EFFECT OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ACTIVATORS ON TUMOR NECROSIS FACTOR-αEXPRESSION IN NEONATAL RAT CARDIAC MYOCYTES

Objective To investigate the effect of peroxisome proliferator-activated receptor-α(PPARα) and PPARγactivators on tumor necrosis factor-α(TNFα) expression in neonatal rat cardiac myocytes. Methods Primary cultures of cardiac myocytes from 1- to 3-day-old Wistar rats were prepared, and myocytes were ex-posed to lipopolysaccharide (LPS) and varying concentrations of PPARαor PPARγactivator (fenofibrate or pioglitazone).RT-PCR and ELISA were used to measure TNFα, PPARα, and PPARγexpression in cultured cardiac myocytes. Transient tr-ansfection of TNFαpromoter with or without nuclear factor-kappaB (NF-κB) binding site to cardiac myocytes was performed. Results Pretreatment of cardiac myocytes with fenofibrate or pioglitazone inhibited LPS-induced TNFαmRNA and protein expression in a dose-dependent manner. However, no significant changes were observed on PPARαor PPARγmRNA expression when cardiac myocytes were pretreated with fenofibrate or pioglitazone. Proportional suppression of TNFαpromoter activity was observed when myocytes was transiently transfected with whole length of TNFαpromoter (-721/+17) after being stimulated with LPS and fenofibrate or pioglitazone, whereas no change of promoter activity was observed with transfection of TNFαreporter construct in deletion of NF-κB binding site (-182/+17). Conclusions PPARαand PPARγactivators may inhibit cardiac TNFαexpression but not accompanied by change of PPARαor PPARγmRNA expression. Therefore PPARαand PPARγactivators appear to play a role in anti-inflammation. The mechanism may partly be involved in suppression of the NF-κB pathway.

Screening of immune cell activators from Astragali Radix using a comprehensive two-dimensional NK-92MI cell membrane chromatography/C18 column/time-of-flight mass spectrometry system

Astragali Radix(AR)is a clinically used herbal medicine with multiple immunomodulatory activities that can strengthen the activity and cytotoxicity of natural killer(NK)cells.However,owing to the complexity of its composition,the specific active ingredients in AR that act on NK cells are not clear yet.Cell membrane chromatography(CMC)is mainly used to screen the active ingredients in a complex system of herbal medicines.In this study,a new comprehensive two-dimensional(2D)NK-92MI CMC/C18 column/time-of-flight mass spectrometry(TOFMS)system was established to screen for potential NK cell activators.To obtain a higher column efficiency,3-mercaptopropyltrimethoxysilane-modified silica was synthesized to prepare the NK-92MI CMC column.In total,nine components in AR were screened from this system,which could be washed out from the NK-92MI/CMC column after 10 min,and they showed good affinity for NK-92MI/CMC column.Two representative active compounds of AR,isoastragaloside Ⅰ and astragaloside IV,promoted the killing effect of NK cells on K562 cells in a dose-dependent manner.It can thus suggest that isoastragaloside Ⅰ and astragaloside Ⅳ are the main immunomodulatory components of AR.This comprehensive 2D NK-92MI CMC analytical system is a practical method for screening immune cell activators from other herbal medicines with immunomodulatory effects.

A Class of High-affinity Bicyclooctane G551D-CFTR Activators Identified by High Throughput Screening

The glycine-to-aspartic acid missense mutation at the codon 551(G551D) of the cystic fibrosis transmembrane conductance regulator(CFTR) is one of the five most frequent cystic fibrosis(CF) mutations associated with a severe CF phenotype. To explore the feasibility of pharmacological correction of disrupted activation of CFTR chloride channel caused by G551D mutation, we developed a halide-sensitive fluorescence miniassay for G551D-CFTR in Fisher rat thyroid(FRT) epithelial cells for the discovery of novel activators of G551D-CFTR. A class of bicyclooctane small molecule compounds that efficiently stimulate G551D-CFTR chloride channel activity was identified by high throughput screening via the FRT cell-based assay. This class of compounds selectively activates G551D-CFTR with a high affinity, whereas little effect of the compounds on wildtype CFTR can be seen. The discovery of a class of bicyclooctane G551D-CFTR activators will permit the analysis of structure-activity relationship of the compounds to identify ideal leads for in vivo therapeutic studies.

