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.

Diatoms as indicators of environmental change in coastal areas:a case study in Lianjiang coast of East China Sea

Owing to the significant differences in environmental characteristics and explanatory factors among estuarine and coastal regions,research on diatom transfer functions and database establishment remains incomplete.This study analysed diatoms in surface sediment samples and a sediment core from the Lianjiang coast of the East China Sea,together with environmental variables.Principal component analysis of the environmental variables showed that sea surface salinity(SSS)and sea surface temperature were the most important factors controlling hydrological conditions in the Lianjiang coastal area,whereas canonical correspondence analysis indicated that SSS and pH were the main environmental factors affecting diatom distribution.Based on the modern diatom species–environmental variable database,we developed a diatom-based SSS transfer function to quantitatively reconstruct the variability in SSS between 1984 and 2021 for sediment core HK3 from the Lianjiang coastal area.The agreement between the reconstructed SSS and instrument SSS data from 1984 to 2021 suggests that diatombased SSS reconstruction is reliable for studying past SSS variability in the Lianjiang coastal area.Three low SSS events in AD 2019,2013,and 1999,together with an increased relative concentration of freshwater diatom species and coarser sediment grain sizes,corresponded to two super-typhoon events and a catastrophic flooding event in Lianjiang County.Thus,a diatom-based SSS transfer function for reconstructing past SSS variability in the estuarine and coastal areas of the East China Sea can be further used to reflect the paleoenvironmental events in this region.

Circadian rhythm dysfunction and psychopathology in the offspring of parents with bipolar disorder:a highrisk study in the Chinese population

Background Understanding the evolution of circadian rhythm dysfunction and psychopathology in the high-risk population has important implications for the prevention of bipolar disorder.Nevertheless,some of the previous studies on the emergence of psychopathologies and circadian dysfunction among high-risk populations were inconsistent and limited.Aims To examine the prevalence rates of sleep and circadian dysfunctions,mental disorders and their symptoms in the offspring of parents with(O-BD)and without bipolar disorder(O-control).Methods The study included 191 O-BD and 202 O-control subjects aged 6-21 years from the Greater Bay Area,China.The diagnoses and symptoms of sleep/circadian rhythm and mental disorders were assessed by the Diagnostic Interview for Sleep Patterns and Disorders,and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version,respectively.Generalised estimating equations and shared frailty proportional hazards models of survival analysis were applied to compare the outcomes in the offspring.Results Adjusting for age,sex and region of recruitment,there was a significantly higher risk of delayed sleep phase symptoms(9.55%vs 2.58%,adjusted OR:4.04)in O-BD than in O-control.O-BD had a nearly fivefold higher risk of mood disorders(11.70%vs 3.47%,adjusted OR:4.68)and social anxiety(6.28%vs 1.49%,adjusted OR:4.70),a fourfold higher risk of depressive disorders(11.17%vs 3.47%,adjusted OR:3.99)and a threefold higher risk of mood symptoms(20.74%vs 10.40%,adjusted OR:2.59)than O-control.Subgroup analysis revealed that O-BD children(aged under 12 years)had a nearly 2-fold higher risk of any mental and behavioural symptoms than O-control,while there was a nearly 4-fold higher risk of delayed sleep phase symptoms,a 7.5-fold higher risk of social anxiety and a 3-fold higher risk of mood symptoms in O-BD adolescents(aged 12 years and over).Conclusions There was an increase in delayed sleep phase symptoms in O-BD adolescents compared with their control counterparts,confirming the central role of circadian rhythm dysfunction in bipolar disorder.The findings of the specific age-related and stage-related developmental patterns of psychopathologies and circadian dysfunction in children and adolescent offspring of parents with bipolar disorder paved the way to develop specific and early clinical intervention and prevention strategies.

Replacement of leisure-time sedentary behavior with various physical activities and the risk of dementia incidence and mortality:A prospective cohort study

