Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis

BACKGROUND Acute liver failure(ALF)has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis.The silent information regulator sirtuin 1(SIRT1)-mediated deacetylation affects multiple biological processes,including cellular senescence,apoptosis,sugar and lipid metabolism,oxidative stress,and inflammation.AIM To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms.METHODS This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)testing.C57BL/6 mice were also intraperitoneally pretreated with SIRT1,p53,or glutathione peroxidase 4(GPX4)inducers and inhibitors and injected with lipopolysaccharide(LPS)/D-galactosamine(D-GalN)to induce ALF.Gasdermin D(GSDMD)^(-/-)mice were used as an experimental group.Histological changes in liver tissue were monitored by hematoxylin and eosin staining.ALT,AST,glutathione,reactive oxygen species,and iron levels were measured using commercial kits.Ferroptosis-and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction.SIRT1,p53,and GSDMD were assessed by immunofluorescence analysis.RESULTS Serum AST and ALT levels were elevated in patients with ALF.SIRT1,solute carrier family 7a member 11(SLC7A11),and GPX4 protein expression was decreased and acetylated p5,p53,GSDMD,and acyl-CoA synthetase long-chain family member 4(ACSL4)protein levels were elevated in human ALF liver tissue.In the p53 and ferroptosis inhibitor-treated and GSDMD^(-/-)groups,serum interleukin(IL)-1β,tumour necrosis factor alpha,IL-6,IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated.In mice with GSDMD knockout,p53 was reduced,GPX4 was increased,and ferroptotic events(depletion of SLC7A11,elevation of ACSL4,and iron accumulation)were detected.In vitro,knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels,the cytostatic rate,and GSDMD expression,restoring SLC7A11 depletion.Moreover,SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group,accompanied by reduced p53,GSDMD,and ACSL4,and increased SLC7A11 and GPX4.Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalNinduced in vitro and in vivo models.CONCLUSION SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

An NMOS output-capacitorless low-dropout regulator with dynamic-strength event-driven charge pump

In this paper,an NMOS output-capacitorless low-dropout regulator(OCL-LDO)featuring dual-loop regulation has been proposed,achieving fast transient response with low power consumption.An event-driven charge pump(CP)loop with the dynamic strength control(DSC),is proposed in this paper,which overcomes trade-offs inherent in conventional structures.The presented design addresses and resolves the large signal stability issue,which has been previously overlooked in the event-driven charge pump structure.This breakthrough allows for the full exploitation of the charge-pump structure's poten-tial,particularly in enhancing transient recovery.Moreover,a dynamic error amplifier is utilized to attain precise regulation of the steady-state output voltage,leading to favorable static characteristics.A prototype chip has been fabricated in 65 nm CMOS technology.The measurement results show that the proposed OCL-LDO achieves a 410 nA low quiescent current(IQ)and can recover within 30 ns under 200 mA/10 ns loading change.

Large-scale loss-of-function perturbations reveal a comprehensive epigenetic regulatory network in breast cancer

Objective:Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression;however,the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer remain elusive.It is important to decipher the comprehensive epigenetic regulatory network in breast cancer cells to identify master epigenetic regulators and potential therapeutic targets.Methods:We employed high-throughput sequencing-based high-throughput screening(HTS^(2))to effectively detect changes in the expression of 2,986 genes following the knockdown of 400 epigenetic regulators.Then,bioinformatics analysis tools were used for the resulting gene expression signatures to investigate the epigenetic regulations in breast cancer.Results:Utilizing these gene expression signatures,we classified the epigenetic regulators into five distinct clusters,each characterized by specific functions.We discovered functional similarities between BAZ2B and SETMAR,as well as CLOCK and CBX3.Moreover,we observed that CLOCK functions in a manner opposite to that of HDAC8 in downstream gene regulation.Notably,we constructed an epigenetic regulatory network based on the gene expression signatures,which revealed 8 distinct modules and identified 10 master epigenetic regulators in breast cancer.Conclusions:Our work deciphered the extensive regulation among hundreds of epigenetic regulators.The identification of 10 master epigenetic regulators offers promising therapeutic targets for breast cancer treatment.

