Biology subjects

Meng, J.

Publications and source records attributed to Meng, J..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

FoxP3-mediated blockage of ryanodine receptor 2 is the molecular basis for the contact-based suppression by regulatory T cells

The suppression mechanism of regulatory T cells is an intensely investigated topic. As our focus has shifted towards a model centered on indirect inhibition of dendritic cells, a universally applicable effector mechanism controlled by FoxP3 expression has not been found. Here, we report that FoxP3 blocks the transcription of ER Ca2+-release channel ryanodine receptor 2. Reduced RyR2 shuts down basal Ca2+ oscillation in Tregs, which reduces m-Calpain activities that is needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency renders the CD4+ T cell pool to become immune suppressive, and behave in the same manner as FoxP3+ Tregs in viral infection, asthma, hypersensitivity, colitis and tumor development. In the absence of FoxP3, RyR2-deficient CD4+ T cells rescue the systemic autoimmunity associated with Scurfy mice. Therefore, FoxP3-mediated Ca2+ signaling inhibition may be a central effector mechanism of Treg immune suppression. One Sentence SummaryCalcium channel RyR2 dictates Treg adhesion-based suppression

immunology↗

bioRxiv2022

K2P channel TWK-40 Regulates a Rhythmic Behavior in C. elegans

Leak potassium (K+) currents, conducted by two-pore domain K+ (K2P) channels, are critical for the stabilization of the membrane potential. The effect of K2P channels on motor rhythm remains enigmatic. We show here that the K2P TWK-40 regulates the rhythmic defecation motor program (DMP) in Caenorhabditis elegans. Disrupting TWK-40 suppresses the expulsion defects of nlp-40 and aex-2 mutants. By contrast, a gain-of-function (gf) mutant of twk-40 significantly reduces the expulsion frequency per DMP cycle. In situ whole-cell patch clamping demonstrates that TWK-40 forms an outward current that hyperpolarize the resting membrane potential of DVB neuron. In addition, TWK-40 substantially contributes to the rhythmic activity of DVB. Specifically, DVB Ca2+ oscillations exhibit obvious defects in twk-40 mutants. Expression of TWK-40(gf) in DVB recapitulates the expulsion deficiency of the twk-40(gf) mutant, and inhibits DVB Ca2+ oscillations in both wild-type and twk-40(lf) animals. Moreover, DVB innervated enteric muscles also exhibit rhythmic Ca2+ defects. Taken together, these results demonstrate that TWK-40 is an essential neuronal inhibitor of DMP, thus revealing a cellular mechanism linking leak K2P channels with rhythmic motor activity.

neuroscience↗

bioRxiv2022

A descending interneuron with depolarized resting membrane potential controls C. elegans motor states

Continuity of behaviors requires animals to make smooth transitions between successive and mutually exclusive behavioral states. Neural principles that govern these transitions are not well understood. C. elegans spontaneously switch between two opposite motor states, forward and backward movement, a phenomenon long thought to reflect the reciprocal inhibition between two interneurons that separately gate the forward and backward motor circuits, AVB and AVA. Combining experimental data and mathematical modeling, we report that spontaneous forward and backward locomotion and their corresponding motor circuits are not separately controlled. AVA and AVB are neither functionally equivalent nor strictly reciprocally inhibitory. Instead, while AVA phasically inhibits the forward promoting interneuron AVB at a fast timescale, it maintains a tonic, extrasynaptic excitation on AVB over the longer timescale. AVAs depolarized spontaneous membrane potential is necessary for this tonic excitation. We propose a new, master neuron model for locomotion. AVA, with tonic and phasic activity of opposite polarities on different time scales, acts as a master neuron to break the symmetry between the underlying forward and backward motor circuits. This offers a parsimonious solution for sustained locomotion consisted of mutually exclusive motor states. TeaserA tonically active C. elegans premotor interneuron functions as the master neuron that underlies continuous modulation of forward and backward movement to ensure smooth transitions between the two opposing motor states.

