联用多步骤虚拟筛选方法发现具有新母核的GABAA受体正性变构调节剂

GABAA受体主要介导哺乳动物中枢神经系统的抑制性信号传递,是镇静催眠药的关键靶点。在寻找具有新母核的镇静催眠药的过程中,计算机辅助药物设计(CADD)方法显示出巨大的优势。在这项研究中,首先,我们通过机器学习模型、分子对接模型和分子力学广义玻恩比表面积(MMGBSA)方法筛选了来自于商业数据库中的41112种化合物。经过筛选,我们得到了16个化合物,然后我们通过全细胞膜片钳电生理学实验验证了4个结构新颖的化合物确实为有效的GABAA受体正性变构调节剂。其中,化合物GPR120在细胞水平和动物水平都得到了实验验证。在重组表达α1β2γ2型受体的皮层神经元中,在10和50µmol∙L^(−1)浓度下,GPR120可将GABA EC3-10电流分别增强71.5%和163.8%。通过全分解贡献分析和点突变实验,我们发现GPR120与GABAA受体结合的关键位点是H102,与阳性药物地西泮相似。为了进一步验证GPR120在动物水平上的功能,我们进行了运动活动测试和翻正反射消失(LORR)实验。GPR120对小鼠的运动活动有抑制作用,6 h后可恢复,说明GPR120是一种中度镇静剂。在戊巴比妥钠(PB)诱导的翻正反射消失实验中,与生理盐水组相比,GPR120(20 mg∙kg^(−1))可显著缩短开始LORR的时间并延长LORR的持续时间。综上所述,通过联用多种虚拟筛选方法,我们发现了GPR120是一种具有新型母核的中度强度镇静剂。

Association of daily sitting time and leisure-time physical activity with body fat among U.S.adults

Background:Prolonged sitting and reduced physical activity lead to low energy expenditures.However,little is known about the joint impact of daily sitting time and physical activity on body fat distribution.We investigated the independent and joint associations of daily sitting time and physical activity with body fat among adults.Methods:This was a cross-sectional analysis of U.S.nationally representative data from the National Health and Nutrition Examination Survey2011-2018 among adults aged 20 years or older.Daily sitting time and leisure-time physical activity(LTPA)were self-reported using the Global Physical Activity Questionnaire.Body fat(total and trunk fat percentage)was determined via dual X-ray absorptiometry.Results:Among 10,808 adults,about 54.6%spent 6 h/day or more sitting;more than one-half reported no LTPA(inactive)or less than 150 min/week LTPA(insufficiently active)with only 43.3%reported 150 min/week or more LTPA(active)in the past week.After fully adjusting for sociodemographic data,lifestyle behaviors,and chronic conditions,prolonged sitting time and low levels of LTPA were associated with higher total and trunk fat percentages in both sexes.When stratifying by LTPA,the association between daily sitting time and body fat appeared to be stronger in those who were inactive/insuufficiently active.In the joint analyses,inactive/insuufficiently active adults who reported sitting more than 8 h/day had the highest total(female:3.99%(95%confidence interval(95%CI):3.09%-4.88%);male:3.79%(95%CI:2.75%-4.82%))and trunk body fat percentages(female:4.21%(95%CI:3.09%-5.32%);male:4.07%(95%CI:2.95%-5.19%))when compared with those who were active and sitting less than 4 h/day.Conclusion:Prolonged daily sitting time was associated with increased body fat among U.S.adults.The higher body fat associated with 6 h/day sitting may not be offset by achieving recommended levels of physical activity.

Steering surface reconstruction of hybrid metal oxides for efficient oxygen evolution reaction in water splitting and zinc-air batteries