Unraveling the regulatory network of flower coloration in soybean:Insights into roles of GmMYBA3 and GmMYBR1

Anthocyanins play crucial roles in pollen protection and pollinator attraction in flowering plants.However,the mechanisms underlying flower color determination and whether floral anthocyanin regulators participate in other processes remain largely unresolved in soybeans(Glycine max).In this study,we investigated the genetic components and mechanisms governing anthocyanin biosynthesis in soybean flowers.Molecular and genetic studies have characterized two antagonistic regulators,the positive activator GmMYBA3 and the negative repressor GmMYBR1,that modulate the gene expression of anthocyanin biosynthesis in soybean flowers.Further findings revealed a regulatory interplay between GmMYBA3 and GmMYBR1 bridged by GmTT8a,highlighting the complexity of anthocyanin regulation in different soybean organs.Exploration of additional soybean cultivars demonstrated the universality of GmMYBA3 and GmMYBR1 in regulating floral anthocyanin biosynthesis-related genes,with GmF3’5’H identified as a crucial determinant of white flower color.This study provides a molecular mechanism underlying soybean flower color determination,paving the way for the molecular modification of soybean flowers to probably enhance their resistance to abiotic stresses and attractiveness to pollinators.

An overview of pigment gland morphogenesis and its regulatory mechanism

Cotton has enormous economic potential,providing high-quality protein,oil,and fibre.But the comprehensive utilization of cottonseed is limited by the presence of pigment gland and its inclusion.Pigment gland is a common characteristic of Gossypium genus and its relatives,appearing as visible dark opaque dots in most tissues and organs of cotton plants.Secondary metabolites,such as gossypol,synthesized and stored in the cavities of pigment glands act as natural phytoalexins,but are toxic to humans and other monogastric animals.However,only a few cotton genes have been identified as being associated with pigment gland morphogenesis to date,and the developmental processes and regulatory mechanism involved in pigment gland formation remain largely unclear.Here,the research progress on the process of pigment gland morphogenesis and the genetic basis of cotton pigment glands is reviewed,for providing a theoretical basis for cultivating cotton with the ideal pigment gland trait.

Regarding the Regulatory Sandbox Route and Mechanism for Governance of Artificial Intelligence

The main challenge in AI governance today is striking a balance between controlling AI dangers and fostering AI innovation.Regulators in a number of nations have progressively extended the regulatory sandbox,which was first implemented in the banking sector,to AI governance in an effort to reduce the conflict between regulation and innovation.The AI regulatory sandbox is a new and feasible route for AI governance in China that not only helps to manage the risks of technology application but also prevents inhibiting AI innovation.It keeps inventors'trial-and-error tolerance space inside the regulatory purview while offering a controlled setting for the development and testing of novel AI that hasn't yet been put on the market.By providing full-cycle governance of AI with the principles of agility and inclusive prudence,the regulatory sandbox offers an alternative to the conventional top-down hard regulation,expost regulation,and tight regulation.However,the current system also has inherent limitations and practical obstacles that need to be overcome by a more rational and effective approach.To achieve its positive impact on AI governance,the AI regulatory sandbox system should build and improve the access and exit mechanism,the coordination mechanism between the sandbox and personal information protection,and the mechanisms of exemption,disclosure,and communication.

Regulatory factors of Nrf2 in age-related macular degeneration pathogenesis

Age-related macular degeneration(AMD)is a complicated disease that causes irreversible visual impairment.Increasing evidences pointed retinal pigment epithelia(RPE)cells as the decisive cell involved in the progress of AMD,and the function of anti-oxidant capacity of PRE plays a fundamental physiological role.Nuclear factor erythroid 2 related factor 2(Nrf2)is a significant transcription factor in the cellular anti-oxidant system as it regulates the expression of multiple anti-oxidative genes.Its functions of protecting RPE cells against oxidative stress(OS)and ensuing physiological changes,including inflammation,mitochondrial damage and autophagy dysregulation,have already been elucidated.Understanding the roles of upstream regulators of Nrf2 could provide further insight to the OS-mediated AMD pathogenesis.For the first time,this review summarized the reported upstream regulators of Nrf2 in AMD pathogenesis,including proteins and miRNAs,and their underlying molecular mechanisms,which may help to find potential targets via regulating the Nrf2 pathway in the future research and further discuss the existing Nrf2 regulators proved to be beneficial in preventing AMD.