Background:Whether or not there is targeted pharmacotherapy for dementia,an active and healthy lifestyle that includes physical activity(PA)may be a better option than medication for preventing dementia.We examined the association between leisure-time sedentary behavior(SB)and the risk of dementia incidence and mortality.We further quantified the effect on dementia risk of replacing sedentary time with an equal amount of time spent on different physical activities.Methods:In the UK Biobank,484,169 participants(mean age=56.5 years;45.2%men)free of dementia were followed from baseline(2006-2010)through July 30,2021.A standard questionnaire measured individual leisure-time SB(watching TV,computer use,and driving)and PA(walking for pleasure,light and heavy do-it-yourself activity,strenuous sports,and other exercise)frequency and duration in the 4 weeks prior to evaluation.Apolipoprotein E(APOE)genotype data were available for a subset of 397,519(82.1%)individuals.A Cox proportional hazard model and an isotemporal substitution model were used in this study.Results:During a median 12.4 years of follow-up,6904 all-cause dementia cases and 2115 deaths from dementia were recorded.In comparison to participants with leisure-time SB<5 h/day,the hazard ratio((HR),95%confidence interval(95%CI))of dementia incidence was 1.07(1.02-1.13)for 5-8 h/day and 1.25(1.13-1.38)for>8 h/day,and the HR of dementia mortality was 1.35(1.12-1.61)for>8 h/day.A 1 standard deviation increment of sedentary time(2.33 h/day)was strongly associated with a higher incidence of dementia and mortality(HR=1.06,95%CI:1.03-1.08 and HR=1.07,95%CI:1.03-1.12,respectively).The association between sedentary time and the risk of developing dementia was more profound in subjects<60 years than in those>60 years(HR=1.26,95%CI:1.00-1.58 vs.HR=1.21,95%CI:1.08-1.35 in>8 h/day,p for interaction=0.013).Replacing 30 min/day of leisure sedentary time with an equal time spent in total PA was associated with a6%decreased risk and 9%decreased mortality from dementia,with exercise(e.g.,swimming,cycling,aerobics,bowling)showing the strongest benefit(HR=0.82,95%CI:0.78-0.86 and HR=0.79,95%CI:0.72-0.86).Compared with APOEε4 noncarriers,APOEε4 carriers are more likely to see a decrease in Alzheimer’s disease incidence and mortality when PA is substituted for SB.Conclusion:Leisure-time SB was positively associated with the risk of dementia incidence and mortality.Replacing sedentary time with equal time spent doing PA may be associated with a significant reduction in dementia incidence and mortality risk.

Social isolation, loneliness and subsequent risk of major adverse cardiovascular events among individuals with type 2 diabetes mellitus

Background Individuals with type 2 diabetes mellitus(T2DM)are more vulnerable to social disconnection compared with the general population;however,there are few relevant studies investigating this issue.Aims To investigate whether social isolation or loneliness may be associated with subsequent risk of developing major adverse cardiovascular events,whether these associations vary according to fatal and non-fatal outcomes and how behavioural,psychological and physiological factors mediate these associations.Methods This longitudinal analysis included data from 19360 individuals with T2DM at baseline(2006-2010)from the UK Biobank.Social isolation and loneliness were measured using self-report questionnaires.The study outcomes included the first events of myocardial infarction(MI)or stroke(n=2273)and all-cause(n=2820)or cardiovascular disease-related mortality through linked hospital data ordeath registries.Results Over a median follow-up of 12.4 years(interquartile range(IQR):11.6-13.3 years),participants who were more socially isolated(most social isolation vs least social isolation)experienced increased risks for all-cause(hazard ratio(HR):1.33,95%confidence interval(Cl):1.19 to 1.47)and cardiovascular disease(HR:1.36,95%Cl:1.17 to 1.59)mortality but not first Ml or stroke.Loneliness(yes vs no)was associated with a greater risk for a composite of incident MI or stroke(HR:1.37,95%Cl:1.19 to 1.57)but not mortality.Social isolation was associated with fatal Ml and stroke,whereas loneliness was associated with non-fatal Ml and stroke.The significant associations of social isolation and loneliness with outcomes were mainly mediated by behavioural factors(mediating proportion:17.8%-28.2%and 17.6%-17.8%,respectively).Conclusions Among individuals with T2DM,social isolation and loneliness are associated with a greater risk of developing major adverse cardiovascular events,with differences in both risks stratified according to fatal and non-fatal events and underlying mediating factors.

