Exercise-induced irisin in bone and systemic irisin administration reveal new regulatory mechanisms of bone metabolism

Irisin is a polypeptide hormone derived from the proteolytic cleavage of fibronectin-type III domain- containing 5 （FNDC5） protein. Once released to circulation upon exercise or cold exposure, irisin stimulates browning of white adipose tissue （WAT） and uncoupling protein I （UCP1） expression, leading to an increase in total body energy expenditure by augmented UCPl-mediated thermogenesis. It is currently unknown whether irisin is secreted by bone upon exercise or whether it regulates bone metabolism in vivo. In this study, we found that 2 weeks of voluntary wheel-running exercise induced high levels of FNDC5 messenger RNA as well as FNDC5/irisin protein expression in murine bone tissues. Increased immunoreactivity due to exercise-induced FNDC5/irisin expression was detected in different regions of exercised femoral bones, including growth plate, trabecular bone, cortical bone, articular cartilage, and bone-tendon interface. Exercise also increased expression of osteogenic markers in bone and that of UCP1 in WAT, and led to bodyweight loss. Irisin intraperitoneal （IP） administration resulted in increased trabecular and cortical bone thickness and osteoblasts numbers, and concurrently induced UCP1 expression in subcutaneous WAT. Lentiviral FNDC5 IP administration increased cortical bone thickness. In vitro studies in bone cells revealed irisin increases osteoblastogenesis and mineralization, and inhibits receptor activator of nuclear factor-kB ligand （RANKL）- induced osteoclastogenesis. Taken together, our findings show that voluntary exercise increases irisin production in bone, and that an increase in circulating irisin levels enhances osteogenesis in mice.

Okadaic acid: a tool to study regulatory mechanisms for neurodegeneration and regeneration in Alzheimer's disease

Okadaic acid： Okadaic acid （OKA）, a polyether （C38 fatty acid） toxin, is a potent and selective inhibitor of protein phosphatase, PP1 and protein phosphatase 2A （PP2A）. It is mainly extracted from a black sponge Hallichondria okadaii and has been suggested to play a potent probe for studying the various molecular, cellular, biochemical and mechanism of neurotoxicity. It is known as a selective and potent in- hibitor of serine/threonine phosphatases 1 and 2A induces hyperphosphorylation of tau in vitro and in vivo. It has been reported that Alzheimer＇s disease （AD） is a complex multi- factorial neurodegenerative disorder and hyperphosphor- ylated tau protein is a major pathological hallmark of AD. The reduced activity of phosphatases like, PP2A has been implicated in the brain of AD patients. OKA also induced inhibition of protein phosphatases cause neurofibrillary tangles （NFTs） like pathological changes and tau hyperphos- phorylation seen in AD pathology. Our and others reports inferred that OKA induces neurodegeneration along with tau hyperphosphorylation, GSK3β activation, oxidative stress, neuroinflammation and neurotoxicity which are char- acteristic of AD pathology （Figure 1）.

Integrative regulatory mechanisms of stomatal movements under changing climate

Global climate change-caused drought stress,high temperatures and other extreme weather profoundly impact plant growth and development,restricting sustainable crop production.To cope with various environmental stimuli,plants can optimize the opening and closing of stomata to balance CO_(2)uptake for photosynthesis and water loss from leaves.Guard cells perceive and integrate various signals to adjust stomatal pores through turgor pressure regulation.Molecular mechanisms and signaling networks underlying the stomatal movements in response to environmental stresses have been extensively studied and elucidated.This review focuses on the molecular mechanisms of stomatal movements mediated by abscisic acid,light,CO_(2),reactive oxygen species,pathogens,temperature,and other phytohormones.We discussed the significance of elucidating the integrative mechanisms that regulate stomatal movements in helping design smart crops with enhanced water use efficiency and resilience in a climate-changing world.