The virulence regulator AbsR in avian pathogenic Escherichia coli has pleiotropic effects on bacterial physiology

Avian pathogenic Escherichia coli(APEC)belonging to extraintestinal pathogenic E.coli(ExPEC)can cause severe infections in extraintestinal tissues in birds and humans,such as the lungs and blood.MprA(microcin production regulation,locus A,herein renamed AbsR,a blood survival regulator),a member of the MarR(multiple antibiotic resistance regulator)transcriptional regulator family,governs the expression of capsule biosynthetic genes in human ExPEC and represents a promising druggable target for antimicrobials.However,a deep understanding of the AbsR regulatory mechanism as well as its regulon is lacking.In this study,we present a systems-level analysis of the APEC AbsR regulon using ChIP-Seq(chromatin immunoprecipitation sequencing)and RNA-Seq(RNA sequencing)methods.We found that AbsR directly regulates 99 genes and indirectly regulates 667 genes.Furthermore,we showed that:1)AbsR contributes to antiphagocytotic effects by macrophages and virulence in a mouse model for systemic infection by directly activating the capsular gene cluster;2)AbsR positively impacts biofilm formation via direct regulation of the T2SS(type II secretion system)but plays a marginal role in virulence;and 3)AbsR directly upregulates the acid tolerance signaling system EvgAS to withstand acid stress but is dispensable in ExPEC virulence.Finally,our data indicate that the role of AbsR in virulence gene regulation is relatively conserved in ExPEC strains.Altogether,this study provides a comprehensive analysis of the AbsR regulon and regulatory mechanism,and our data suggest that AbsR likely influences virulence primarily through the control of capsule production.Interestingly,we found that AbsR severely represses the expression of the type I-F CRISPR(clustered regularly interspaced short palindromic repeats)-Cas(CRISPR associated)systems,which could have implications in CRISPR biology and application.

Contribution to Computer Waste Management:Knowledge of the Regulatory Framework by Industry Stakeholders in Guinea

In African countries,regulations on the management of WTE(Waste from Information Technology Equipment)are non-existent or sometimes insufficient,if they exist.This study shows how to mention waste from information technology equipment in a country that does not have a regulatory legislative framework or organized management channels.A methodological approach based on documentary research and semi-directed interviews was adopted in this work.The results showed that 54.55%of institutional managers are unaware of the existence of regulations for the management of WTE,both at the national and international levels;72.72%of these managers do not have a specific implementing text for this management;72.73%of institutions have adopted an acquisition policy based on the needs of workers and 81.82%of institutions store WTE in warehouses.Relations with waste collection SMEs(Small and Midsize Enterprises),especially for IT equipment,are limited for 72.73%of institutions.In terms of improving the capacity to manage WEEE(Waste Electrical and Electronic Equipment),90.91%of institutions do not offer training or awareness raising.Overall,no significant indicators are in place to assess WEEE management in institutions,which reflects a lack of commitment and awareness among institutional managers.In addition,there are no financial means for ecological and sustainable management.Although 27.27%of managers are aware of the dangers to human health and the environment related to IT equipment,they are often unaware of the harmful consequences of abandoning it in nature.

The Effect of Plant Growth Regulators on Physico-Chemical Properties of Safflower (Carthamus tinctorius L.) Derived Biodiesel

Global concerns about the environmental impact of combustion emissions from petroleum fuels influence new research to seek for alternative energy sources. The current study investigates the possibility of using safflower (Carthamus tinctorius L.) as an alternative biodiesel raw material. Four plant growth regulators (PGR) were used to boost the production of safflower. Thirteen treatments were constituted from the four plant regulators and applied to the safflower crop arranged in completely randomised design, repeated three times. The results show that the effect of plant growth regulators was not more than that of the control. More studies have to be channelled towards the relationship between safflower and plant growth regulators.