neuroscience↗

bioRxiv2022

Global Spatial Transcriptome of Macaque Brain at Single-Cell Resolution

Global profile of gene expression at single-cell resolution remains to be determined for primates. Using a recently developed technology ("Stereo-seq"), we have obtained a comprehensive single-cell spatial transcriptome map at the whole-brain level for cynomolgus monkeys, with [~]600 genes per cell for 10 m-thick coronal sections (up to 15 cm2 in size). Large-scale single-nucleus RNA-seq analysis for [~]1 million cells helped to identify cell types corresponding to Stereo-seq gene expression profiles, providing a 3-D cell type atlas of the monkey brain. Quantitative analysis of Stereo-seq data revealed molecular fingerprints that mark distinct neocortical layers and subregions, as well as domains within subcortical structures including hippocampus, thalamus, striatum, cerebellum, hypothalamus and claustrum. Striking whole-brain topography and coordinated patterns were found in the expression of genes encoding receptors and transporters for neurotransmitters and neuromodulators. These results pave the way for cellular and molecular understanding of organizing principles of the primate brain.

cell biology↗

bioRxiv2022

CRISPR-mediated correction of skeletal muscle Ca2+ handling in a novel DMD patient-derived pluripotent stem cell model

Mutations in the dystrophin gene cause the most common and currently incurable Duchenne muscular dystrophy (DMD) characterized by progressive muscle wasting. Although abnormal Ca2+ handling is a pathological feature of DMD, mechanisms underlying defective Ca2+ homeostasis remain unclear. Here we generate a novel DMD patient-derived pluripotent stem cell (PSC) model of skeletal muscle with an isogenic control using clustered regularly interspaced short palindromic repeat (CRISPR)- mediated precise gene correction. Transcriptome analysis identifies dysregulated gene sets in the absence of dystrophin, including genes involved in Ca2+ handling, excitation-contraction coupling and muscle contraction. Specifically, analysis of intracellular Ca2+ transients and mathematical modeling of Ca2+ dynamics reveal significantly reduced cytosolic Ca2+ clearance rates in DMD-PSC derived myotubes. Pharmacological assays demonstrate Ca2+ flux in myotubes is determined by both intracellular and extracellular sources. DMD-PSC derived myotubes display significantly reduced velocity of contractility. Compared with a non-isogenic wild type PSC line, these pathophysiological defects could be rescued by CRISPR-mediated precise gene correction. Our study provides new insights into abnormal Ca2+ homeostasis in DMD and suggests that Ca2+ signaling pathways amenable to pharmacological modulation are potential therapeutic targets. Importantly, we have established a human physiology-relevant in vitro model enabling rapid pre-clinical testing of potential therapies for DMD.

cell biology↗

bioRxiv2022

Excited-state dynamics of the all-trans protonated retinal Schiff base in CRABPII-based rhodopsin mimics

The rhodopsin mimic is a chemically synthetized complex with the retinyl Schiff base (RSB) formed between protein and the retinal chromophore, which can mimic the natural rhodopsin-like protein. The artificial rhodopsin mimic is more stable and designable than the natural protein and hence has wider uses in photon detection devices. The mimic structure RSB, like the case in the actual rhodopsin-like protein, undergoes isomerization and protonation throughout the photoreaction process. As a result, understanding the dynamics of the RSB in the photoreaction process is critical. In this study, the transient absorption spectra (TAS) of three mutants of the cellular retinoic acid-binding protein II (CRABPII)-based rhodopsin mimic at PH = 3 were recorded, from which the related excited-state dynamics of the all-trans protonated RSB (AT-PRSB) were investigated. The transient fluorescence spectra (TFS) measurements are used to validate some of the dynamic features. We find that the excited-state dynamics of AT-PRSB in three mutants share a similar pattern that differs significantly from the dynamics of 15-cis PRSB (15C-PRSB) of the rhodopsin mimic in neutral solution. By comparing the dynamics across the three mutants, we discovered that the aromatic residues near the {beta}-ionone ring structure of the retinal may help stabilize the AT-PRSB and hence slow down its isomerization rate. Furthermore, from the three mutants, we find one protein with near-infrared fluorescence emission up to 688 nm, leading to further possible applications in sensing or bioimaging.

biochemistry↗

bioRxiv2022

m6A-TSHub: unveiling the context-specific m6A methylation and m6A-affecting mutations in 23 human tissues