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy.Isocitrate dehydrogenases(IDHs)are a class of key proteins in energy metabolism,including IDH1,IDH2,and IDH3,which are involved in the oxidative decarboxylation of isocitrate to yield a-ketoglutarate(a-KG).Mutants of IDH1 or IDH2 can produce D-2-hydroxyglutarate(D-2HG)with a-KG as the substrate,and then mediate the occurrence and development of cancer.At present,no IDH3 mutation has been reported.The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2,implying IDH1 as a promising anti-cancer target.Therefore,in this review,we summarized the regulatory mechanisms of IDH1 on cancer from four aspects:metabolic reprogramming,epigenetics,immune microenvironment,and phenotypic changes,which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies.In addition,we also reviewed available IDH1 inhibitors so far.The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

Proteo-transcriptomic profiles reveal key regulatory pathways and functions of LDHA in the ovulation of domestic chickens(Gallus gallus)

Background In poultry, the smooth transition of follicles from the preovulatory-to-postovulatory phase impacts egg production in hens and can benefit the poultry industry. However, the regulatory mechanism underlying follicular ovulation in avians is a complex biological process that remains unclear.Results Critical biochemical events involved in ovulation in domestic chickens(Gallus gallus) were evaluated by transcriptomics, proteomics, and in vitro assays. Comparative transcriptome analyses of the largest preovulatory follicle(F1) and postovulatory follicle(POF1) in continuous laying(CL) and intermittent laying(IL) chickens indicated the greatest difference between CL_F1 and IL_F1, with 950 differentially expressed genes(DEGs), and the smallest difference between CL_POF1 and IL_POF1, with 14 DEGs. Additionally, data-independent acquisition proteomics revealed 252 differentially abundant proteins between CL_F1 and IL_F1. Perivitelline membrane synthesis, steroid biosynthesis, lysosomes, and oxidative phosphorylation were identified as pivotal pathways contributing to ovulation regulation. In particular, the regulation of zona pellucida sperm-binding protein 3, plasminogen activator, cathepsin A, and lactate dehydrogenase A(LDHA) was shown to be essential for ovulation. Furthermore, the inhibition of LDHA decreased cell viability and promoted apoptosis of ovarian follicles in vitro.Conclusions This study reveals several important biochemical events involved in the process of ovulation, as well as crucial role of LDHA. These findings improve our understanding of ovulation and its regulatory mechanisms in avian species.

Molecular regulatory events of flower and fruit abscission in horticultural plants

Flower and fruit abscission is a highly programmed physiological process,which is closely related to the yield of horticultural plants.The coordination of many regulatory factors associated with metabolic and signaling pathways plays a key role in the flower and fruit shedding.Hormones,peptides,carbohydrates,polyamines or cell wall modifying proteins regulate flower and fruit shedding.This article reviewed the recent studies of flower and fruit abscission,including the molecular regulation mechanism of abscission zone formation,typical structure and location of abscission zones,and other factors affecting flower and fruit abscission,such as stresses,hormones,peptides,carbohydrates,polyamines and cell wall modifying proteins.Overall,the review summarizes the developmental mechanism and the diversity of abscission zones,and the key factors affecting flower and fruit abscission of horticultural plants,aiming to provide guidance for studying the molecular regulatory mechanism of flower and fruit abscission.

3D genome organization and its study in livestock breeding

Eukaryotic genomes are hierarchically packaged into cell nucleus,affecting gene regulation.The genome is organized into multiscale structural units,including chromosome territories,compartments,topologically associating domains(TADs),and DNA loops.The identification of these hierarchical structures has benefited from the development of experimental approaches,such as 3C-based methods(Hi-C,ChIA-PET,etc.),imaging tools(2D-FISH,3D-FISH,Cryo-FISH,etc.)and ligation-free methods(GAM,SPRITE,etc.).In recent two decades,numerous studies have shown that the 3D organization of genome plays essential roles in multiple cellular processes via various mechanisms,such as regulating enhancer activity and promoter-enhancer interactions.However,there are relatively few studies about the 3D genome in livestock species.Therefore,studies for exploring the function of 3D genomes in livestock are urgently needed to provide a more comprehensive understanding of potential relationships between the genome and production traits.In this review,we summarize the recent advances of 3D genomics and its biological functions in human and mouse studies,drawing inspiration to explore the 3D genomics of livestock species.We then mainly focus on the biological functions of 3D genome organization in muscle development and its implications in animal breeding.

Research progress of microRNA in the regulatory mechanism of hypoxic-ischemic encephalopathy

MicroRNA(miRNA)plays a key role in the molecular regulation of neurological diseases,and the molecular mechanism of miRNA is closely related to the occurrence and development of hypoxic-ischemic encephalopathy.Recently,it has been reported that various miRNA molecules can inhibit target mRNA and even degrade target mRNA by changing the complete complementary or incomplete complementary binding to the target mRNA.Therefore,miRNA is of great significance for the study of mRNA related to hypoxic ischemic encephalopathy.This article briefly reviews the molecular mechanisms,functions and regulation of miRNAs on hypoxic-ischemic encephalopathy.

