. This experimental system is highly powerful to explore stress response factors that mediate the metabolic switch between cell and tissue identities. Developmental plasticity per se is an emerging trait for in vitro systems and crop improvement. It is supposed to underlie multi-stress tolerance. High plasticity can protect plants throughout life cycles against variable abiotic and biotic conditions. We provide proof of concepts for the existing hypothesis that alternative oxidase (AOX) can be relevant for developmental plasticity and be associated to yield stability. Our perspective on AOX as relevant coordinator of cell reprogramming is supported by real-time polymerase chain reaction (PCR) analyses and gross metabolism data from calorespirometry complemented by SHAM-inhibitor studies on primed, elevated partial pressure of oxygen (EPPO)–stressed, and endophyte-treated seeds. In silico studies on public experimental data from diverse species strengthen generality of our insights. Finally, we highlight ready-to-use concepts for plant selection and optimizing in vivo and in vitro propagation that do not require further details on molecular physiology and metabolism. This is demonstrated by applying our research & technology concepts to pea genotypes with differential yield performance in multilocation fields and chickpea types known for differential robustness in the field. By using these concepts and tools appropriately, also other marker candidates than AOX and complex genomics data can be efficiently validated for prebreeding and seed vigor prediction.

The Healing of Oxidative Injuries with Trehalose in UVB-Irradiated Rabbit Corneas.

Our previous research revealed that trehalose, a nonreducing disaccharide of glucose and an important stress responsive factor, proved to have anti-inflammatory, antiapoptotic, and particularly antioxidant properties in UVB-irradiated corneas. Trehalose reduced oxidative stress in corneas induced by UVB irradiation, by means of a decrease in the antioxidant/prooxidant imbalance in the corneal epithelium. In this study, we demonstrate that trehalose of 3% or 6% concentration in eye drops directly decreases oxidative stress in UVB-irradiated corneas, by removing the excessive amount of reactive oxygen species (ROS). Trehalose drops applied on corneas during UVB irradiation once daily for four days resulted in a reduction or even absence of the oxidative stress, DNA damage, and peroxynitrite formation (detected by nitrotyrosine residues), seen in buffer-treated corneas. Furthermore, trehalose treatment applied curatively after repeated irradiation for the subsequent fourteen days led to the renewal of corneal transparency and significant suppression or even absence of neovascularization. This was in contrast to buffer-treated irradiated corneas, where the intracorneal inflammation was developed and the untransparent corneas were vascularized. In conclusion, the treatment of UVB-irradiated corneas with trehalose eye drops removed the excessive amount of ROS in the corneal epithelium, leading to the suppression of oxidative stress and favorable corneal healing. The 6% trehalose showed a higher intensive antioxidant effect.

Intestinal responses of the oriental fruit fly Bactrocera dorsalis (Hendel) after ingestion of an entomopathogenic bacterium strain.

Bactrocera dorsalis (Hendel) is the main fruit fly pest of tropical and subtropical countries. The application of insecticides to manage this pest has led to serious resistance problems; therefore, new ways to control B. dorsalis are required. Pathogenic bacteria are sources of biocontrol agents for pest management. We determined that a pathogenic bacterial strain, Serratia marcescens PS-1, isolated from a moribund striped flea beetle (Phyllotreta striolata), was lethal to B. dorsalis adults following ingestion. Histological analyses revealed that PS-1 damaged the intestinal epithelium, resulting in cell death within 24 h. We then generated a gut transcriptomic data set using RNA-Seq at two time points (6 and 24 h) after PS-1 infection. We found that genes encoding the peritrophic matrix constituent were down-regulated, whereas genes involved in lipid and glycan metabolism, and renewal of the gut epithelium, along with genes encoding digestive enzymes and stress response factors, were up-regulated. In addition, 14 cecropin genes were identified and cloned from B. dorsalis. To our knowledge, the number of cecropins identified in the present study is greater than that reported in the insects of earlier studies. Moreover, some of the cecropins identified were significantly down-regulated after PS-1 treatment. Our findings provide new insights into the insect gut response to pathogenic bacterial invasion and may aid the development of new strategies for the biological control of B. dorsalis. © 2019 Society of Chemical Industry.