THE INCREASE IN PLASMINOGEN ACTIVATOR INHIBITOR TYPE-1 EXPRESSION BY STIMULATION OF ACTIVATORS FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS IN HUMAN ENDOTHELIAL CELLS

Objective.To investigate the effect of peroxis ome proliferator-activated recept ors(PPARs )activators on plasminogen activator inhibitor ty pe-1(PAI-1)expression in human umbilical vein e ndothelial cells and the possi-ble mechanism.Methods.Human umbilical vein endothelial ce lls(HUVECs )were obtained from normal fetus,and cul-tured conventionally.Then the HUVECs were exposed to test agents(linolenic acid,linoleic acid,oleic acid,stearic acid and prostaglandin J 2 respectively)in varying concentrations with fresh media.RT -PCR and ELISA were applied to determine the expression of PPARs and PAI-1in HUVECs.Results.PPARα,PPARδand PPARγmRNA were detected by using RT-PCR in HUVECs.Treatment of HUVECs with PPARαand PPARγactivators---linolenic acid,linoleic acid,oleic acid and prostaglandin J 2 respectively,but not with stearic a cid could augment PAI-I mRNA expression and protein secretion in a concentration-dependent manner.However,the mRNA expressions of 3subclasses of PPAR with their activators in HUVECs were not changed compared w ith controls.Conclusion.HUVECs express PPARs.PPARs activators may increase PAI-1expression in ECs,but the underlying mechanism remains uncle ar.Although PPARs expression was not enhanced after stimulated by their activators in ECs,the role of functionally active PPARs in regulating PA I-1expression in ECs needs to be further investigated by using transient gen e transfection assay.

THE EFFECT OF RADIX SALVIAE MILTIORRHIZAE ON THE INHIBITORY ACTIVITY OF VASCULAR SMOOTH MUSCLE CELLS TO THE PLASMINOGEN ACTIVATORS SECRETED BY ENDOTHELIAL CELLS

Cultured porcine endothelial cells (EC) produce and secrete plasminogenactivators (PA). If the serum free media incubated by vascular smooth muscle cells(SMC-CM) were mixed with the same media incubated by endothelial cells (EC-CM),the PA activities of the latter decreased significantly. Cocultivation of EC with SMC alsoresulted in a significant decrease (70.7%) of PA activities produced by EC. Sodiumdodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of SMC-CMfollowed by reverse fibrin autography demonstrated that the PA inhibitor had a molecularweight of 49000-62000. In this study we also investigated the effect of a Chinese herbalmedicine-Radix Salviae Miltiorrhizae (RSM) on the inhibitory activity of SMC. The re-sults showed that RSM significantly decreased the inhibitory activity of SMC against thePA secreted by EC.

Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients:a randomised,double-blinded,placebo-controlled phase-II trial

Background Alzheimer’s disease(AD)is associated with metabolic abnormalities linked to critical elements of neurodegeneration.We recently administered combined metabolic activators(CMA)to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals.CMA promotes mitochondrial fatty acid uptake from the cytosol,facilitates fatty acid oxidation in the mitochondria,and alleviates oxidative stress.Methods Here,we designed a randomised,double-blinded,placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients.One-dose CMA included 12.35 g L-serine(61.75%),1 g nicotinamide riboside(5%),2.55 g N-acetyl-L-cysteine(12.75%),and 3.73 g L-carnitine tartrate(18.65%).AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84.The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms.The secondary aim of this study was to evaluate the safety and tolerability of CMA.A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients.Results We showed a significant decrease of AD Assessment Scale-cognitive subscale(ADAS-Cog)score on day 84 vs day 0(P=0.00001,29%improvement)in the CMA group.Moreover,there was a significant decline(P=0.0073)in ADAS-Cog scores(improvement of cognitive functions)in the CMA compared to the placebo group in patients with higher ADAS-Cog scores.Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis.Moreover,the plasma levels of proteins and metabolites associated with NAD+and glutathione metabolism were significantly improved after CMA treatment.Conclusion Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics,metabolomics,proteomics and imaging analysis.