Surface reconstruction yields real active species in electrochemical oxygen evolution reaction(OER)conditions;however,rationally regulating reconstruction in a targeted manner for constructing highly active OER electrocatalysts remains a formidable challenge.Here,an electrochemical activation strategy with selective etching was utilized to guide the reconstruction process of a hybrid cobalt-molybdenum oxide(CoMoO_(4)/Co_(3)O_(4)@CC)in a favorable direction to improve the OER performance.Both in-situ Raman and multiple ex-situ characterization tools demonstrate that controlled surface reconstruction can be easily achieved through Mo etching,with the formation of a dynamically stable amorphous-crystalline heterostructure.Theoretical calculations together with experimental results reveal that the synergistic effects between amorphous CoOOH and crystalline Co_(3)O_(4) are crucial in enhancing the catalytic performance.Consequently,the reconstructed CoMoO_(4)/Co_(3)O_(4)@CC exhibits a low overpotential of 250 mV to achieve a current density of 10 mA cm^(-2) in 1 M KOH,and more importantly it can be practiced in electrolytic water splitting and rechargeable zinc-air batteries devices,achieving ultra-long stability for over 500 and 1200 h,respectively.This work provides a promising route for the construction of high-performance electrocatalysts.

Critical approaches in the catalytic transformation of sugar isomerization and epimerization after Fischer-History,challenges,and prospects

The transformation of aldose to ketose or common sugars into rare saccharides,including rare ketoses and aldoses,is of great value and interest to the food industry and for saccharidic biomass utilization,medicine,and the synthesis of drugs.Nowadays,high-fructose corn syrup(HFCS)is industrially produced in more than 10 million tons annually using immobilized glucose isomerase.Some low-calorie saccharides such as tagatose and psicose,which are becoming popular sweeteners,have also been produced on a pilot scale in order to replace sucrose and HFCS.However,current catalysts and catalytic processes are still difficult to utilize in biomass conversion and also have strong substrate dependence in producing high-value,rare sugars.Considering the specific reaction properties of saccharides and catalysts,since the pioneering discovery by Fischer,various catalysts and catalytic systems have been discovered or developed in attempts to extend the reaction pathways,improve the reaction efficiency,and to potentially produce commercial products.In this review,we trace the history of sugar isomerization/epimerization reactions and summarize the important breakthroughs for each reaction as well as the difficulties that remain unresolved to date.

Effects of nutrient limitations on the sinking velocity of Thalassiosira weissflogii

The sinking of diatoms is critic al to the formation of oceanic biological pumps and coastal hypoxic zones.However,little is known about the effects of different nutrient restrictions on diatom sinking.In this study,we measured the sinking velocity(SV) of Thalassiosira weissflogii using a new phytoplankton video observation instrument and analyzed major biochemical components under varying nutrient conditions.Our results showed that the SV of T.weissflogii under different nutrient limitation conditions varied substantially.The highest SV of(1.77±0.02) m/d was obtained under nitrate limitation,signific antly surpassing that under phosphate limitation at(0.98±0.13) m/d.As the nutrient limitation was released,the SV steadily decreased to(0.32±0.03) m/d and(0.15±0.05) m/d,respectively.Notably;under conditions with limited nitrate and phosphate concentrations,the SV values of T.weissflogii significantly positively correlated with the lipid content(P <0.001),with R^(2) values of 0.86 and 0.69,respectively.The change of the phytoplankton SV was primarily related to the intracellular compo sition,which is controlled by nutrient conditions but did not significantly correlate with transparent extracellular polymer and biosilica contents.The results of this study help to understand the regulation of the vertical sinking process of diatoms by nutrient restriction and provide new insights into phytoplankton dynamics and their relationship with the marine nutrient structure.

Effects of phosphorus limitation on sinking velocities of phytoplankton during summer in the Changjiang River Estuary

The sinking of phytoplankton is critical to organic matter transportation in the ocean and it is an essential process for the formation of coastal hypoxic zones.This study was based on a field investigation conducted during the summer of 2022 in the Changjiang River(Yangtze River) Estuary(CJE) and its adjacent waters.The settling column method was employed to measure the sinking velocity(SV) of different size fractions of phytoplankton at the surface of the sea and to analyze their environmental control mechanisms.The findings reveal significant spatial variation in phytoplankton SV(-0.55-2.41 m/d) within the CJE.High-speed sinking was predominantly observed in phosphate-depleted regions beyond the CJE front.At the same time,an upward trend was more commonly observed in the phosphate-rich regions near the CJE mouth.The SV ranges for different sizefractionated phytoplankton,including micro-(>20 μm),nano-(2-20 μm),and picophytoplankton(0.7-2 μm),were-0.50-4.74 m/d,-1.04-1.59 m/d,and-1.24-1.65 m/d,respectively.Correlation analysis revealed a significant negative correlation between SV and dissolved inorganic phosphorus(DIP),implying that the influence of DIP contributes to SV.The variations in phytoplankton alkaline phosphatase activity suggested a significant increase in SV across all size fractions in the event of phosphorus limitation.Phytoplankton communities with limited photo synthetic capacity(maximum photochemical efficience,Fv/Fm <0.3) were found to have higher SV than that of communities with strong capacity,suggesting a link between sinking and alterations in physiological conditions due to phosphate depletion.The findings from the in situ phosphate enrichment experiments confirmed a marked decrease in SV following phosphate supplementation.These findings suggest that phosphorus limitation is the primary driver of elevated SV in the CJE.This study enhances the comprehension of the potential mechanisms underlying hypoxic zone formation in the CJE,providing novel insights into how nearshore eutrophication influences organic carbon migration.