Identification of gene and microRNA changes in response to smoking in human airway epithelium by bioinformatics analyses.

Smoking is a substantial risk factor for many respiratory diseases. This study aimed to identify the gene and microRNA changes related to smoking in human airway epithelium by bioinformatics analysis.From the Gene Expression Omnibus (GEO) database, the mRNA datasets GSE11906, GSE22047, GSE63127, and microRNA dataset GSE14634 were downloaded, and were analyzed using GEO2R. Functional enrichment analysis of the differentially expressed genes (DEGs) was enforced using DAVID. The protein–protein interaction (PPI) network and differentially expressed miRNAs (DEMs)- DEGs network were executed by Cytoscape.In total, 107 DEGs and 10 DEMs were determined. Gene Ontology (GO) analysis revealed that DEGs principally enriched in oxidation-reduction process, extracellular space and oxidoreductase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway demonstrated that DEGs were principally enriched in metabolism of xenobiotics by cytochrome P450 and chemical carcinogenesis. The PPI network revealed 15 hub genes, including NQO1, CYP1B1, AKR1C1, CYP1A1, AKR1C3, CEACAM5, MUCL1, B3GNT6, MUC5AC, MUC12, PTGER4, CALCA, CBR1, TXNRD1, and CBR3. Cluster analysis showed that these hub genes were associated with adenocarcinoma in situ, squamous cell carcinoma, cell differentiation, inflammatory response, oxidative DNA damage, oxidative stress response and tumor necrosis factor. Hsa-miR-627-5p might have the most target genes, including ITLN1, TIMP3, PPP4R4, SLC1A2, NOVA1, RNFT2, CLDN10, TMCC3, EPHA7, SRPX2, PPP1R16B, GRM1, HS3ST3A1, SFRP2, SLC7A11, and KLHDC8A.We identified several molecular changes induced by smoking in human airway epithelium. This study may provide some candidate genes and microRNAs for assessing the risk of lung diseases caused by smoking.

Silencing RRM2 inhibits multiple myeloma bytargeting the Wnt/β‑catenin signaling pathway.

Ribonucleotide reductase M2 (RRM2) is one of the two subunits that comprise ribonucleotide reductase (RR), the enzyme that catalyzes the conversion of ribonucleotide 5′-diphosphates into 2′-deoxyribonucleotides, which are required for DNA synthesis. RRM2 is a stress response factor important for the development of several tumors. However, its role in multiple myeloma (MM) remains to be fully elucidated. The present study aimed to investigate the role of RRM2 in MM. The expression of RRM2 in patients with MM was analyzed using the Oncomine database. The results demonstrated that RRM2 expression was higher in MM compared with healthy subjects. Reverse transcription-quantitative polymerase chain reaction and western blot results revealed that RRM2 expression was decreased following transfection with a small interfering RNA targeting RRM2 into NCI-H929 cells. RR activity and Cell Counting Kit-8 assays demonstrated that RRM2 silencing reduced RR activity and inhibited cell proliferation. Annexin V-propidium iodide staining indicated that the percentage of apoptotic NCI-H929 cells was increased following RRM2 silencing compared with that in the control group. Increased phosphorylation of H2AX indicated that RRM2 silencing may activate the DNA-damage response pathway in NCI-H929 cells. Western blot analysis revealed that protein levels of the apoptosis-associated factor Bcl-2 were reduced, whereas Bax, cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1 were upregulated following RRM2 silencing compared with the control group. In addition, the results demonstrated that RRM2 silencing may inhibit target gene expression in the Wnt/β-catenin signaling pathway by increasing the phosphorylation of glucose synthase kinase 3β. These findings indicated that RRM2 may be involved in the proliferation and apoptosis of MM cells via the Wnt/β-catenin signaling pathway, suggesting that RRM2 may represent a novel therapeutic target for MM.