Chemistry-led investigations into the mode of action of NAMPT activators,resulting in the discovery of non-pyridyl class NAMPT activators

The cofactor nicotinamide adenine dinucleotide(NAD+)plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+levels is an established approach to enhancing healthy aging.Recently,several classes of nicotinamide phosphoribosyl transferase(NAMPT)activators have been shown to increase NAD+levels in vitro and in vivo and to demonstrate beneficial effects in animal models.The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors,however the basis for the switch from inhibitory activity to activation is not well understood.Here we report an evaluation of the structure activity relationships of NAMPT activators by designing,synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators.The results of these studies led us to hypothesise that these activators act via a through-water interaction in the NAMPT active site,resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead,which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.

Improving cooperativity of transcription activators by oligomerization domains in mammalian cells

Cooperative activation is critical for the applications of synthetic biology in mammalian cells.In this study,we have developed cooperative transcription factor by fusing oligomerization domain in mammalian cells.Firstly,we demonstrated that two oligomerized domains(CI434 and CI)successfully improved transcription factor cooperativity in bacterial cells but failed to increase cooperativity in mammalian cells,possibly because the additional mammalian activation domain disrupted their oligomerization capability.Therefore,we chose a different type of oligomerized domain(CarHC),whose ability to oligomerize is not dependent on its C-terminal domains,to fuse with a transcription factor(RpaR)and activation domain(VTR3),forming a potential cooperative transcription activator RpaR-CarH-VTR3 for mammalian regulatory systems.Compared with RpaR-VTR3,the cooperativity of RpaR-CarH-VTR3 was significantly improved with higher Hill coefficient and a narrower input range in the inducible switch system in mammalian cells.Moreover,a mathematical model based on statistical mechanics model was developed and the simulation results supported the hypothesis that the tetramer of the CarH domain in mammalian cells was the reason for the cooperative capacity of RpaR-CarH-VTR3.

Novel thieno[2,3-b]quinoline-procaine hybrid molecules:A new class of allosteric SHP-1 activators evolved from PTP1B inhibitors

Small molecule activators could equally provide powerful tools as inhibitors do for interrogating cellular signal transduction.However,targeted protein activation is chemically challenging.Developing activators against Src homology region 2 domain-containing phosphatase-1(SHP-1)to block STAT3 pathway represents a promising strategy for DLBCL therapy.Here we reported a new class of thieno[2,3-b]quinolineprocaine hybrid molecules as SHP-1 allosteric activators.The representative hybrid compound 3b displayed SHP-1 activating effect with EC50 of 5.48±0.28μmol/L.Further investigations confirmed that 3b allosterically interacted with SHP-1,switched it from close to open conformation,blocked SHP-1/p-STAT3 pathway,induced apoptosis and inhibited ABC-DLBCL cell proliferation in vitro,and delayed tumor growth in the xenograft model of SU-DHL-2.Overall,this work offered a novel paradigm to develop SHP-1 allosteric activators through chemical space evolution of PTPs inhibitors,and firstly validated the therapeutic strategy that directly activating SHP-1 alone could be a potential therapy against ABC-DLBCL via blocking STAT3 pathway.

Recent research in mechanical properties of geopolymer-based ultrahigh-performance concrete:A review