Genetic and environmental control of rice tillering

Increasing tiller number is a target of high-yield rice breeding. Identification of tiller-defect mutants and their corresponding genes is helpful for clarifying the molecular mechanism of rice tillering. Summarizing research progress on the two processes of rice tiller formation, namely the formation and growth of axillary meristem, this paper reviews the effects of genetic factors, endogenous hormones, and exogenous environment on rice tillering, finding that multiple molecular mechanisms and signal pathways regulating rice tillering cooperate rice tillering, and discusses future research objectives and application of its regulatory mechanism. Elucidation of theis mechanism will be helpful for breeding high-yielding rice cultivars with ideal plant type via molecular design breeding.

Oligomerization of drug transporters:Forms,functions,and mechanisms

Drug transporters are essential players in the transmembrane transport of a wide variety of clinical drugs.The broad substrate spectra and versatile distribution pattern of these membrane proteins infer their pharmacological and clinical significance.With our accumulating knowledge on the three-dimensional structure of drug transporters,their oligomerization status has become a topic of intense study due to the possible functional roles carried out by such kind of post-translational modification(PTM).In-depth studies of oligomeric complexes formed among drug transporters as well as their interactions with other regulatory proteins can help us better understand the regulatory mechanisms of these membrane proteins,provide clues for the development of novel drugs,and improve the therapeutic efficacy.In this review,we describe different oligomerization forms as well as their structural basis of major drug transporters in the ATP-binding cassette and solute carrier superfamilies,summarize our current knowledge on the influence of oligomerization for protein expression level and transport function of these membrane proteins,and discuss the regulatory mechanisms of oligomerization.Finally,we highlight the challenges associated with the current oligomerization studies and propose some thoughts on the pharmaceutical application of this important drug transporter PTM.

Social credit:a comprehensive literature review

To avoid credit fraud,social credit within an economic system has become an increasingly important criterion for the evaluation of economic agent activity and guaranteeing the development of a market economy with minimal supervision costs.This paper provides a comprehensive review of the social credit literature from the perspectives of theoretical foundation,scoring methods,and regulatory mechanisms.The study considers the credit of various economic agents within the social credit system such as countries(or governments),corporations,and individuals and their credit variations in online markets(i.e.,network credit).A historical review of the theoretical(or model)development of economic agents is presented together with significant works and future research directions.Some interesting conclusions are summarized from the literature review.(1)Credit theory studies can be categorized into traditional and emerging schools both focusing on the economic explanation of social credit in conjunction with creation and evolution mechanisms.(2)The most popular credit scoring methods include expert systems,econometric models,artificial intelligence(AI)techniques,and their hybrid forms.Evaluation indexes should vary across different target agents.(3)The most pressing task for regulatory mechanisms that supervise social credit to avoid credit fraud is the establishment of shared credit databases with consistent data standards.

Regulatory dynamics of the higher-plant PSI-LHCI supercomplex during state transitions

State transition is a fundamental light acclimation mechanism of photosynthetic organisms in response to the environmental light conditions.This process rebalances the excitation energy between photosystemI(PSl)and photosystem Il through regulated reversible binding of the light-harvesting complex Il(LHCll)to PSl.However,the structural reorganization of PSI-LHCI,the dynamic binding of LHCll,and the regulatory mechanisms underlying state transitions are less understood in higher plants.In this study,using cryoelectron microscopy we resolved the structures of PSI-LHCI in both state 1(PSI-LHCI-ST1)and state 2(PSILHCI-LHCll-ST2)from Arabidopsis thaliana.Combined genetic and functional analyses revealed novel contacts between Lhcb1 and PsaK that further enhanced the binding of the LHCll trimer to the PSI core with the known interactions between phosphorylated Lhcb2 and the PsaL/PsaH/PsaO subunits.Specifically,PsaO was absent in the PSI-LHCI-ST1 supercomplex but present in the PSI-LHCI-LHCIl-ST2 supercomplex,in which the PsaL/PsaK/PsaA subunits undergo several conformational changes to strengthen the binding of PsaO in ST2.Furthermore,the PSI-LHCI module adopts a more compact configuration with shorter Mg-to-Mg distances between the chlorophylls,which may enhance the energy transfer efficiency from the peripheral antenna to the PSl core in ST2.Collectively,our work provides novel structural and functional insights into the mechanisms of light acclimation during state transitions in higher plants.