Low Level of Cystic Fibrosis Transmembrane Conductance Regulator Is Associated with Human Sperm Autophagy and Vitality

Low sperm motility is one of the main causes of male infertility. Cystic fibrosis transmembrane conductance regulator (CFTR, an anion channel protein) is related to the progressive motility of sperm. CFTR disruptor CFTRinh-172 or forskolin (FSK) in this study were used to treat human sperm separately, and the rates of sperm autophagy and progressive motility, mitochondrial membrane potential (MMP) and ATP concentration, and the expression levels of related factors were detected to explore their relationship. It was showed that sperms treated with CFTRinh-172 or FSK reduced the levels of cAMP, CFTR and PKA, but increased sperm autophagy rate, expression levels of AMPK and LC3B. However, reactive oxygen species content had no significant difference. It was indicated that low level of CFTR performed with cAMP and its downstream effectors such as PKA and AMPK to regulate mitochondrial structure and function, leading to increased autophagy rate and reduced vitality of sperm.

Species-specific regulatory pathways of small RNAs play sophisticated roles in flower development in Dimocarpus longan Lour.

Flower development plays vital role in horticultural plants.Post-transcriptional regulation via small RNAs is important for plant flower development.To uncover post-transcriptional regulatory networks during the flower development in Dimocarpus longan Lour.‘Shixia’,an economically important fruit crop in subtropical regions,we collected and analyzed sRNA deep-sequencing datasets and degradome libraries Apart from identifying miRNAs and phased siRNA generating loci(PHAS loci),120 hairpin loci,producing abundant sRNAs,were identified by in-house protocols.Our results suggested that 56 miRNA-target pairs,2221-nt-PHAS loci,and 111 hairpin loci are involved in posttranscriptional gene silencing during longan reproductive development.Lineage-specific or species-specific post-transcriptional regulatory modules have been unveiled,including miR482-PHAS and miRN15.miR482-PHAS might be involved in longan flower development beyond their conserved roles in plant defense,and miRN15 is a novel miRNA likely associated with a hairpin locus(HPL-056)to regulate strigolactone receptor gene DWARF14(D14)and the biogenesis of phasiRNAs from D14.These small RNAs are enriched in flower buds,suggesting they are likely involved in post-transcriptional regulatory networks essential for longan flower development via the strigolactone signaling pathway.

Positive regulatory role of R2R3 MYBs in terpene biosynthesis in Lilium‘Siberia’

Terpenoids are the main components contributing to the fragrance of Lilium‘Siberia’,and LiTPS2 plays a critical role in the biosynthesis of monoterpenoids.Although the major terpene synthases in Lilium‘Siberia’have been identified,how these TPS genes are transcriptionally regulated remains elusive in this distinguished flower.This study aimed to identify transcription factors that regulate the terpene synthesis in Lilium,and disclose the related underlying transcriptional regulation mechanism.In this study,we identified three R2R3-MYB TFs—LiMYB1,LiMYB305 and LiMYB330,which were involved in regulating the biosynthesis of terpenes in Lilium‘Siberia’.Quantitative real-time PCR showed spatial and temporal expression patterns consistent with the emission patterns of terpene compounds.When LiMYB1,LiMYB305 and LiMYB330were overexpressed in flowers,the release of some main monoterpenes,such as linalool and ocimene,as well as the expression of TPS genes,especially for LiTPS2,were enhanced.A virus-induced gene silencing(VIGS)assay showed that silencing these three LiMYBs decreased the level of monoterpenes by down-regulating the expression of the TPS genes.The yeast one-hybrid and transient expression assays indicated that all three LiMYBs could bind to and activate the promoter of LiTPS2.Moreover,the yeast two-hybrid assay verified that LiMYB1 could interact with LiMYB308 and LiMYB330,indicating their synergistic roles in the regulation of floral terpene biosynthesis.In general,these results indicated that LiMYB1,LiMYB305,and LiMYB330 might play essential roles in terpene biosynthesis in Lilium and would provide a new perspective for the transcriptional regulation of volatile terpenes in flowers.

