亲子关系与CLOCK基因rs1801260多态性对学前儿童亲社会行为的交互影响:性别的调节作用

研究探讨了亲子关系与CLOCK基因rs1801260多态性对学前儿童亲社会行为的交互影响及性别的调节作用。以694名学前儿童(M_(年龄)=5.06岁,SD=0.87)及其父母为测试对象,收集儿童的唾液样本进行基因分型,由儿童父母填写亲子关系和儿童亲社会行为量表。研究结果发现,亲子亲密与亲子冲突对亲社会行为的主效应显著。亲子冲突、CLOCK基因rs1801260多态性和性别三重交互影响儿童的亲社会行为,即与携带C等位基因的男孩相比,携带TT基因型的男孩在低亲子冲突下会表现出更多的亲社会行为,在高亲子冲突下则表现出更少的亲社会行为。但亲子冲突与CLOCK基因rs1801260多态性对女孩亲社会行为的交互作用不显著。研究结果为深入理解学前儿童亲社会行为形成的基因-环境交互作用机制提供了证据。

A frequency servo SoC with output power stabilization loop technology for miniaturized atomic clocks

A frequency servo system-on-chip(FS-SoC)featuring output power stabilization technology is introduced in this study for high-precision and miniaturized cesium(Cs)atomic clocks.The proposed power stabilization loop(PSL)technique,incorporating an off-chip power detector(PD),ensures that the output power of the FS-SoC remains stable,mitigating the impact of power fluctuations on the atomic clock's stability.Additionally,a one-pulse-per-second(1PPS)is employed to syn-chronize the clock with GPS.Fabricated using 65 nm CMOS technology,the measured phase noise of the FS-SoC stands at-69.5 dBc/Hz@100 Hz offset and-83.9 dBc/Hz@1 kHz offset,accompanied by a power dissipation of 19.7 mW.The Cs atomic clock employing the proposed FS-SoC and PSL obtains an Allan deviation of 1.7×10^(-11) with 1-s averaging time.

Hypothalamic circuits and aging:keeping the circadian clock updated

Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels,including transcriptional,translational,and post-translational processes,resulting from cellular stress and circadian derangements.The circadian clock emerges as a key regulator,sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes,such as stem-cell function,cellular stress responses,and inter-tissue communication,which become disrupted during aging.Given the crucial role of hypothalamic circuits in regulating organismal physiology,metabolic control,sleep homeostasis,and circadian rhythms,and their dependence on these processes,strategies aimed at enhancing hypothalamic and circadian function,including pharmacological and non-pharmacological approaches,offer systemic benefits for healthy aging.Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions,like the hypothalamus,while reducing side effects associated with systemic drug delivery,thereby presenting new therapeutic possibilities for diverse age-related conditions.

MEMS Huygens Clock Based on Synchronized Micromechanical Resonators

With the continuous miniaturization of electronic devices,microelectromechanical system(MEMS)oscillators that can be combined with integrated circuits have attracted increasing attention.This study reports a MEMS Huygens clock based on the synchronization principle,comprising two synchronized MEMS oscillators and a frequency compensation system.The MEMS Huygens clock improved shorttime stability,improving the Allan deviation by a factor of 3.73 from 19.3 to 5.17 ppb at 1 s.A frequency compensation system based on the MEMS oscillator’s temperature-frequency characteristics was developed to compensate for the frequency shift of the MEMS Huygens clock by controlling the resonator current.This effectively improved the long-term stability of the oscillator,with the Allan deviation improving by 1.6343105 times to 30.9 ppt at 6000 s.The power consumption for compensating both oscillators simultaneously is only 2.85 mW·℃^(-1).Our comprehensive solution scheme provides a novel and precise engineering solution for achieving high-precision MEMS oscillators and extends synchronization applications in MEMS.

Physics package based on intracavity laser cooling ^(87)Rb atoms for space cold atom microwave clock

This article proposes a new physics package to enhance the frequency stability of the space cold atom clock with the advantages of a microgravity environment. Clock working processes, including atom cooling, atomic state preparation,microwave interrogation, and transition probability detection, are integrated into the cylindrical microwave cavity to achieve a high-performance and compact physics package for the space cold atom clock. We present the detailed design and ground-test results of the cold atom clock physics package in this article, which demonstrates a frequency stability of 1.2×10^(-12) τ^(-1/2) with a Ramsey linewidth of 12.5 Hz, and a better performance is predicted with a 1 Hz or a narrower Ramsey linewidth in microgravity environment. The miniaturized cold atom clock based on intracavity cooling has great potential for achieving space high-precision time-frequency reference in the future.