Contemporary strategies and approaches for characterizing composition and enhancing biofilm penetration targeting bacterial extracellular polymeric substances

Extracellular polymeric substances(EPS)constitutes crucial elements within bacterial biofilms,facili-tating accelerated antimicrobial resistance and conferring defense against the host's immune cells.Developing precise and effective antibiofilm approaches and strategies,tailored to the specific charac-teristics of EPS composition,can offer valuable insights for the creation of novel antimicrobial drugs.This,in turn,holds the potential to mitigate the alarming issue of bacterial drug resistance.Current analysis of EPS compositions relies heavily on colorimetric approaches with a significant bias,which is likely due to the selection of a standard compound and the cross-interference of various EPS compounds.Considering the pivotal role of EPS in biofilm functionality,it is imperative for EPS research to delve deeper into the analysis of intricate compositions,moving beyond the current focus on polymeric materials.This ne-cessitates a shift from heavy reliance on colorimetric analytic methods to more comprehensive and nuanced analytical approaches.In this study,we have provided a comprehensive summary of existing analytical methods utilized in the characterization of EPS compositions.Additionally,novel strategies aimed at targeting EPS to enhance biofilm penetration were explored,with a specific focus on high-lighting the limitations associated with colorimetric methods.Furthermore,we have outlined the challenges faced in identifying additional components of EPS and propose a prospective research plan to address these challenges.This review has the potential to guide future researchers in the search for novel compounds capable of suppressing EPS,thereby inhibiting biofilm formation.This insight opens up a new avenue for exploration within this research domain.

Multiple pulp stones emerge across all teeth during mixed dentition:A case report

BACKGROUND This paper reports a rare presentation of multiple pulp stones(PSs)emerging in all teeth during mixed dentition.It offers valuable insights into the clinical diagnosis,treatment,and prognosis of multiple PSs,shedding light on their occurrence during the mixed dentition period.CASE SUMMARY A 10-year-old girl presented with repeated pain in the mandibular right posterior teeth.Intraoral examination revealed carious lesions,abnormal tooth shapes,and anomalies in tooth number.Radiographic examinations showed multiple PSs with diverse shapes,sizes,and quantities in all teeth,alongside anomalies in tooth shape and number.Root canal therapy was initiated,but the patient initially lacked timely follow-up.Upon return for treatment completion,an extracted tooth revealed irregular calculus within the pulp cavity.CONCLUSION This case underscores the importance of considering multiple PSs in mixed dentition,necessitating comprehensive evaluation and management strategies.

Prediction model for hepatitis B e antigen seroconversion in chronic hepatitis B with peginterferon-alfa treated based on a responseguided therapy strategy