Birth weight,ideal cardiovascular health metrics in adulthood,and incident cardiovascular disease

Background:Prenatal and postnatal factors may have joint effects on cardiovascular health,and we aimed to assess the joint association of birth weight and ideal cardiovascular health metrics(ICVHMs)prospectively in adulthood with incident cardiovascular disease(CVD).Methods:In the UK Biobank,227,833 participants with data on ICVHM components and birth weight and without CVD at baseline were included.The ICVHMs included smoking,body mass index,physical activity,diet information,total cholesterol,blood pressure,and hemoglobin A1c.The Cox proportional hazards model was used to estimate the hazard ratios(HRs)and 95%confidence intervals(CIs)in men and women.Results:Over a median follow-up period of 13.0 years(2,831,236 person-years),we documented 17,477 patients with incident CVD.Compared with participants with birth weights of 2.5-4.0 kg,the HRs(95%CIs)of CVD among those with low birth weights was 1.08(1.00-1.16)in men and 1.23(1.16-1.31)in women.The association between having a birth weight<2.5 kg and CVD risk in men was more prominent for those aged<50 years than for those of older age(P for interaction=0.026).Lower birth weight and non-ideal cardiovascular health metrics were jointly related to an increased risk of CVD.Participants with birth weights<2.5 kg and ICVHMs score 0-1 had the highest risk of incident CVD(HR[95%CI]:3.93[3.01-5.13]in men;4.24[3.33-5.40]in women).The joint effect(HR[95%CI]:1.36[1.17-1.58])could be decomposed into 24.7%(95%CI:15.0%-34.4%)for a lower birth weight,64.7%(95%CI:56.7%-72.6%)for a lower ICVHM score,and 10.6%(95%CI:2.7%-18.6%)for their additive interaction in women.Conclusions:Birth weight and ICVHMs were jointly related to CVD risk.Attaining a normal birth weight and ideal ICVHMs may reduce the risk of CVD,and a simultaneous improvement of both prenatal and postnatal factors could further prevent additional cases in women.

Entire Sign-Changing Solutions to the Fractional Critical Schrodinger Equation

In this paper,we consider the fractional critical Schrödinger equation(FCSE)(-Δ)^(s)u-|u|2^(*)s-2 u=0,where u∈˙H^(s)(R^(N)),N≥4,0<s<1 and 2^(*)s=2 N/N-2 s is the critical Sobolev exponent of order s.By virtue of the variational method and the concentration compactness principle with the equivariant group action,we obtain some new type of nonradial,sign-changing solutions of(FCSE)in the energy space˙H^(s)(R^(N)).The key component is that we take the equivariant group action to construct several subspace of˙H^(s)(R^(N))with trivial intersection,then combine the concentration compactness argument in the Sobolev space with fractional order to show the compactness property of Palais-Smale sequences in each subspace and obtain the multiple solutions of(FCSE)in˙H^(s)(R^(N)).

Multi-omics Data Reveal the Effect of Sodium Butyrate on Gene Expression and Protein Modification in Streptomyces

Streptomycetes possess numerous gene clusters and the potential to produce a large amount of natural products.Histone deacetylase(HDAC)inhibitors play an important role in the regulation of histone modifications in fungi,but their roles in prokaryotes remain poorly understood.Here,we investigated the global effects of the HDAC inhibitor,sodium butyrate(SB),on marine-derived Streptomyces olivaceus FXJ 8.021,particularly focusing on the activation of secondary metabolite biosynthesis.The antiSMASH analysis revealed 33 secondary metabolite biosynthetic gene clusters(BGCs)in strain FXJ 8.021,among which the silent lobophorin BGC was activated by SB.Transcriptomic data showed that the expression of genes involved in lobophorin biosynthesis(ge00097–ge00139)and CoA-ester formation(e.g.,ge02824),as well as the glycolysis/gluconeogenesis pathway(e.g.,ge01661),was significantly up-regulated in the presence of SB.Intracellular CoA-ester analysis confirmed that SB triggered the biosynthesis of CoA-ester,thereby increasing the precursor supply for lobophorin biosynthesis.Further acetylomic analysis revealed that the acetylation levels on 218 sites of 190 proteins were up-regulated and those on 411 sites of 310 proteins were down-regulated.These acetylated proteins were particularly enriched in transcriptional and translational machinery components(e.g.,elongation factor GE04399),and their correlations with the proteins involved in lobophorin biosynthesis were established by protein–protein interaction network analysis,suggesting that SB might function via a complex hierarchical.