As the most pervasive epigenetic marker present on mRNA and lncRNA, N6-methyladenosine (m6A) RNA methylation has been shown to participate in essential biological processes. Recent studies revealed the distinct patterns of m6A methylome across human tissues, and a major challenge remains in elucidating the tissue-specific presence and circuitry of m6A methylation. We present here a comprehensive online platform m6A-TSHub for unveiling the context-specific m6A methylation and genetic mutations that potentially regulate m6A epigenetic mark. m6A-TSHub consists of four core components, including (1) m6A-TSDB: a comprehensive database of 184,554 functionally annotated m6A sites derived from 23 human tissues and 499,369 m6A sites from 25 tumor conditions, respectively; (2) m6A-TSFinder: a web server for high-accuracy prediction of m6A methylation sites within a specific tissue from RNA sequences, which was constructed using multi-instance deep neural networks with gated attention; (3) m6A-TSVar: a web server for assessing the impact of genetic variants on tissue-specific m6A RNA modification; and (4) m6A-CAVar: a database of 587,983 TCGA cancer mutations (derived from 27 cancer types) that were predicted to affect m6A modifications in the primary tissue of cancers. The database should make a useful resource for studying the m6A methylome and genetic factor of epitranscriptome disturbance in a specific tissue (or cancer type). m6A-TSHub is accessible at: www.xjtlu.edu.cn/biologicalsciences/m6ats.

bioinformatics↗

bioRxiv2021

Allele segregation analysis of F1 hybrids between independent Brassica allohexaploid lineages

In the Brassica genus we find both diploid species (one genome) and allotetraploid species (two different genomes) but no naturally occurring hexaploid species (three different genomes, AABBCC). Although hexaploids can be produced via human intervention, these neo- polyploids have quite unstable genomes and usually suffer from severe genome reshuffling. Whether these genome rearrangements continue in later generations and whether genomic arrangements follow similar, reproducible patterns between different lines is still unknown. We crossed Brassica hexaploids resulting from different species combinations to produce five F1 hybrids, and analyzed the karyotypes of the parents and the F1 hybrids, as well as allele segregation in a resulting test-cross population via molecular karyotyping using SNP array genotyping. Although some genomic regions were found to be more likely to be duplicated, deleted or rearranged, a consensus pattern was not shared between genotypes. Brassica hexaploids had a high tolerance for fixed structural rearrangements, but which rearrangements occur and become fixed over many generations does not seem to show either strong reproducibility or to indicate selection for stability. On average, we observed 10 de novo chromosome rearrangements contributed almost equally from both parents to the F1 hybrids. At the same time, the F1 hybrid meiosis produced on average 8.6 new rearrangements. Hence, the increased heterozygosity in the F1 hybrid did not significantly improve genome stability in our hexaploid hybrids, and might have had the opposite effect. However, hybridization between lineages was readily achieved and may be exploited for future genetics and breeding purposes.

genetics↗

bioRxiv2021

Extrasynaptic signaling enables an asymmetric juvenile motor circuit to produce a symmetric mature gait.

In many animals, there is a direct correspondence between the motor patterns that drive locomotion and the motor neuron innervation onto the muscle groups. For example, the adult C. elegans moves with symmetric and alternating dorsal-ventral bending waves arising from symmetric motor neuron input onto the dorsal and ventral muscles. In contrast to the adult, the C. elegans motor circuit at the juvenile larval stage has asymmetric wiring between motor neurons and muscles, but still generates adult-like bending waves with dorsal-ventral symmetry. We show that in the juvenile circuit, wiring between excitatory and inhibitory motor neurons coordinates the contraction of dorsal muscles with relaxation of ventral muscles, producing dorsal bends. However, ventral bending is not driven by analogous wiring. Instead, ventral muscles are excited uniformly by premotor interneurons through extrasynaptic signaling. Ventral bends occur in anti-phasic entrainment to activity of the same motor neurons that drive dorsal bends. During maturation, the juvenile motor circuit is replaced by two motor subcircuits that separately drive dorsal and ventral bending. Modeling reveals that the juveniles immature motor circuit is an adequate solution to generate adult-like dorsal-ventral bending before the animal matures. Developmental rewiring between functionally degenerate circuit solutions, that both generate symmetric bending patterns, minimizes behavioral disruption across maturation. HighlightsO_LIC. elegans larvae generate symmetric motor pattern with an asymmetrically wired motor circuit. C_LIO_LISynaptic wiring between excitatory and inhibitory motor neurons drives dorsal bending. C_LIO_LIExtrasynaptic excitation by premotor interneurons entrains ventral muscles for anti-phasic ventral bending. C_LIO_LIA developmental strategy to enable mature motor pattern before the circuit structurally matures. C_LI

neuroscience↗

bioRxiv2021

DNA replication stress stratifies prognosis and enables exploitable therapeutic vulnerabilities of HBV-associated hepatocellular carcinoma: an in silico strategy towards precision oncology