BACKGROUND Models for predicting hepatitis B e antigen(HBeAg)seroconversion in patients with HBeAg-positive chronic hepatitis B(CHB)after nucleos(t)ide analog treatment are rare.AIM To establish a simple scoring model based on a response-guided therapy(RGT)strategy for predicting HBeAg seroconversion and hepatitis B surface antigen(HBsAg)clearance.METHODS In this study,75 previously treated patients with HBeAg-positive CHB underwent a 52-week peginterferon-alfa(PEG-IFNα)treatment and a 24-wk follow-up.Logistic regression analysis was used to assess parameters at baseline,week 12,and week 24 to predict HBeAg seroconversion at 24 wk post-treatment.The two best predictors at each time point were used to establish a prediction model for PEG-IFNαtherapy efficacy.Parameters at each time point that met the corresponding optimal cutoff thresholds were scored as 1 or 0.RESULTS The two most meaningful predictors were HBsAg≤1000 IU/mL and HBeAg≤3 S/CO at baseline,HBsAg≤600 IU/mL and HBeAg≤3 S/CO at week 12,and HBsAg≤300 IU/mL and HBeAg≤2 S/CO at week 24.With a total score of 0 vs 2 at baseline,week 12,and week 24,the response rates were 23.8%,15.2%,and 11.1%vs 81.8%,80.0%,and 82.4%,respectively,and the HBsAg clearance rates were 2.4%,3.0%,and 0.0%,vs 54.5%,40.0%,and 41.2%,respectively.CONCLUSION We successfully established a predictive model and diagnosis-treatment process using the RGT strategy to predict HBeAg and HBsAg seroconversion in patients with HBeAg-positive CHB undergoing PEG-IFNαtherapy.

藏语音素转写的算法研究

藏语语音合成技术中,字-音转换是一项必不可少的关键性研究任务,即将藏语音节转写成对应的音素序列。从藏语语音合成技术的任务出发,以藏语传统文法为依据,分析其现代藏语音节的拼写结构和连续文本的复杂特征,提出一种基于拼写结构的藏语音素转写算法。经测试表明,只要是拼写规范的音节,则音素转写准确率高达99%以上。另外,所提出的音素转写方案不仅可以有效地处理语音合成技术中的字-音转换任务,而且对藏文排序、藏语文教学以及藏文信息处理的其它研发任务具有一定的参考意义,对于规范藏语、简化藏文编码等起到显而易见的作用。

Analysis of a Large-Scale Strong Convective Weather under a Weak Water Vapor Condition in Shanxi, China in Spring

This article uses NCEP 1° × 1° grid point reanalysis data, conventional meteorological observation data, FY2G satellite TBB data, radar combined reflectivity data, ground-encrypted automatic station observation data, etc., through the synoptic diagnostic analysis method for a comprehensive analysis of a large-scale underreporting of a strong convective weather process under weak water vapor conditions on the 13th April 2017. The results show that the severe convective weather process is affected by the short-wave disturbance in the northwesterly airflow, triggered by the uplift of the westerly trough, the mid-low shear line and the mesoscale front of the boundary layer in the dry northwest. The jet stream is also an important system for the development of this strong convective weather. In the case of weak water vapor and energy conditions, if there is strong dynamic uplift, vertical wind shear and large temperature differences, strong convection can still occur;the convection occurrence area corresponds to the high potential vorticity abnormal area. The movement speed and direction of the cloud cluster are also consistent with the movement of the high potential vorticity anomaly area;the potential vorticity anomaly will cause the cyclonic circulation to increase, and the upward movement will also increase, which is conducive to the development of strong convective weather. According to the position of the dew point front in the β mesoscale, the ground cold pool corresponds to the small value area of the convective cloud cluster TBB. The front of the cold pool is accompanied by a mesoscale ground convergence line, and the uplift is strengthened, which is conducive to the development and forward movement of thunderstorms;the outflow of the cold pool is guided by 700 hPa. When the wind direction is the same, the movement speed will increase, and the stronger the outflow, the faster the movement speed.

Ecological Landscape Planning and Design of Zhuxi River in Chongqing

Based on the theories and methods of ecology,landscape architecture and water conservancy,combined with the current status of the ecological environment of Zhuxi River in Chongqing,ecological environment protection,landscape space shaping and river culture creation are determined as the core of the design.Based on the design concept of ecological landscape restoration,river ecological protection,waterfront landscape layout,cultural shaping,wetland construction,sponge city construction,etc.are proposed.The design and construction of the Zhuxi River ecological landscape will effectively improve its ecological environment and help to shape a good social and economic environment.This is a useful exploration in the practical application of domestic river ecological landscape design research.