Due to the growing need for sustainable and ultra-high-strength construction materials,scientists have created an innovative ultra-high-performance concrete called Geopolymer based ultra-highperformance concrete(GUHPC).Besides,in the last few decades,there have been a lot of explosions and ballistic attacks around the world,which have killed many civilians and fighters in border areas.In this context,this article reviews the fresh state and mechanical properties of GUHPC.Firstly,the ingredients of GUHPC and fresh properties such as setting time and flowability are briefly covered.Secondly,the review of compressive strength,flexure strength,tensile strength and modulus of elasticity of fibrous GUHPC.Thirdly,the blast and projectile impact resistance performance was reviewed.Finally,the microstructural characteristics were reviewed using the scanning electron microscope and X-ray Powder Diffraction.The review outcome reveals that the mechanical properties were increased when 30%silica fume was added to a higher dose of steel fibre to improve the microstructure of GUHPC.It is hypothesized that the brittleness of GUHPC was mitigated by adding 1.5%steel fibre reinforcement,which played a role in the decrease of contact explosion cratering and spalling.Removing the need for cement in GUHPC was a key factor in the review,indicating a promising potential for lowering carbon emissions.However,GUHPC research is still in its early stages,so more study is required before its full potential can be utilized.

Electroacupuncture targeting the immune system to alleviate sepsis

Sepsis is a life-threatening inflammatory syndrome with high morbidity and mortality rates.However,options for sepsis are still limited to general treatment in intensive care units(ICUs),and effective therapies that improve sepsis survival are required.Immune disturbances play a vital role in the pathology of sepsis and are associated with protracted inflammation,susceptibility to infections,and death.Therefore,many investigators have focused on the potential benefits of immunomodulation therapy for sepsis.Electroacupuncture(EA)has been practiced in clinics for many years and has shown advantages in treating infectious diseases.Over the last few decades,our understanding of the efficacy and mechanisms of EA in sepsis has undergone considerable developments.We searched the literature regarding“CNKI,Wan Fang Data,VIP Database,PubMed,and Ingenta Connect”from 2010 to 2023,using the keywords“sepsis”“septic”and“electroacupuncture”and 336 sources were searched.Finally,we included 82 studies that targeted the immune system to determine EA’s anti-inflammatory and immunomodulatory effects on sepsis.In this review,we found that EA has clinical benefits in relieving septic inflammation,improving immune function,and attenuating related multi-organ injury through several mechanisms,such as activation of the cholinergic anti-inflammatory pathway(CAP),vagaladrenal axis,inhibition of the nuclear factor Kappa-B(NF-κB)signaling pathway,signal transducers and activators of transcription(STAT)signaling pathway,and improvement of immune cell function.Therefore,EA may be a promising complementary therapy for sepsis treatment.We also expect these data will contribute to further studies on EA in sepsis.

基于GRU-DRSN的双通道人体活动识别

人体活动识别(human activity recognizition, HAR)在医疗、军工、智能家居等领域有很大的应用空间。传统机器学习方法特征提取难度较大且精度不高。针对上述问题并结合传感器时序特性,提出了一种融合CBAM(convolutional block attention module)注意力机制的GRU-DRSN双通道并行模型,有效避免了传统串行模型因网络深度加深引起梯度爆炸和消失问题。同时并行结构使得两条支路具有相同的优先级,使用深度残差收缩网络(deep residual shrinkage network, DRSN)提取数据的深层空间特征,同时使用门控循环结构(gated recurrent unit, GRU)学习活动样本在时间序列上的特征,同时进行提取样本不同维度的特征,并通过CBAM模块进行特征的权重分配,最后通过Softmax层进行识别,实现了端对端的人体活动识别。使用公开数据集(wireless sensor data mining, WISDM)进行验证,模型平均精度达到了97.6%,与传统机器学习模型和前人所提神经网络模型相比,有更好的识别效果。

“ACTIVE”英语学科育人模式构建与应用

本研究以“立德树人”为核心理念,构建“ACTIVE”英语学科育人模式。该模式通过六个关键维度--学科育人(AIM)、文化浸润(Culture)、思维可见(Thinking)、技术融合(Integration)、美德根植(Virtue)和情感共鸣(Empathy)--全面激发学生英语学习的热情,培养他们的语言能力,同时注重道德品质的熏陶和文化素养的提升,促进英语学科素养落地。本研究不仅为英语教学实践提供了新的视角,也为其他学科育人模式的构建提供了有益的参考和借鉴。