BackgroundHepatitis B virus (HBV), the main risk factor for hepatocellular carcinoma (HCC) development, integrates into the host genome, causing genetic instability, which may trigger malignancies to exhibit chronic DNA replication stress, providing exploitable therapeutic vulnerabilities. Therefore, customizing prognostication approach and expanding therapeutic options are of great clinical significance to HBV-associated HCCs. MethodsA robust machine-learning framework was designed to develop a DNA replication stress-related prognostic index (PIRS) based on 606 retrospectively collected HBV-associated HCC cases. Molecular profiles and drug response of HCC cell lines were leveraged to predict therapeutic targets and agents for patients with high mortality risk. ResultsCompared with established population-based predictors, PIRS manifested superior performance for prognostic prediction in HBV-associated HCCs. Lower PIRS tightly associated with higher expression of HBV oncoproteins, activated immune/metabolism pathways and higher likelihood of responding to immunotherapy; while higher PIRS showed co-occurrence manner with elevated Ki-67 progression marker and cancer stemness, and significantly enriched in DNA replication stress, cell cycle pathways, chromatin remodeling regulons, and presented an immune-cold phenotype with unfavorable clinical outcome. Through large-scale in silico drug screening, four potential therapeutic targets (TOP2A, PRMT1, CSNK1D, and PPIH) and five agents including three topoisomerase inhibitors (teniposide, doxorubicin, and epirubicin) and two CDK inhibitors (JNJ-7706621 and PHA-793887) were identified for patients with high PIRS. ConclusionsOverall, PIRS holds potential to improve the population-based therapeutic strategies in HCC and sheds new insight to the clinical management for those HBV carriers; current analytic framework provides a roadmap for the rational clinical development of personalized treatment.

bioinformatics↗

bioRxiv2021

Establishment of a prognosis prediction model based on pyroptosis-related signatures associated with the immune microenvironment and molecular heterogeneity in clear cell renal carcinoma

BackgroundPytoptosis is essential for tumorigenesis and progression of clear cell renal cell carcinoma (ccRCC). However, the heterogeneity of pyroposis and its relationship with the tumor microenvironment (TME) remain unclear. The aim of the present study was to identify proptosis-related subtypes and construct a prognosis prediction model based on pyroptosis signatures. MethodsFirst, heterogenous pyroptosis subgroups were explored based on 33 pyroptosis-related genes and ccRCC samples from TCGA, and the model establsihed by LASSO regression was verified by ICGC database. Then, the clinical significance, functional status, immune infiltration, cell-cell communication, genomic alteration and drug sensitivity of different subgroups were further analyzed. Finally, the LASSO-Cox algorithm was applied to narrow down the candidate genes to develop a robust and concise prognostic model. ResultsTwo heterogenous pyroptosis subgroups were identified: pyroptosis-low immunity-low C1 subtype, and pyroptosis-high immunity-high C2 subtype. Compared with C1, C2 was associated with a higher clinical stage or grade and a worse prognosis. More immune cell infiltration was observed in C2 than that in C1, while the response rate in C2 subgroup was lower than that in C1 subgroup. Pyroptosis related genes were mainly expressed in myeloid cells, and T cells and epithelial cells might influence other cell clusters via Pyroptosis related pathway. In addition, C1 was characterized by MTOR and ATM mutation, while C2 was characterized by more significant alterations in SPEN and ROS1 mutation. Finally, we constructed and validated a robust and promising signature based on the pyroptosis-related risk score for assessing the prognosis in ccRCC. ConclusionWe identified two heterogeneous pyroptosis subtypes and 5 reliable risk signatures to establish a prognosis prediction model. Our findings may help better understand the role of pyroptosis in ccRCC progression and provide a new perspective in the management of ccRCC patients.