Mutations in epigenetic regulator KMT2C detected by liquid biopsy are associated with worse survival in prostate cancer patients

Background:KMT2(lysine methyltransferase)family enzymes are epigenetic regulators that activate gene transcription.KMT2C is mainly involved in enhancer-associated H3K4me1,and is also one of the top mutated genes in cancer(6.6%in pan-cancer).Currently,the clinical significance of KMT2C mutations in prostate cancer is understudied.Methods:We included 221 prostate cancer patients diagnosed between 2014 and 2021 in West China Hospital of Sichuan University with cell-free DNA-based liquid biopsy test results in this study.We investigated the association between KMT2C mutations,other mutations,and pathways.Furthermore,we evaluated the prognostic value of KMT2C mutations,measured by overall survival(OS)and castration resistance-free survival(CRFS).Also,we explored the prognostic value of KMT2C mutations in different patient subgroups.Lastly,we investigated the predictive value of KMT2C mutations in individuals receiving conventional combined anti-androgen blockade(CAB)and abiraterone(ABI)as measured by PSA progression-free survival(PSA-PFS).Results:The KMT2C mutation rate in this cohort is 7.24%(16/221).KMT2C-mutated patients showed worse survival than KMT2C-wild type(WT)patients regarding both CRFS and OS(CRFS:mutated:9.9 vs.WT:22.0 months,p=0.015;OS:mutated:71.9 vs.WT 137.4 months,p=0.012).KMT2C mutations were also an independent risk factor in OS[hazard ratio:3.815(1.461,9.96),p=0.006]in multivariate analyses.Additionally,we explored the association of KMT2C mutations with other genes.This showed that KMT2C mutations were associated with Serine/Threonine-Protein Kinase 11(STK11,p=0.004)and Catenin Beta 1(CTNNB1,p=0.008)mutations.In the CAB treatment,KMT2C-mutated patients had a significantly shorter PSA-PFS compared to KMT2C-WT patients.(PSA-PFS:mutated:9.9 vs.WT:17.6 months,p=0.014).Moreover,KMT2C mutations could effectively predict shorter PSA-PFS in 10 out of 23 subgroups and exhibited a strong trend in the remaining subgroups.Conclusions:KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CRFS and OS,and KMT2C mutations were associated with STK11 and CTNNB1 mutations.Furthermore,KMT2C mutations indicated rapid progression during CAB therapy and could serve as a potential biomarker to predict therapeutic response in prostate cancer.

Comparative genomic analysis of N6-methyladenosine regulators in nine rosaceae species and functional characterization in response to drought stress in pear

N 6-methylated adenine(m6 A)is an emerging epigenetic marker in eukaryotic organisms that plays an important role in biological functions and in enriching genetic information.m6 A exerts these functions via the dynamic interplay among m6 A writers,erasers,and readers.However,little is known about the underlying mechanisms of m6 A in plant growth and stress responses.Here,we identified 276 masked m6 A regulators from nine Rosaceae species(Pyrus bretschneideri,Pyrus betulifolia,Pyrus communis,Malus domestica,Fragaria vesca,Prunus avium,Prunus mume,Prunus persica,and Rubus occidentalis).We classified and named these genes in more detail based on phylogenetic and synteny analysis.The expansion of m6 A regulators in Maloideae was dated back to the recent whole-genome duplication(WGD)in Rosaceae.Based on the expression pattern analysis and gene structure analysis of m6 A regulators,m6 A was shown to be a significant factor in regulating plant development and resistance.In addition,PbrMTA1-silenced pear plants displayed significantly reduced drought tolerance and chlorophyll content,as well as increased electrolyte leakage and concentrations of malondialdehyde and H2 O2.