区域推进小学英语学科育人的探索及实践

文章以“立德树人”根本任务为契机,通过构建区域“积极主动(ACTIVE)”英语学科育人模式,不断完善多方协同、全员参与的育人机制,积极探讨在小学英语课堂中落实学科育人的有效方法和途径。

2024 Adult Compendium of Physical Activities:A third update of the energy costs of human activities

Background:The Compendium of Physical Activities was published in 1993 to improve the comparability of energy expenditure values assigned to self-reported physical activity(PA)across studies.The original version was updated in 2000,and again in 2011,and has been widely used to support PA research,practice,and public health guidelines.Methods:This 2024 update was tailored for adults 19-59 years of age by removing data from those≥60 years.Using a systematic review and supplementary searches,we identified new activities and their associated measured metabolic equivalent(MET)values(using indirect calorimetry)published since 2011.We replaced estimated METs with measured values when possible.Results:We screened 32,173 abstracts and 1507 full-text papers and extracted 2356 PA energy expenditure values from 701 papers.We added303 new PAs and adjusted 176 existing MET values and descriptions to reflect the addition of new data and removal of METs for older adults.We added a Major Heading(Video Games).The 2024 Adult Compendium includes 1114 PAs(912 with measured and 202 with estimated values)across 22 Major Headings.Conclusion:This comprehensive update and refinement led to the creation of The 2024 Adult Compendium,which has utility across research,public health,education,and healthcare domains,as well as in the development of consumer health technologies.The new website with the complete lists of PAs and supporting resources is available at https://pacompendium.com.

Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease

BACKGROUND Alcohol-associated liver disease(ALD)is a leading cause of liver-related morbidity and mortality,but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis.Peroxisome proliferator activated receptor(PPAR)α and δ play a key role in lipid metabolism and intestinal barrier homeostasis,which are major contributors to the pathological progression of ALD.Meanwhile,elafibranor(EFN),which is a dual PPARαand PPARδagonist,has reached a phase III clinical trial for the treatment of metabolic dysfunctionassociated steatotic liver disease and primary biliary cholangitis.However,the benefits of EFN for ALD treatment is unknown.AIM To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model.METHODS ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol(EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly(1 mL/kg)for 8 weeks.EFN(3 and 10 mg/kg/day)was orally administered during the experimental period.Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis,fibrosis,and intestinal barrier integrity.The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays.RESULTS The hepatic steatosis,apoptosis,and fibrosis in the ALD mice model were significantly attenuated by EFN treatment.EFN promoted lipolysis and β-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells,primarily through PPARαactivation.Moreover,EFN inhibited the Kupffer cell-mediated inflammatory response,with blunted hepatic exposure to lipopolysaccharide(LPS)and toll like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)signaling.EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses.The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation.CONCLUSION EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis,enhancing hepatocyte autophagic and antioxidant capacities,and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.

A comparison study on structure-function relationship of polysaccharides obtained from sea buckthorn berries using different methods:antioxidant and bile acid-binding capacity

In this study,the structural characters,antioxidant activities and bile acid-binding ability of sea buckthorn polysaccharides(HRPs)obtained by the commonly used hot water(HRP-W),pressurized hot water(HRP-H),ultrasonic(HRP-U),acid(HRP-C)and alkali(HRP-A)assisted extraction methods were investigated.The results demonstrated that extraction methods had significant effects on extraction yield,monosaccharide composition,molecular weight,particle size,triple-helical structure,and surface morphology of HRPs except for the major linkage bands.Thermogravimetric analysis showed that HRP-U with filamentous reticular microstructure exhibited better thermal stability.The HRP-A with the lowest molecular weight and highest arabinose content possessed the best antioxidant activities.Moreover,the rheological analysis indicated that HRPs with higher galacturonic acid content and molecular weight showed higher viscosity and stronger crosslinking network(HRP-C,HRP-W and HRP-U),which exhibited stronger bile acid binding capacity.The present findings provide scientific evidence in the preparation technology of sea buckthorn polysaccharides with good antioxidant and bile acid binding capacity which are related to the structure affected by the extraction methods.