molecular biology↗

bioRxiv2021

Dystrophin regulates peripheral circadian SRF signalling

Dystrophin is a sarcolemmal protein essential for muscle contraction and maintenance, absence of which leads to the devastating muscle wasting disease Duchenne muscular dystrophy (DMD)[1, 2]. Dystrophin has an actin-binding domain [3-5], which specifically binds and stabilises filamentous (F)-actin[6], an integral component of the RhoA-actin-serum response factor (SRF)-pathway[7]. The RhoA-actin-SRF-pathway plays an essential role in circadian signalling whereby the hypothalamic suprachiasmatic nucleus, transmits systemic cues to peripheral tissues, activating SRF and transcription of clock target genes[8, 9]. Given dystrophin binds F-actin and disturbed SRF-signalling disrupts clock entrainment, we hypothesised that dystrophin loss causes circadian deficits. Here we show for the first time alterations in the RhoA-actin-SRF-signalling-pathway, in both dystrophin-deficient myotubes and dystrophic mouse models. Specifically, we demonstrate reduced F/G-actin ratios and nuclear MRTF, dysregulation of core clock and downstream target-genes, and down-regulation of key circadian genes in muscle biopsies from DMD patients harbouring an array of mutations. Further, disrupted circadian locomotor behaviour was observed in dystrophic mice indicative of disrupted SCN signalling, and indeed dystrophin protein was absent in the SCN of dystrophic animals. Dystrophin is thus a critically important component of the RhoA-actin-SRF-pathway and a novel mediator of circadian signalling in peripheral tissues, loss of which leads to circadian dysregulation.

cell biology↗

bioRxiv2021

Integrated Multi-Omics Data Reveals the Molecular Subtypes of Prostate Cancer

Prostate cancer (PCa), the second most common male malignancy, is the fifth leading cause of cancer-related death and places notable burdens on medical resources. Most of the previous subtypes only focused on one or fewer types of data or ignored the genomic heterogeneity among PCa patients with diverse genetic backgrounds. Therefore, it is essential to precisely identify the specific molecular features and judge potential clinical outcomes based on multi-omics data. In the current study, we first identified the PCa multi-omics classification (PMOC) system based on the multi-omics, including mRNA, miRNA, lncRNA, DNA methylation, and gene mutation, using a total of ten state-of-the-art clustering algorithms. The PMOC1 subtype, also called the inflammatory subtype, contains the highest expression levels of immune checkpoint proteins, moderate activated immune-associated pathways. The PMOC2 tumor-activated subtype demonstrated the worst prognosis, which might be impacted by the activated cell cycle and DNA repair pathways, and also characterized by the most genetic alterations of mutant TP53, mutant APC and copy number alteration of 8q24.21 region. The PMOC3 subtype is likely to be a balance subtype, with the activated oncogenic signaling pathways, including hypoxia, angiogenesis, epithelial mesenchymal transition, and PI3K/AKT pathways. As well as with the activated proinflammatory pathways, including IL6/JAK/STAT3, IL2/STAT5, Notch and TNF- signaling. Additionally, PMOC3 subtype also linked with the activation of the androgen response and the high response rate of ARSI treatment. Taken together, we defined the PMOC system for PCa patients via multi-omics data and consensus results of ten algorithms, this multi-omics consensus PCa molecular classification can further assist in the precise clinical treatment and development of targeted therapy.

cancer biology↗

bioRxiv2021

Multi-omics consensus ensemble refines the classification of muscle-invasive bladder cancer with stratified prognosis, tumour microenvironment and distinct sensitivity to frontline therapies

The molecular classification of muscle-invasive bladder cancer (MIBC) based on transcriptomic signatures has been extensively studied. The complementary nature of information provided by different molecular profiles motivated us to refine MIBC classification by aggregating multi-omics data. We generated a consensus ensemble through ten multi-omics integrative clustering approaches on 396 MIBCs from TCGA. A total of 701 MIBCs from different sequencing technologies were used for external validation. Associations between subtypes and prognosis, molecular profiles, the tumour microenvironment, and potential response to frontline therapies were further analyzed. Nearest template prediction and random forest classification were used to develop a predictive signature/classifier for MIBC refinement. We identified four integrative consensus subtypes of MIBC, which were further designated basal-inflamed, basal-noninflamed, luminal-excluded and luminal-desert by immune profiling. Of note, the refinement of basal-like MIBC classification adds to the literature by identifying a basal-noninflamed MIBC subtype presenting with a significantly poor outcome and a global immune-cold phenotype, which might be triggered by Chr4 deletion and high activation of the oncogenic NRF2 pathway. In contrast, basal-inflamed MIBC showed high immunocyte infiltration and high expression of potential targets for immunotherapy. Using an external metastatic MIBC cohort in which patients received anti-PD-L1 treatment, we suggested that basal-inflamed MIBC had a higher likelihood of responding to immunotherapy than other MIBCs. The R package "refineMIBC" was offered as a research tool to refine MIBC from a single-sample perspective (https://github.com/xlucpu/refineMIBC). This consensus ensemble refines the intrinsic MIBC subtypes, which provides a blueprint for the clinical development of rational targeted and immunotherapeutic strategies.

