查看更多>>摘要：Evidence available on the independent and combined associations of sleep duration,bedtime,and genetic predisposition with hearing loss was lacking.The present study included 15,827 participants from the Dongfeng-Tongji cohort study.Genetic risk was characterized by polygenic risk score(PRS)based on 37 genetic loci related to hearing loss.We conducted multivariate logistic regression models to assess the odds ratio(OR)for hearing loss with sleep duration and bedtime,as well as the joint association and interaction with PRS.Results showed that hearing loss was independently associated with sleeping＞9 h/night compared to the recommended 7 to＜8 h/night,and with bedtime＜9:00 p.m.and＞9:00 p.m.to 10:00 p.m.compared to those with bedtime＞10:00 p.m.to 11:00 p.m.,with estimated ORs of 1.25,1.27,and 1.16,respectively.Meanwhile,the risk of hearing loss increased by 29％for each 5-risk allele increment of PRS.More importantly,joint analyses showed that the risk of hearing loss was 2-fold in sleep duration＞9 h/night and high PRS,and 2.18-fold in bedtime＜9:00 p.m.and high PRS.With significant joint effects of sleep duration and bedtime on hearing loss,we found an interaction of sleep duration with PRS in those with early bedtime and an interaction of bedtime with PRS in those with long sleep duration on hearing loss(Pint＜0.05),and such relationships were more evident in high PRS.Similarly,the above relationships were also observed for age-related hearing loss and noise-induced hearing loss,particularly the latter.In addition,age-modified effects of sleep patterns on hearing loss were likewise observed,with stronger estimation among those aged＜65 years.Accordingly,longer sleep duration,early bedtime,and high PRS were independently and jointly related to increased risk of hearing loss,suggesting the importance of considering both genetics and sleep pattern for risk assessment of hearing loss.
查看更多>>摘要：Translational experimental approaches that help us better trace Parkinson's disease(PD)pathophysiological mechanisms leading to new therapeutic targets are urgently needed.In this article,we review recent experimental and clinical studies addressing abnormal neuronal activity and pathological network oscillations,as well as their underlying mechanisms and modulation.Our aim is to enhance our knowledge about the progression of Parkinson's disease pathology and the timing of its symptom's manifestation.Here,we present mechanistic insights relevant for the generation of aberrant oscillatory activity within the cortico-basal ganglia circuits.We summarize recent achievements extrapolated from available PD animal models,discuss their advantages and limitations,debate on their differential applicability,and suggest approaches for transferring knowledge on disease pathology into future research and clinical applications.
查看更多>>摘要：It has long been proposed that emotionally"prepared"(i.e.,fear-related)stimuli are privileged in the unconscious acquisition of conditioned fear.However,as fear processing is suggested to highly depend on the coarse,low-spatial-frequency(LSF)components of the fear-related stimuli,it is plausible that LSF may play a unique role in the unconscious fear conditioning even with emotionally neutral stimuli.Here,we provided empirical evidence that,following classical fear conditioning,an invisible,emotionally neutral conditioned stimulus(CS+)with LSF,but not with high spatial frequency(HSF),can rapidly elicit stronger skin conductance responses(SCRs)and larger pupil diameters than its CS-counterpart.In comparison,consciously perceived emotionally neutral CS+with LSF and HSF elicited comparable SCRs.Taken together,these results support that the unconscious fear conditioning does not necessarily entail emotionally prepared stimuli but prioritizes LSF information processing and highlight the crucial distinctions between the unconscious and the conscious fear learning.These findings not only coincide with the postulation that a rapid,spatial-frequency-dependent subcortical route is engaged in unconscious fear processing but also suggest the existence of multiple routes for conscious fear processing.
查看更多>>摘要：Adipose browning has demonstrated therapeutic potentials in several diseases.Here,by conducting transcriptomic profiling at the single-cell and single-nucleus resolution,we reconstituted the cellular atlas in mouse inguinal subcutaneous white adipose tissue(iWAT)at thermoneutrality or chronic cold condition.All major nonimmune cells within the iWAT,including adipose stem and progenitor cells(ASPCs),mature adipocytes,endothelial cells,Schwann cells,and smooth muscle cells,were recovered,allowing us to uncover an overall and detailed blueprint for transcriptomes and intercellular cross-talks and the dynamics during white adipose tissue brown remodeling.Our findings also unravel the existence of subpopulations in mature adipocytes,ASPCs,and endothelial cells,as well as new insights on their interconversion and reprogramming in response to cold.The adipocyte subpopulation competent of major histocompatibility complex class Ⅱ(MHCⅡ)antigen presentation is potentiated.Furthermore,a subcluster of ASPC with CD74 expression was identified as the precursor of this MHCⅡ+adipocyte.Beige adipocytes are transdifferented from preexisting lipid generating adipocytes,which exhibit developmental trajectory from de novo differentiation of amphiregulin cells(Aregs).Two distinct immune-like endothelial subpopulations are present in iWAT and are responsive to cold.Our data reveal fundamental changes during cold-evoked adipose browning.