Syphilitic uveitis in HIV-positive patients: report of a case series, treatment outcomes, and comprehensive review of the literature

AIM:To report the clinical characteristics,treatment and outcomes of active syphilitic uveitis in human immunodeficiency virus(HIV)positive patients and compare them with the previously published data.METHODS:Retrospective analysis of the case series from an infectious disease center in southern China was conducted.Comprehensive review of previously published cases of HIV positive syphilitic uveitis was conducted using the PubMed and Web of Science databases and the references listed in the identified articles.RESULTS:Twelve HIV positive patients with active syphilitic uveitis were collected.All were male,with age of 36.3y(range 27 to 53y).Five(41.7%)had a history of syphilis,and three of them had received anti-syphilis treatment.Ocular manifestations included corneal epithelial defect(13%),complicated cataract(17.4%),vitreous opacity(82.6%),optic disc edema(26.1%),macular edema(30.4%),neuro-retinitis(43.5%),and retinal hemorrhage(26.1%).After standardized syphilitic treatment,intraocular inflammation was reduced and vision improved in all cases.The literature review summarizes 105 previously reported cases of HIV positive syphilitic uveitis.High serum rapid plasma regain(RPR)titers may be associated with severe uveitis and poor vision.Treatment with penicillin,ceftriaxone sodium,or penicillin plus benzylpenicillin instead of using benzylpenicillin alone can significantly improve bestcorrected visual acuity(BCVA)in HIV positive ocular syphilis patients.CONCLUSION:For HIV positive syphilitic uveitis patients,prompt diagnosis and appropriate treatment and follow-up are paramount.In our series,the clinical manifestations are diverse.Syphilis patients treated by penicillin G or long-acting penicillin before may still develop syphilitic uveitis.Patients who relapse after long-term penicillin treatment can still benefit from penicillin G.

Construction of porous disc-like lithium manganate for rapid and selective electrochemical lithium extraction from brine

In order to satisfy the growing global demand for lithium, selective extraction of lithium from brine has attracted extensive attention. LiMn_(2)O_(4)-based electrochemical lithium recovery system is one of the best choices for commercial applications because of its high selectivity and low energy consumption.However, the low ion diffusion coefficient of lithium manganate limits the further development of electrochemical lithium recovery system. In this work, a novel porous disc-like LiMn_(2)O_(4) was successfully synthesized for the first time via two-step annealing manganese(Ⅱ) precursors. The as-prepared LiMn_(2)O_(4) exhibits porous disc-like morphology, excellent crystallinity, high Li^(+)diffusion coefficient(average 7.6×10^(-9)cm^(2)·s^(-1)), high cycle stability(after 30 uninterrupted extraction and release cycles, the crystal structure hardly changed) and superior rate capacity(93.5% retention from 10-120 mA·g^(-1)). The porous structure and disc-like morphology further promote the contact between lithium ions and electrode materials. Therefore, the assembled electrochemical lithium extraction device with LiMn_(2)O_(4) as positive electrode and silver as negative electrode can realize the rapid and selective extraction of lithium in simulated brine(adsorption capacity of lithium can reach 4.85 mg·g^(-1) in 1 h). The mechanism of disc-like LiMn_(2)O_(4) in electrochemical lithium extraction was proposed based on the analysis of electrochemical characterization and quasi in situ XRD. This novel structure may further promote the practical application of electrochemical lithium extraction from brine.

Effect of mono-/divalent metal ions on the conductivity characteristics of DNA solutions transferring through a microfluidic channel

Interactions between deoxyribonucleic acid(DNA) and metal ions are vital for maintaining life functions, however,there are still unsolved questions about its mechanisms. It is of great practical significance to study these issues for medical chip design, drug development, health care, etc. In this investigation, the conductivity properties of λ-DNA solutions with mono-/divalent metal ions(Na+, K^(+), Mg^(2+), and Ca^(2+)) are experimentally studied as they are electrically driven through a 5 μm microfluidic channel. Experimental data indicate that the conductivities of λ-DNA solutions with metal ions(M+/M2+) basically tend to reduce firstly and then increase as the voltage increases, of which the turning points varied with the metal ions. When the voltage surpasses turning points, the conductivity of λ-DNA-M+solutions increases with the concentration of metal ions, while that of λ-DNA-M^(2+)solutions decrease. Moreover, the conductivity of λ-DNA-M^(2+)solutions is always smaller than that of λ-DNA-M+solutions, and with high-concentration M^(2+), it is even smaller than that of the λ-DNA solution. The main reasons for the above findings could be attributed to the polarization of electrodes and different mechanisms of interactions between metal ions and λ-DNA molecules. This investigation is helpful for the precise manipulation of single DNA molecules in micro-/nanofluidic space and the design of new biomedical micro-/nanofluidic sensors.