Study on the Operation Mechanism and Effect of the Yellow River Water and Sediment Regulation System

In order to scientifically deal with the problems of less water and more sediment in the Yellow River and the uncoordinated relationship between water and sediment,it is necessary to establish a perfect water and sediment regulation system.Through the calculation of the sediment transport capacity of the Yellow River and the application of the water and sediment regulation system,it is found that the sediment transport efficiency of the Yellow River will increase with the increase of water flow,and there will be an obvious inflection point near the flat discharge.The joint regulation of the backbone reservoir group can discharge the large discharge close to the minimum flat discharge of the downstream river,which improves the sediment transport capacity of the river and alleviates the problem of sediment deposition.In this paper,through the introduction of the Yellow River water and sediment regulation project system,regulation indicators and mechanisms,the author discusses in detail the Yellow River water and sediment regulation scheme and its operation effect,hoping to provide help promote the improvement of the Yellow River governance effect.

Bactericidal bissulfone B7 targets bacterial pyruvate kinase to impair bacterial biology and pathogenicity in plants

The prevention and control of rice bacterial leaf blight(BLB)disease has not yet been achieved due to the lack of effective agrochemicals and available targets.Herein,we develop a series of novel bissulfones and a novel target with a unique mechanism to address this challenge.The developed bissulfones can control Xanthomonas oryzae pv.oryzae(Xoo),and 2-(bis(methylsulfonyl)methylene)-N-(4-chlorophenyl)hydrazine-1-carboxamide(B_(7))is more effective than the commercial drugs thiodiazole copper(TC)and bismerthiazol(BT).Pyruvate kinase(PYK)in Xoo has been identified for the first time as the target protein of our bissulfone B_(7).PYK modulates bacterial virulence via a CRP-like protein(Clp)/two-component system regulatory protein(reg R)axis.The elucidation of this pathway facilitates the use of B_(7)to reduce PYK expression at the transcriptional level,block PYK activity at the protein level,and impair the interaction within the PYK-Clp-reg R complex via competitive inhibition,thereby attenuating bacterial biology and pathogenicity.This study offers insights into the molecular and mechanistic aspects underlying anti-Xoo strategies that target PYK.We believe that these valuable discoveries will be used for bacterial disease control in the future.

The next decade of SET:from an oncoprotein to beyond

This year marks the fourth decade of research into the protein SET,which was discovered in 1992.SET was initially identified as an oncoprotein but later shown to be a multifaceted protein involved in regulating numerous biological processes under both physiological and pathophysiological conditions.SET dysfunction is closely associated with diseases,such as cancer and Alzheimer's disease.With the increasing understanding of how SET works and how it is regulated in cells,targeting aberrant SET has emerged as a potential strategy for disease intervention.In this review,we present a comprehensive overview of the advancements in SET studies,encompassing its biological functions,regulatory networks,clinical implications,and pharmacological inhibitors.Furthermore,we provide insights into the future prospects of SET research,with a particular emphasis on its promising potential in the realm of immune modulation.

Expression and regulatory mechanism of S100A14 in breast cancer

Objective To explore the expression of S100A14 in breast cancer tissue,and the EGF and S100A14 feedback regulatory mechanism.Methods S100A14 mRNA level in 52 cases of breast cancer and adjacent normal tissue was detected by quantitative real-time PCR.S100A14 protein in 21 cases of breast cancer and adjacent normal tissue was detected by Western blot.

Liver cell therapies:cellular sources and grafting strategies

The liver has a complex cellular composition and a remarkable regenerative capacity.The primary cell types in the liver are two parenchymal cell populations,hepatocytes and cholangiocytes,that perform most of the functions of the liver and that are helped through interactions with non-parenchymal cell types comprising stellate cells,endothelia and various hemopoietic cell populations.The regulation of the cells in the liver is mediated by an insoluble complex of proteins and carbohydrates,the extracellular matrix,working synergistically with soluble paracrine and systemic signals.In recent years,with the rapid development of genetic sequencing technologies,research on the liver’s cellular composition and its regulatory mechanisms during various conditions has been extensively explored.Meanwhile breakthroughs in strategies for cell transplantation are enabling a future in which there can be a rescue of patients with end-stage liver diseases,offering potential solutions to the chronic shortage of livers and alternatives to liver transplantation.This review will focus on the cellular mechanisms of liver homeostasis and how to select ideal sources of cells to be transplanted to achieve liver regeneration and repair.Recent advances are summarized for promoting the treatment of end-stage liver diseases by forms of cell transplantation that now include grafting strategies.