An intricate regulation of Wbl A controlling production of silent tylosin analogues and abolishment of expressible nikkomycin

Genome sequencing has revealed that actinomycetes possess the potential to produce many more secondary metabolites than previously thought.The existing challenge is to devise efficient methods to activate these silent biosynthetic gene clusters(BGCs).In Streptomyces ansochromogenes,disruption of wbl A,a pleiotropic regulatory gene,activated the expression of cryptic tylosin analogues and abolished nikkomycin production simultaneously.Overexpressing pathway-specific regulatory genes tylR1 and tylR2 can also trigger the biosynthesis of silent tylosin analogues,in which TylR1 exerted its function via enhancing tylR2 expression.Bacterial one-hybrid system experiments unveiled that Wbl A directly inhibits the transcription of tylR1 and tylR2 to result in the silence of tylosin analogues BGC.Furthermore,Wbl A can activate the nikkomycin production through up-regulating the transcription of pleiotropic regulatory gene adp A.More interestingly,Adp A can activate san G(an activator gene in nikkomycin BGC)but repress wbl A.Our studies provide a valuable insight into the complex functions of pleiotropic regulators.

Energy-aware Integrated Scheduling for Container Terminals with Conflict-free AGVs

For automated container terminals,the effective integrated scheduling of different kinds of equipment such as quay cranes(QCs),automated guided vehicles(AGVs),and yard cranes(YCs)is of great significance in reducing energy consumption and achieving sustainable development.Aiming at the joint scheduling of AGVs and YCs with consideration of conflict-free path planning for AGVs as well as capacity constraints on AGV-mate which is also called buffer bracket in blocks,a mixed integer programming model is established to minimize the energy consumption of AGVs and YCs for the given loading/unloading task.A solution method based on a novel bi-level genetic algorithm(BGA),in which the outer and the inner layer search the optimal dispatching strategy for QCs and YCs,respectively,is designed.The validity of the model and the algorithm is verified by simulation experiments,which take the Port of Qingdao as an example and the performance under different conflicting resolution strategies is compared.The results show that,for the given task,the proposed solution to conflict-free path and the schedule provided by the algorithm can complete the task with minimum energy consumption without loss of AGVs utilization,and the number of AGV-mates should be adjusted according to the task rather than keeping unchanged.Comparison results indicate that our proposed approach could efficiently find solutions within 6%optimality gaps.Energy consumption is dropped by an average of 15%.

Microbial quorum sensing signaling molecules and their roles in the biosynthesis of natural products

Microorganisms act as a double-edged sword that can bring benefits and diseases to humans.Their physiological and metabolic processes are under precise control of intricate regulatory networks,in which signaling systems are critical for cells coordinating or competing with each other to overcome unfavorable environmental conditions,including the prompt and acute responses to endogenous or exogenous stimuli.

Enhancement of salinomycin production by ribosome engineering in Streptomyces albus

Dear Editor,Streptomyces can produce a large variety of secondary metabolites as a major source of anti-infective, antitumor or immune-suppressive agents widely applied in clinical treatment. Antibiotics-resistant bacteria are spreading at alarming rates.

Important role of a LAL regulator Sta R in the staurosporine biosynthesis and high-production of Streptomyces fradiae CGMCC 4.576

Staurosporine, belonging to indolocarbazole compounds, is regarded as an excellent lead compound for synthesizing antitumor agents as a potent inhibitor against various protein kinases. In this study, two separate clusters(cluster A and cluster B),corresponding to biosyntheses of K-252 c(staurosporine aglycone) and sugar moiety, were identified in Streptomyces fradiae CGMCC 4.576 and heterologously expressed in Streptomyces coelicolor M1146 separately or together. Sta R, a cluster-situated LAL family regulator, activates staurosporine biosynthesis by binding to the promoter regions of sta O-sta C and sta G-sta N. The conserved sequences GGGGG and GCGCG were found through gradually truncating promoters of sta O and sta G, and further determined by mutational experiments. Overexpression of sta R with the supplementation of 0.01 g L^–1 Fe SO4 increased staurosporine production to 5.2-fold compared with that of the parental strain Streptomyces fradiae CGMCC 4.576 in GYM medium. Our results provided an approach for improvement of staurosporine production mediated by a positive regulator and established the basis for dissecting the regulatory mechanisms of other indolocarbazole compounds with clinical application value.