Regulatory role of NFAT1 signaling in articular chondrocyteactivities and osteoarthritis pathogenesis

Osteoarthritis (OA), the most common form of joint disease, is characterized clinically by joint pain, stiffness,and deformity. OA is now considered a whole joint disease;however, the breakdown of the articular cartilage remains themajor hallmark of the disease. Current treatments targeting OA symptoms have a limited impact on impeding orreversing the OA progression. Understanding the molecular and cellular mechanisms underlying OA development isa critical barrier to progress in OA therapy. Recent studies by the current authors’ group and others have revealedthat the nuclear factor of activated T cell 1 (NFAT1), a member of the NFAT family of transcription factors, regulatesthe expression of many anabolic and catabolic genes in articular chondrocytes of adult mice. Mice lacking NFAT1exhibit normal skeletal development but display OA in both appendicular and spinal facet joints as adults. Thisreview mainly focuses on the recent advances in the regulatory role of NFAT1 transcription factor in the activities ofarticular chondrocytes and its implication in the pathogenesis of OA.

The regulatory role of Pin1 in neuronal death

Regulated cell death predominantly involves apoptosis,autophagy,and regulated necrosis.It is vital that we understand how key regulatory signals can control the process of cell death.Pin1 is a cis-trans isomerase that catalyzes the isomerization of phosphorylated serine or threonine-proline motifs of a protein,thereby acting as a crucial molecular switch and regulating the protein functionality and the signaling pathways involved.However,we know very little about how Pin1-associated pathways might play a role in regulated cell death.In this paper,we review the role of Pin1 in regulated cell death and related research progress and summarize Pin1-related pathways in regulated cell death.Aside from the involvement of Pin1 in the apoptosis that accompanies neurodegenerative diseases,accumulating evidence suggests that Pin1 also plays a role in regulated necrosis and autophagy,thereby exhibiting distinct effects,including both neurotoxic and neuroprotective effects.Gaining an enhanced understanding of Pin1 in neuronal death may provide us with new options for the development of therapeutic target for neurodegenerative disorders.

肿瘤细胞周期调控研究进展

细胞周期是1个细胞能分裂成2个子细胞并由独特的细胞周期调控系统指导的一系列事件。细胞周期调控系统的失调是肿瘤发生的根本原因,本文将围绕细胞周期的关键调控点,探讨肿瘤细胞周期调控的研究进展,为研发肿瘤治疗的新策略提供理论基础。

Revisiting Port Regulatory Governance & Substance: Towards a Holistic Supply Chain Approach

The evolution and integration of ports in global logistics chains has altered their traditional role while has initiated restructuring processes in many ports worldwide. While most of the research addresses this issue by highlighting the need for re-positioning and redefining the role of the port within the supply chains, not much attention has been given to the structure, scope and reach as well as to the tools of regulation hat competent authorities could exploit in order to avert potential abusive actions of global powerful actors along the containerized transport chain, that would affect the competitive functioning of distinct segment or the integrity of supply chains. In this context, we propose the reconceptualization and reinforcement of the regulatory governance structures of ports on a national and international level as well as the extension of the scope of ports’ regulations along the supply chain to counterbalance the globalization, consolidation and integration of containerized transport actors.

Research on the Theory of Governmental Environmental Regulatory Responsibility

In recent years,the environmental pollution caused by the rapid development of tourist attractions has increasingly become the focus of society,which has triggered scholars to think about the government's responsibility for environmental regulation,and has generated a variety of theories in the academic world.For example,the stakeholder theory extends corporate governance to the regulation of tourism scenic spots,and achieves the purpose of perfecting the environmental regulation of tourism scenic spots by continuously enriching the scope of stakeholders'subjects;the property rights theory analyzes the transaction costs generated by various economic activities in the regulation of tourism scenic spots from macro and micro perspectives,and the public goods theory clarifies the concept,types and characteristics of tourism scenic spots as public goods.Therefore,based on stakeholder theory,property rights theory and public goods theory,this paper explores and clarifies the content of the government's responsibility in the environmental regulation of tourism scenic spots,and tries to further enrich the theoretical results of the government's environmental regulation responsibility,in order to provide new ideas for the sustainable development of tourism scenic spots from the theoretical point of view.