查看更多>>摘要：Detection in high fidelity of tipping points,the emergence of which is often induced by invisible changes in internal structures or/and external interferences,is paramountly beneficial to understanding and predicting complex dynamical systems(CDSs).Detection approaches,which have been fruitfully developed from several perspectives(e.g.,statistics,dynamics,and machine learning),have their own advantages but still encounter difficulties in the face of high-dimensional,fluctuating datasets.Here,using the reservoir computing(RC),a recently notable,resource-conserving machine learning method for reconstructing and predicting CDSs,we articulate a model-free framework to accomplish the detection only using the time series observationally recorded from the underlying unknown CDSs.Specifically,we encode the information of the CDS in consecutive time durations of finite length into the weights of the readout layer in an RC,and then we use the learned weights as the dynamical features and establish a mapping from these features to the system's changes.Our designed framework can not only efficiently detect the changing positions of the system but also accurately predict the intensity change as the intensity information is available in the training data.We demonstrate the efficacy of our supervised framework using the dataset produced by representative physical,biological,and real-world systems,showing that our framework outperforms those traditional methods on the short-term data produced by the time-varying or/and noise-perturbed systems.We believe that our framework,on one hand,complements the major functions of the notable RC intelligent machine and,on the other hand,becomes one of the indispensable methods for deciphering complex systems.
查看更多>>摘要：The therapeutic outcomes of conventional oral medications against ulcerative colitis(UC)are restricted by inefficient drug delivery to the colitis mucosa and weak capacity to modulate the inflammatory microenvironment.Herein,a fluorinated pluronic(FP127)was synthesized and employed to functionalize the surface of mulberry leaf-derived nanoparticles(MLNs)loading with resveratrol nanocrystals(RNs).The obtained FP127@RN-MLNs possessed exosome-like morphologies,desirable particle sizes(around 171.4 nm),and negatively charged surfaces(-14.8 mV).The introduction of FP127 to RN-MLNs greatly improved their stability in the colon and promoted their mucus infiltration and mucosal penetration capacities due to the unique fluorine effect.These MLNs could efficiently be internalized by colon epithelial cells and macrophages,reconstruct disrupted epithelial barriers,alleviate oxidative stress,provoke macrophage polarization to M2 phenotype,and down-regulate inflammatory responses.Importantly,in vivo studies based on chronic and acute UC mouse models demonstrated that oral administration of chitosan/alginate hydrogel-embedding FP127@RN-MLNs achieved substantially improved therapeutic efficacies compared with nonfluorinated MLNs and a first-line UC drug(dexamethasone),as evidenced by decreased colonic and systemic inflammation,integrated colonic tight junctions,and intestinal microbiota balance.This study brings new insights into the facile construction of a natural,versatile nanoplatform for oral treatment of UC without adverse effects.
查看更多>>摘要：The kinetics of Criegee intermediates are important for atmospheric modeling.However,the quantitative kinetics of Criegee intermediates are still very limited,especially for those with hydroxy groups.Here,we calculate rate constants for the unimolecular reaction of E-glycolaldehyde oxide[E-hydroxyethanal oxide,E-(CH20H)CH00],for its reactions with H20 and(H20)2,and for the reaction of the E-(CH2OH)CHOO...H20 complex with H20.For the highest level of electronic structure,we use W3X-L//CCSD(T)-F12a/cc-pVDZ-F12 for the unimolecular reaction and the reaction with water and W3X-L//DF-CCSD(T)-F12b/jun-cc-pVDZ for the reaction with 2 water molecules.For the dynamics,we use a dual-level strategy that combines conventional transition state theory with the highest level of electronic structure and multistructural canonical variational transition state theory with small-curvature tunneling with a validated density functional for the electronic structure.This dynamical treatment includes high-frequency anharmonicity,torsional anharmonicity,recrossing effects,and tunneling.We find that the unimolecular reaction of E-(CH20H)CHOO depends on both temperature and pressure.The calculated results show that E-(CH20H)CHOO...H20+H20 is the dominant entrance channel,while previous investigations only considered Criegee intermediates+(H20)2.In addition,we find that the atmospheric lifetime of E-(CH20H)CHOO with respect to 2 water molecules is particularly short with a value of 1.71 × 10-6 s at 0 km,which is about 2 orders of magnitude shorter than those usually assumed for Criegee intermediate reactions with water dimer.We also find that the OH group in E-(CH20H)CHOO enhances its reactivity.
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