Reconstruction of a hybrid nucleoside antibiotic gene cluster based on scarless modification of large DNA fragments

Genetic modification of large DNA fragments(gene clusters) is of great importance in synthetic biology and combinatorial biosynthesis as it facilitates rational design and modification of natural products to increase their value and productivity.In this study,we developed a method for scarless and precise modification of large gene clusters by using RecET/RED-mediated polymerase chain reaction(PCR) targeting combined with Gibson assembly.In this strategy,the biosynthetic genes for peptidyl moieties(HPHT) in the nikkomycin biosynthetic gene cluster were replaced with those for carbamoylpolyoxamic acid(CPOAA)from the polyoxin biosynthetic gene cluster to generate a^40 kb hybrid gene cluster in Escherichia coli with a reusable targeting cassette.The reconstructed cluster was introduced into Streptomyces lividans TK23 for heterologous expression and the expected hybrid antibiotic,polynik A,was obtained and verified.This study provides an efficient strategy for gene cluster reconstruction and modification that could be applied in synthetic biology and combinatory biosynthesis to synthesize novel bioactive metabolites or to improve antibiotic production.

A widespread response of Gram-negative bacterial acyl-homoserine lactone receptors to Gram-positive Streptomyces γ-butyrolactone signaling molecules

Cell-cell communication is critical for bacterial survival in natural habitats,in which miscellaneous regulatory networks are encompassed.However,elucidating the interaction networks of a microbial community has been hindered by the population complexity.This study reveals thatγ-butyrolactone(GBL)molecules from Streptomyces species,the major antibiotic producers,can directly bind to the acyl-homoserine lactone(AHL)receptor of Chromobacterium violaceum and influence violacein production controlled by the quorum sensing(QS)system.Subsequently,the widespread responses of more Gram-negative bacterial AHL receptors to Gram-positive Streptomyces signaling molecules are unveiled.Based on the cross-talk between GBL and AHL signaling systems,combinatorial regulatory circuits(CRC)are designed and proved to be workable in Escherichia coli(E.coli).It is significant that the QS systems of Gram-positive and Gram-negative bacteria can be bridged via native Streptomyces signaling molecules.These findings pave a new path for unlocking the comprehensive cell-cell communications in microbial communities and facilitate the exploitation of innovative regulatory elements for synthetic biology.

Molecular mechanism of mureidomycin biosynthesis activated by introduction of an exogenous regulatory gene ssa A into Streptomyces roseosporus

Mureidomycins(MRDs), a group of unique uridyl-peptide antibiotics, exhibit antibacterial activity against the highly refractory pathogen Pseudomonas aeruginosa. Our previous study showed that the cryptic MRD biosynthetic gene cluster(BGC) mrd in Streptomyces roseosporus NRRL 15998 could not be activated by its endogenous regulator 02995 but activated by an exogenous activator Ssa A from sansanmycin’s BGC ssa of Streptomyces sp. strain SS. Here we report the molecular mechanism for this inexplicable regulation. EMSAs and footprinting experiments revealed that Ssa A could directly bind to a 14-nt palindrome sequence of 5′-CTGRCNNNNGTCAG-3′ within six promoter regions of mrd. Disruption of three representative target genes(SSGG-02981, SSGG-02987 and SSGG-02994) showed that the target genes directly controlled by Ssa Awere essential for MRD production. The regulatory function was further investigated by replacing six regions of SSGG-02995 with those of ssa A.Surprisingly, only the replacement of 343–450 nt fragment encoding the 115–150 amino acids(AA) of Ssa A could activate MRD biosynthesis. Further bioinformatics analysis showed that the 115–150 AA situated between two conserved domains of Ssa A.Our findings significantly demonstrate that constitutive expression of a homologous exogenous regulatory gene is an effective strategy to awaken cryptic biosynthetic pathways in Streptomyces.

Existence of three nontrivial solutions for semilinear elliptic equations on RN

We establish the existence theorem of three nontrivial solutions for a class of semilinear elliptic equation on RN by using variational theorems of mixed type due to Marino and Saccon and linking theorem.

Transcriptomic Analysis of Thermoanaerobacter tengcongensis Grown at Different Temperatures by RNA Sequencing

Genome sequencing of more than 80 thermophiles has pro- vided powerful databases for the preliminary determination of genes essential to thermal adaptation （Berka et al., 2003; Berezovsky and Shakhnovich, 2005; Andrews et al., 2010）. A laboratory strain of Thermoanaerobacter tengcongensis MB4 has been shown to grow at temperatures over the range 50℃ to 80℃, with an optimum of 75℃ （Xue et al., 2001） and its thermal adaptation mechanisms have been studied with the sequencing of its genome （Bao et al., 2002）. Using two- dimensional gel electrophoresis （2DE） and Matrix-Assisted Laser Desorption/Ionization Time of Flight （MALDI-TOF/ TOF） mass spectrometry, Wang et al.