cancer biology↗

bioRxiv2021

Monotreme middle ear is not primitive for Mammalia

The study on evolution of the mammalian middle ear has been fueled by continuous discoveries of Mesozoic fossils in the last two decades. Wang et al.1 recently reported a specimen of Vilevolodon diplomylos (IMMNH-PV01699)2 that adds to the increasing knowledge about the auditory apparatus of haramiyidans, an extinct Mesozoic group of mammaliaforms. The authors hypothesized that a middle ear with a monotreme-like incus and malleus and incudomallear articulation was primitive for mammals, which challenges the convention that the monotreme middle ear is specialized3 or autapomorphic4 in mammals. We raise concerns about terminology and identification of the incus presented by Wang et al. and show that their analysis does not support their hypothesis; instead, it supports the one by Mao et al.5,6.

paleontology↗

bioRxiv2020

Enzyme catalysis prior to aromatic residues: reverse engineering of a dephosphoCoA kinase

It is well-known that the large diversity of protein functions and structures is derived from the broad spectrum of physicochemical properties of the 20 canonical amino acids. According to the generally accepted hypothesis, protein evolution was continuously associated with enrichment of this alphabet, increasing stability, specificity and spectrum of catalytic functions. Aromatic amino acids are considered the latest addition to genetic code. The main objective of this study was to test whether enzymatic catalysis can spare the aromatic amino acids (aromatics) by determining the effect of amino acid alphabet reduction on structure and function of dephospho-CoA kinase (DPCK). We designed two mutant variants of a putative DPCK from Aquifex aeolicus by substituting (i) Tyr, Phe and Trp or (ii) all aromatics (including His), i.e. [~]10% of the total sequence. Their structural characterization indicates that removal of aromatic amino acids may support rich secondary structure content although inevitably impairs a firm globular arrangement. Both variants still possess ATPase activity, although with 150-300 times lower efficiency in comparison with the wild-type phosphotransferase activity. The transfer of the phosphate group to the dephospho-CoA substrate is however heavily uncoupled and only one of the variants is still able to perform the reaction. Here we provide support to the hypothesis that proteins in the early stages of life could support at least some enzymatic activities, despite lower efficiencies resulting from the lack of a firm hydrophobic core. Based on the presented data we hypothesize that further protein scaffolding role may be provided by ligands upon binding. SignificanceAll extant proteins rely on the standard coded amino acid alphabet. However, early proteins lacked some of these amino acids that were incorporated into the genetic code only after the evolution of their respective metabolic pathways, aromatic amino acids being among the last additions. This is intriguing because of their crucial role in hydrophobic core packing, indispensable for enzyme catalysis. We designed two aromatics-less variants of a highly conserved enzyme from the CoA synthesis pathway, capable of enzyme catalysis and showing significant ordering upon substrate binding. To our knowledge, this is the first example of enzyme catalysis in complete absence of aromatic amino acids and presents a possible mechanism of how aromatics-less enzymes could potentially support an early biosphere.

biochemistry↗

bioRxiv2020

ATF-4 and hydrogen sulfide signalling mediate longevity from inhibition of translation or mTORC1

Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H2S) production. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H2S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H2S levels, or enhancing mechanisms that H2S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.

physiology↗

bioRxiv2020

Integrative Analysis the characterization of peroxiredoxins in pan-cancer

Peroxiredoxins (PRDXs) are antioxidant enzymes protein family members that involves the process of several biological functions, such as differentiation, cell growth. Considerable evidence demonstrates that PRDXs play critical roles in the occurrence and development of carcinomas. However, a systematic analysis of PRDXs in cancers is deficiency. Therefore, we perform a comprehensive analysis of PRDXs in 33 cancer types including mRNA expression profiles, genetic alterations, methylation, prognostic values, potential biological pathways and target drugs. Moreover, we validated that PRDX6 could regulate cancer cell proliferation via JAK2-STAT3 pathway and involve into the process of cell cycle in bladder cancer.

cancer biology↗