Decoding the proteomic changes involved in the biofilm formation of Enterococcus faecalis SK460 to elucidate potential biofilm determinants

BackgroundEnterococcus faecalis is a major clinically relevant nosocomial bacterial pathogen frequently isolated from polymicrobial infections. The biofilm forming ability of E. faecalis attributes a key role in its virulence and drug resistance. Biofilm cells are phenotypically and metabolically different from their planktonic counterparts and many aspects involved in E. faecalis biofilm formation are yet to be elucidated. The strain E. faecalis SK460 used in the present study is esp (Enterococcal surface protein) and fsr (two-component signal transduction system) negative non-gelatinase producing strong biofilm former isolated from a chronic diabetic foot ulcer patient. We executed a label-free quantitative proteomic approach to elucidate the differential protein expression pattern at planktonic and biofilm stages of SK460 to come up with potential determinants associated with Enterococcal biofilm formation.ResultsThe Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of proteomic data revealed that biofilm cells expressed higher levels of proteins which are associated with glycolysis, amino acid biosynthesis, biosynthesis of secondary metabolites, microbial metabolism in diverse environments and stress response factors. Besides these basic survival pathways, LuxS-mediated quorum sensing, arginine metabolism, rhamnose biosynthesis, pheromone and adhesion associated proteins were found to be upregulated during the biofilm transit from planktonic stages. The selected subsets were validated by quantitative real-time PCR. In silico functional interaction analysis revealed that the genes involved in upregulated pathways pose a close molecular interaction thereby coordinating the regulatory network to thrive as a biofilm community.ConclusionsThe present study describes the first report of the quantitative proteome analysis of an esp and fsr negative non gelatinase producing E. faecalis. Proteome analysis evidenced enhanced expression of glycolytic pathways, stress response factors, LuxS quorum signaling system, rhamnopolysaccharide synthesis and pheromone associated proteins in biofilm phenotype. We also pointed out the relevance of LuxS quorum sensing and pheromone associated proteins in the biofilm development of E. faecalis which lacks the Fsr quorum signaling system. These validated biofilm determinants can act as potential inhibiting targets in Enterococcal infections.

The Nucleoshuttling of the ATM Protein: A Unified Model to Describe the Individual Response to High- and Low-Dose of Radiation?

The evaluation of radiation-induced (RI) risks is of medical, scientific, and societal interest. However, despite considerable efforts, there is neither consensual mechanistic models nor predictive assays for describing the three major RI effects, namely radiosensitivity, radiosusceptibility, and radiodegeneration. Interestingly, the ataxia telangiectasia mutated (ATM) protein is a major stress response factor involved in the DNA repair and signaling that appears upstream most of pathways involved in the three precited RI effects. The rate of the RI ATM nucleoshuttling (RIANS) was shown to be a good predictor of radiosensitivity. In the frame of the RIANS model, irradiation triggers the monomerization of cytoplasmic ATM dimers, which allows ATM monomers to diffuse in nucleus. The nuclear ATM monomers phosphorylate the H2AX histones, which triggers the recognition of DNA double-strand breaks and their repair. The RIANS model has made it possible to define three subgroups of radiosensitivity and provided a relevant explanation for the radiosensitivity observed in syndromes caused by mutated cytoplasmic proteins. Interestingly, hyper-radiosensitivity to a low dose and adaptive response phenomena may be also explained by the RIANS model. In this review, the relevance of the RIANS model to describe several features of the individual response to radiation was discussed.

Mitochondrial peptides-appropriate options for therapeutic exploitation.

Besides their well-known function in cellular bioenergetics, the role of mitochondria in signaling regulation of cells homeostasis and survival has been uncovered during the past few decades. Possessing an independent genome and a unique genetic code, mitochondria biosynthesize protective stress response factors, the "mitochondrial-derived peptides," import and deposit peptides within their matrix and are the target of peptides bound to bioactive agents, aiming at alleviation of pathology-related malfunction of the electron transport chain. As the rapidly evolving field of mitochondrial peptides is appropriate for therapeutic exploitation, a brief overview of the major recent findings is timely needed. Here, the focus is on the following issues: (i) the biological effects of mitochondrial-derived peptides (humanin, humanin-like peptides and MOTS-c) and their use in therapy, (ii) the abnormal accumulation of β-amyloid peptide within the mitochondrial matrix and (iii) the effectiveness of "mitochondrial cell-penetrating/targeting peptides" as vehicles for delivery of bioactive agents into dysfunctional mitochondria.