A brief history of the Compendium of Physical Activities

The Compendium of Physical Activities(Compendium)was developed to address consistent assignment of physical activity(PA)intensity values used in PA epidemiology research of the association between PA and health outcomes.1The known protective effects of PA on incident health outcomes traces to the mid-1900s,with over 50 studies examining coronary heart disease(CHD)as the outcome of interest.

Association between physical activity and risk of gastroesophageal reflux disease:A systematic review and meta-analysis

Background:Lifestyle plays an important role in preventing and managing gastroesophageal reflux disease(GERD).In response to the conflicting results in previous studies,we performed a systematic review and meta-analysis to investigate this association.Methods:Relevant studies published until January 2023 were retrieved from 6 databases,and the prevalence of symptomatic gastroesophageal reflux(GER)or GERD was determined from the original studies.A random effects model was employed to meta-analyze the association by computing the pooled relative risk(RR)with 95%confidence intervals(95%CIs).Furthermore,subgroup and dose-response analyses were performed to explore subgroup differences and the association between cumulative physical activity(PA)time and GERD.Results:This meta-analysis included 33 studies comprising 242,850 participants.A significant negative association was observed between PA and the prevalence of symptomatic GER(RR=0.74,95%CI:0.66-0.83;p<0.01)or GERD(RR=0.80,95%CI:0.76-0.84;p<0.01),suggesting that engaging in PA might confer a protective benefit against GERD.Subgroup analyses consistently indicated the presence of this association across nearly all subgroups,particularly among the older individuals(RR_(<40 years):RR_(≥40 years)=0.85:0.69,p<0.01)and smokers(RR_(smoker):RR_(non-smoker)=0.67:0.82,p=0.03).Furthermore,a dose-response analysis revealed that individuals who engaged in 150 min of PA per week had a 72.09%lower risk of developing GERD.Conclusion:Maintaining high levels of PA decreased the risk of GERD,particularly among older adults and smokers.Meeting the recommended PA level of 150 min per week may significantly decrease the prevalence of GERD.

Association of accelerometer-measured sleep duration and different intensities of physical activity with incident type 2 diabetes in a population-based cohort study

Purpose:The aim of the current study was to investigate the association of accelerometer-measured sleep duration and different intensities of physical activity(PA)with the risk of incident type 2 diabetes in a population-based prospective cohort study.Methods:Altogether,88,000 participants(mean age=62.2±7.9 years,mean±SD)were included from the UK Biobank.Sleep duration(short:<6 h/day;normal:6-8 h/day;long:>8 h/day)and PA of different intensities were measured using a wrist-won accelerometer over a 7-day period between 2013 and 2015.PA was classified according to the median or World Health Organization-recommendation:total volume of PA(high,low),moderate-to-vigorous PA(MVPA)(recommended,not recommended),and light-intensity PA(high,low).Incidence of type 2diabetes was ascertained using hospital records or death registries.Results:During a median follow-up of 7.0 years,1615 incident type 2 diabetes cases were documented.Compared with normal sleep duration,short(hazard ratio(HR)=1.21,95%confidence interval(95%CI):1.03-1.41)but not long sleep duration(HR=1.01,95%CI:0.89-1.15)was associated with excessive type 2 diabetes risk.This increased risk among short sleepers seems to be protected against by PA.Compared with normal sleepers with high or recommended PA,short sleepers with low volume of PA(HR=1.81,95%CI:1.46-2.25),not recommended(below the World Health Organization-recommended level of)MVPA(HR=1.92,95%CI:1.55-2.36),or low light-intensity PA(HR=1.49,95%CI:1.13-1.90)had a higher risk of type 2 diabetes,while short sleepers with a high volume of PA(HR=1.14,95%CI:0.88-1.49),recommended MVPA(HR=1.02,95%CI:0.71-1.48),or high light-intensity PA(HR=1.14,95%CI:0.92-1.41)did not.Conclusion:Accelerometer-measured short but not long sleep duration was associated with a higher risk of incident type 2 diabetes.A higher level of PA,regardless of intensity,potentially ameliorates this excessive risk.