Multilevel regulation of N^(6)-methyladenosine RNA modifications: Implications in tumorigenesis and therapeutic opportunities

N^(6)-methyladenosine(m^(6)A)RNA modification is widely perceived as the most abundant and common modification in transcripts.This modification is dynamically regulated by specific m^(6)A“writers”,“erasers”and“readers”and is reportedly involved in the occurrence and development of many diseases.Since m^(6)A RNA modification was discovered in the 1970s,with the progress of relevant research technologies,an increasing number of functions of m^(6)A have been reported,and a preliminary understanding of m^(6)A has been obtained.In this review,we summarize the mechanisms through which m^(6)A RNA modification is regulated from the perspectives of expression,posttranslational modification and protein interaction.In addition,we also summarize how external and internal environmental factors affect m^(6)A RNA modification and its functions in tumors.The mechanisms through which m^(6)A methylases,m^(6)A demethylases and m^(6)A-binding proteins are regulated are complicated and have not been fully elucidated.Therefore,we hope to promote further research in this field by summarizing these mechanisms and look forward to the future application of m^(6)A in tumors.

Regulation mechanism and pathogenic role of lncRNA plasmacytoma variant translocation 1 (PVT1) in human diseases

Plasmacytoma variant translocation 1 (PVT1) is a long non-coding RNA (lncRNA) gene identified as a recurrent breakpoint of Burkitt’s lymphomas. Human PVT1 gene is located on region 8q24.21, a well-known cancer risk region, and encodes at least 26 linear ncRNA isoforms and 26 circular RNA isoforms, as well as 6 microRNAs. Several PVT1 functioning models have been reported recently such as competing endogenous RNA (ceRNA) activity and regulating protein stability of oncogenes, especially MYC oncogene. The promoter of PVT1 gene is a boundary element of tumor-suppressor DNA. CircPVT1 derived from PVT1 gene is also a critical non-coding oncogenic RNA. Although substantial advancements have been made in understanding the roles of PVT1 in cancer recently, the detailed mechanisms underlying its functions remain unclear. Herein, we summarize the recent progressions on the mechanisms underlying PVT1 regulated gene expression at different levels. We also discuss the interaction between lncRNA and protein, RNA and DNA, as well as the potential cancer therapy strategy by targeting these networks.

Interleukin 6 and interferon gamma haplotypes are related to cytokine serum levels in dogs in an endemic Leishmania infantum region

Background The Ibizan Hound is a canine breed native to the Mediterranean region,where leishmaniasis is an endemic zoonosis.Several studies indicate a low prevalence of this disease in Ibizan Hound dogs,whereas other canine breeds present a high prevalence.However,the underlying molecular mechanisms still remain unknown.The aim of this work is to analyse the relationship between serum levels of cytokines and the genomic profiles in two canine breeds,Ibizan Hound(resistant canine breed model)and Boxer(susceptible canine breed model).Methods In this study,we analyse the haplotypes of genes encoding cytokines related to immune response of Leishmania infantum infection in twenty-four Boxers and twenty-eight Ibizan Hounds apparently healthy using CanineHD DNA Analysis BeadChip including 165,480 mapped positions.The haplo.glm extension of haplo.score was used to perform a General Linear Model(GLM)regression to estimate the magnitude of individual haplotype effects within each cytokine.Results Mean levels of interferon gamma(IFN-γ),interleukin 2(IL-2)and IL-18 in Boxer dogs were 0.19±0.05 ng/ml,46.70±4.54 ng/ml,and 36.37±30.59 pg/ml,whereas Ibizan Hound dogs present 0.49±0.05 ng/ml,64.55±4.54 ng/ml,and 492.10±31.18 pg/ml,respectively.The GLM regression shows fifteen haplotypes with statistically significant effect on the cytokine serum levels(P<0.05).The more relevant are IL6-CGAAG and IFNG-GCA haplotypes,which increase and decrease the IL-2,IL-8 and IFN-γserum levels,respectively.Conclusions Haplotypes in the IFNG and IL6 genes have been correlated to serum levels of IFN-γ,IL-2 and IL-18,and a moderate effect has been found on IL8 haplotype correlated to IL-8 and IL-18 serum levels.The results indicate that the resistance to L.infantum infection could be a consequence of certain haplotypes with a high frequency in the Ibizan Hound dog breed,while susceptibility to the disease would be related to other specific haplotypes,with high frequency in Boxer.Future studies are needed to elucidate whether these differences and haplotypes are related to different phenotypes in immune response and expression gene regulation to L.infantum infections in dogs and their possible application in new treatments and vaccines.