Current evidence on urbanicity and the impact of neighbourhoods on anxiety and stress-related disorders.

To synthesize recent knowledge on the association of urbanization (and neighbourhood factors) and anxiety and stress-related disorders. The quality of urban neighbourhoods and neighbourhood factors - physical (e.g. green space), social (e.g. social cohesion) and biological (e.g. stress response) factors - are directly linked to the presence and severity of anxiety disorders, although data on posttraumatic stress disorder (PTSD) are pauce. Preliminary data indicate that architectural and space design elements in PTSD can either increase anxiety and lead to trauma triggers or relieve symptoms and reinforce safety. In addition, there is emerging evidence that being raised in urban environments with a wide range of microbial exposure dampens the immune response to psychosocial stressors. Evidence points to a higher prevalence of anxiety disorders and PTSD in urban environments. Current research is focused on the role of neighbourhood factors in prevention and treatment. Few studies have assessed comprehensive treatment models in urban populations and the potential moderating role of these factors on treatment outcomes. Several lines of inquiry are starting to address how urban living impacts on biological stress regulation pathways. As urbanization continues, improved understanding of urban mental health is central to informing mental health promotion policies.

NHR-49/PPARα regulates HLH-30/TFEB-mediated innate immune response via a flavincontaining monooxygenase in C. elegans

Abstract The nematode C. elegans mounts an innate immune response against Gram-positive bacteria S. aureus by the transcriptional induction of multiple host defense genes. The expression of a majority of these genes is under the control of HLH-30, C. elegans homolog of TFEB (transcription factor EB) that also functions in the innate immune response in mammals. In addition to its role in host defense against S. aureus, HLH-30 acts as a nutritionally-controlled stress response factor. We wanted to deconvolve the response of C. elegans to nutritional challenge from the antibacterial response against S. aureus. To this end, we performed RNAseq profiling in wildtype and hlh-30 mutants that were either infected with S. aureus or were starved. Our RNAseq analysis showed that multiple HLH-30-dependent or-independent genes are specifically induced by S. aureus infection, and not by starvation. One of the genes that is highly induced by infection and not starvation is fmo-2, which encodes a member of the flavin-containing monooxygenase (FMO) family in C. elegans. We decided to characterize the role of FMO-2 in host defense in C. elegans by employing genetic, transgenic, and molecular approaches. We found that FMO-2 is important for host defense against S. aureus infection, and its induction during S. aureus infection is controlled by two transcription factors, HLH-30 and NHR-49 (C. elegans ortholog of the mammalian nuclear-hormone receptor, PPARα). Our results propose a model in which NHR-49 functions upstream of HLH-30 to bind to fmo-2 promoter and to induce its upregulation by functioning specifically in C. elegans intestine (the site of innate immune response), thereby providing host defense against S. aureus infection.