Effect of titin phosphorylation on degradation of titin from skeletal muscles

The degradation of titin could make the myofibrillar fragmentation to improve meat tenderization during postmortem.This study aimed to investigate effect of phosphorylation on titin degradation.Protein kinase A(PKA)and alkaline phosphatase(AP)were added to crude titin extracted from ovine longissimus lumborum(LL)muscles.Phosphorylated/dephosphorylated titin were incubated withμ-calpain at 4℃ for 2 days.Results showed titin in AP group started degradation earlier than that in PKA and control groups.There were 20,16 and 12 phosphorylated sites identified by iTRAQ in the PKA,control and AP group,respectively.3D structure of dephosphorylated titin fragment was simulated and its molecular dynamics trajectory analysis was performed using Discovery StudioTM.The dihedral angle in AP group was less and the dephosphorylated fragment had a higher kinetic energy and total energy.We suggested that changes caused by AP treatment might make titin unstable,which easily degraded byμ-calpain.

Meta-silencer with designable timbre

Timbre,as one of the essential elements of sound,plays an important role in determining sound properties,whereas its manipulation has been remaining challenging for passive mechanical systems due to the intrinsic dispersion nature of resonances.Here,we present a meta-silencer supporting intensive mode density as well as highly tunable intrinsic loss and offering a fresh pathway for designable timbre in broadband.Strong global coupling is induced by intensive mode density and delicately modulated with the guidance of the theoretical model,which efficiently suppresses the resonance dispersion and provides desirable frequency-selective wave-manipulation capacity for timbre tuning.As proof-of-concept demonstrations for our design concepts,we propose three meta-silencers with the designing targets of high-efficiency broadband sound attenuation,efficiency-controlled sound attenuation and designable timbre,respectively.The proposed meta-silencers all operate in a broadband frequency range from 500 to 3200 Hz and feature deep-subwavelength sizes around 50 mm.Our work opens up a fundamental avenue to manipulate the timbre with passive resonances-controlled acoustic metamaterials and may inspire the development of novel multifunctional devices in noise-control engineering,impedance engineering,and architectural acoustics.

Exploration of Scientific Research Mentorship on the Cultivation of Undergraduate Students Innovation Ability

In order to improve the quality of undergraduate training and cultivate students innovation ability,more and more colleges and universities are implementing the research mentorship system among undergraduates.The study summarizes the main role of mentorship on the cultivation of innovation ability,analyzes the problems in the implementation of mentorship,and proposes corresponding solutions.

Implementation Status and Strategy of Undergraduate Tutorial System in the Context of Academy System

The cooperative education mode of academy system and undergraduate tutorial system is an important reform mode for cultivating top-notch innovative talents in colleges and universities.However,there is still room for improvement in the operation of tutorial system.For example,the lack of synergy in the academy system leads to problems such as insufficient understanding between teachers and students and limited guidance effect.Therefore,this study analyzes the implementation status of tutorial system,and puts forward the corresponding strategies for the existing problems.

喉罩通气全身麻醉下经纤维支气管镜辅助置入Montgomery T型硅酮支架治疗气管狭窄的临床研究

目的探讨喉罩通气全身麻醉下经纤维支气管镜辅助置入Montgomery T型硅酮支架治疗气管狭窄的疗效及安全性。方法回顾性分析10例气管切开术后良性气道狭窄拔管困难经喉罩通气全麻下经纤支镜辅助置入Montgomery T型硅酮支架治疗的患者的临床资料。比较患者T管置入前后生活质量评分、动脉血氧分压(PaO_2)、动脉血二氧化碳分压(PaCO_2)、呼吸困难评分、嗓音综合质量评分的变化及患者并发症发生情况。结果患者术后1周生活质量评分、PaO_2较术前均明显提高(P<0.05),嗓音质量综合评分及呼吸困难评分较术前明显下降(P<0.05),无严重并发症发生。结论喉罩通气全麻下经纤支镜辅助置入Montgomery T型硅酮支架治疗气管狭窄安全有效,可作为气管插管后气道狭窄致拔管困难患者的一种选择。