JUND regulates pancreatic β cell survival during metabolic stress

ObjectiveIn type 2 diabetes (T2D), oxidative stress contributes to the dysfunction and loss of pancreatic β cells. A highly conserved feature of the cellular response to stress is the regulation of mRNA translation; however, the genes regulated at the level of translation are often overlooked due to the convenience of RNA sequencing technologies. Our goal is to investigate translational regulation in β cells as a means to uncover novel factors and pathways pertinent to cellular adaptation and survival during T2D-associated conditions. MethodsTranslating ribosome affinity purification (TRAP) followed by RNA-seq or RT-qPCR was used to identify changes in the ribosome occupancy of mRNAs in Min6 cells. Gene depletion studies used lentiviral delivery of shRNAs to primary mouse islets or CRISPR-Cas9 to Min6 cells. Oxidative stress and apoptosis were measured in primary islets using cell-permeable dyes with fluorescence readouts of oxidation and activated cleaved caspase-3 and-7, respectively. Gene expression was assessed by RNA-seq, RT-qPCR, and western blot. ChIP-qPCR was used to determine chromatin enrichment. ResultsTRAP-seq in a PDX1-deficiency model of β cell dysfunction uncovered a cohort of genes regulated at the level of mRNA translation, including the transcription factor JUND. Using a panel of diabetes-associated stressors, JUND was found to be upregulated in mouse islets cultured with high concentrations of glucose and free fatty acid, but not after treatment with hydrogen peroxide or thapsigargin. This induction of JUND could be attributed to increased mRNA translation. JUND was also upregulated in islets from diabetic db/db mice and in human islets treated with high glucose and free fatty acid. Depletion of JUND in primary islets reduced oxidative stress and apoptosis in β cells during metabolic stress. Transcriptome assessment identified a cohort of genes, including pro-oxidant and pro-inflammatory genes, regulated by JUND that are commonly dysregulated in models of β cell dysfunction, consistent with a maladaptive role for JUND in islets. ConclusionsA translation-centric approach uncovered JUND as a stress-responsive factor in β cells that contributes to redox imbalance and apoptosis during pathophysiologically relevant stress.

Novel model for age-related OA: ER stress in articular cartilage induces joint degeneration in mice

Purpose: The lifetime risk of osteoarthritis (OA) to an individual is 45% and arthritis is the most common form of disability in the United States, making burden to the individual and society extensive. Age is the most important risk factor for adult-onset OA and ER stress response declines with age. Multiple lines of evidence indicates that pathological ER stress contributes to OA progression. In this work, tested the hypothesis that ER stress in articular chondrocytes alone is sufficient to drive joint degeneration in adult mice. In addition to ER stress, one group of mice was subjected to intense exercise to determine if mechanical stress would hasten joint degeneration. Methods: In the inducible-ER-stress mouse (I-ERS), ER stress was induced by expressing a mis-folded protein, mutant cartilage oligomeric matrix protein, in adult articular chondrocytes (from 16 to 20 weeks). There were three treatment groups: 1) control, 2) ER stress and 3) ER stress with treadmill exercise. Results: Four weeks of ER stress in healthy articular cartilage stimulated joint degeneration including increases matrix metalloproteinase (MMP) activity, inflammation, chondrocyte death, decreases in articular cartilage thickness and proteoglycan content and gait dysfunction, all of which are outcomes associated with OA. Intense exercise increased OARSI score, loss of proteoglycans, articular cartilage thinning and gait dysfunction suggesting that some aspects of OA are exacerbated by mechanical stress. Conclusions: OA is a multifactorial disease involving many risk factors including genetic factors, age, BMI, sex, joint injury and repetitive mechanical stress. Many models recapitulate post-traumatic OA and fewer models address age-related cellular stress. In these studies, physiology relevant ER chondrocyte stress was used to induce joint degeneration in previously healthy joints. This unique model of non-trauma adult-onset OA is useful for 1) defining the role of ER stress in the molecular pathology of OA, 2) for studying age-related OA and 3) testing prevention/treatment strategies and complements other OA models. Defining the role that ER stress plays in OA will lead to a better understand of this complex pathology and may offer new therapeutic strategies.

AP2/ERF Transcription Factor Regulatory Networks in Hormone and Abiotic Stress Responses in Arabidopsis

Dynamic environmental changes such as extreme temperature, water scarcity and high salinity affect plant growth, survival, and reproduction. Plants have evolved sophisticated regulatory mechanisms to adapt to these unfavorable conditions, many of which interface with plant hormone signaling pathways. Abiotic stresses alter the production and distribution of phytohormones that in turn mediate stress responses at least in part through hormone- and stress-responsive transcription factors. Among these, the APETALA2/ETHYLENE RESPONSIVE FACTOR (AP2/ERF) family transcription factors (AP2/ERFs) have emerged as key regulators of various stress responses, in which they also respond to hormones with improved plant survival during stress conditions. Apart from participation in specific stresses, AP2/ERFs are involved in a wide range of stress tolerance, enabling them to form an interconnected stress regulatory network. Additionally, many AP2/ERFs respond to the plant hormones abscisic acid (ABA) and ethylene (ET) to help activate ABA and ET dependent and independent stress-responsive genes. While some AP2/ERFs are implicated in growth and developmental processes mediated by gibberellins (GAs), cytokinins (CTK), and brassinosteroids (BRs). The involvement of AP2/ERFs in hormone signaling adds the complexity of stress regulatory network. In this review, we summarize recent studies on AP2/ERF transcription factors in hormonal and abiotic stress responses with an emphasis on selected family members in Arabidopsis. In addition, we leverage publically available Arabidopsis gene networks and transcriptome data to investigate AP2/ERF regulatory networks, providing context and important clues about the roles of diverse AP2/ERFs in controlling hormone and stress responses.

Transcriptome Analysis of Chinese Chestnut (Castanea mollissima Blume) in Response to Dryocosmus kuriphilus Yasumatsu Infestation.

Chinese chestnut (Castanea mollissima Blume) can be infested by Dryocosmus kuriphilus Yasumatsu, resulting in gall formation and yield losses. Research on the control of gall wasps using genomics approaches is rarely reported. We used RNA-seq to investigate the dynamic changes in the genes of a chestnut species (C. mollissima B.) during four gall-formation stages caused by D. kuriphilus. A total of 21,306 genes were annotated by BLAST in databases. Transcriptome comparison between different gall-formation stages revealed many genes that were differentially expressed compared to the control. Among these, 2410, 7373, 6294, and 9412 genes were differentially expressed in four gall-formation stages: initiation stage (A), early growth stage (B), late growth stage (C), and maturation stage (D), respectively. Annotation analysis indicated that many metabolic processes (e.g., phenylpropanoid biosynthesis, secondary metabolism, plant–pathogen interaction) were affected. Interesting genes encoding putative components of signal transduction, stress response, and transcription factors were also differentially regulated. These genes might play important roles in response to D. kuriphilus gall formation. These new data on the mechanism by which D. kuriphilus infests chestnuts could help improve chestnut resistance.

Toll-like receptor 3 regulates Zika virus infection and associated host inflammatory response in primary human astrocytes.

The connection between Zika virus (ZIKV) and neurodevelopmental defects is widely recognized, although the mechanisms underlying the infectivity and pathology in primary human glial cells are poorly understood. Here we show that three isolated strains of ZIKV, an African strain MR766 (Uganda) and two closely related Asian strains R103451 (Honduras) and PRVABC59 (Puerto Rico) productively infect primary human astrocytes, although Asian strains showed a higher infectivity rate and increased cell death when compared to the African strain. Inhibition of AXL receptor significantly attenuated viral entry of MR766 and PRVABC59 and to a lesser extend R103451, suggesting an important role of TAM receptors in ZIKV cell entry, irrespective of lineage. Infection by PRVABC59 elicited the highest release of inflammatory molecules, with a 8-fold increase in the release of RANTES, 10-fold increase in secretion of IP-10 secretion and a 12-fold increase in IFN-β secretion when compared to un-infected human astrocytes. Minor changes in the release of several growth factors, endoplasmic reticulum (ER)-stress response factors and the transcription factor, NF-κB were detected with the Asian strains, while significant increases in FOXO6, MAPK10 and JNK were detected with the African strain. Activation of the autophagy pathway was evident with increased expression of the autophagy related proteins Beclin1, LC3B and p62/SQSTM1 with all three strains of ZIKV. Pharmacological inhibition of the autophagy pathway and genetic inhibition of the Beclin1 showed minimal effects on ZIKV replication. The expression of toll-like receptor 3 (TLR3) was significantly increased with all three strains of ZIKV; pharmacological and genetic inhibition of TLR3 caused a decrease in viral titers and in viral-induced inflammatory response in infected astrocytes. We conclude that TLR3 plays a vital role in both ZIKV replication and viral-induced inflammatory responses, irrespective of the strains, while the autophagy protein Beclin1 influences host inflammatory responses.