A redundant subspace weighting procedure for clock ensemble

A redundant-subspace-weighting(RSW)-based approach is proposed to enhance the frequency stability on a time scale of a clock ensemble.In this method,multiple overlapping subspaces are constructed in the clock ensemble,and the weight of each clock in this ensemble is defined by using the spatial covariance matrix.The superimposition average of covariances in different subspaces reduces the correlations between clocks in the same laboratory to some extent.After optimizing the parameters of this weighting procedure,the frequency stabilities of virtual clock ensembles are significantly improved in most cases.

Piperine regulates the circadian rhythms of hepatic clock gene expressions and gut microbiota in high-fat diet-induced obese rats

The interplay between the host circadian clock and microbiota has significant influences on host metabolism processes,and circadian desynchrony triggered by high-fat diet(HFD)is closely related to metabolic disorders.In this study,the modulatory effects of piperine(PIP)on lipid metabolism homeostasis,gut microbiota community and circadian rhythm of hepatic clock gene expressions in obese rats were investigated.The Sprague-Dawley(SD)rats were fed with normal diet(ND),HFD and HFD supplemented with PIP,respectively.After 9 weeks,rats were sacrificed with tissue and fecal samples collected for circadian analysis.Results showed that chronic PIP administration ameliorated the obesity-induced alterations in lipid metabolism and dysregulation of hepatic clock gene expressions in obese rats.The gut microbial communities studied through 16S rRNA sequencing showed that PIP ameliorated the imbalanced nicrobiota and recovered the circadian rhythm of Lactobacillaceae,Desulfovibrionaceae,Paraprevotellaceae,and Lachnospiraceae.The fecal metabolic profiles indicated that 3-dehydroshikimate,cytidine and lithocholyltaurine were altered,which were involved in the amino acid and fatty acid metabolism process.These findings could provide theoretical basis for PIP to work as functional food to alleviate the lipid metabolism disorder,circadian rhythm misalignment,and gut microbiota dysbiosis with wide applications in the food and pharmaceutic industries.

A Yb optical clock with a lattice power enhancement cavity

We construct a power enhancement cavity to form an optical lattice in an ytterbium optical clock.It is demonstrated that the intra-cavity lattice power can be increased by about 45 times,and the trap depth can be as large as 1400Er when laser light with a power of only 0.6 W incident to the lattice cavity.Such high trap depths are the key to accurate evaluation of the lattice-induced light shift with an uncertainty down to~1×10-18.By probing the ytterbium atoms trapped in the power-enhanced optical lattice,we obtain a 4.3 Hz-linewidth Rabi spectrum,which is then used to feedback to the clock laser for the close loop operation of the optical lattice clock.We evaluate the density shift of the Yb optical lattice clock based on interleaving measurements,which is-0.46(62)mHz.This result is smaller compared to the density shift of our first Yb optical clock without lattice power enhancement cavity mainly due to a larger lattice diameter of 344μm.

Flowering-time regulation by the circadian clock:From Arabidopsis to crops

Precise timing of flowering in plants is critical for their growth and reproductive processes.One factor controlling flowering time is the cycle of light and darkness within a day,known as the photoperiod.Plants are classified into long-day,short-day,and day-neutral plants based on light requirements for floral initiation.Although the molecular mechanisms that govern this differentiation remain incompletely understood,studies have consistently shown that the circadian clock plays a central role in regulating photoperiod response across diverse plant species.However,there is a scarcity of reviews describing the regulatory network linking the circadian clock with photoperiodic flowering.This review summarizes that regulatory network,focusing on the distinct roles of clock genes in long-day and short-day plants.We also discuss the strategies of clock gene mutations contributing to geographic variation in longday and short-day crops.

A novel small-animal locomotor activity recording device for biological clock research

The rodent running-wheel recording apparatus is a reliable approach for studying cir-cadian rhythm.This study demonstrated how to construct a simple and intelligent running-wheel recording system.The running wheel was attached to the cage's base,whereas the Hall sensor was attached to the cage's cover.Then,the RJ25 adaptor relayed the running signal to the main control board.Finally,the main control board was connected to the USB port of the computer with the USB connection.Data were collected using the online-accessible,self-created software Magturning.Through Magturning,generated data were saved and exported in real time.Afterward,the device was validated by collecting data on the locomotor activities of mice under dif-ferent light conditions.In conclusion,this new device can record circadian activity of rodents.Our device is appropriate for interdisciplinary investigations related to biological clock research.

Capsaicin alleviates the hepatic clock gene disruption and gut microbiota dysbiosis in circadian rhythm disorder mouse model

As the body’s internal clock,the circadian rhythm regulates the energy expenditure,appetite,and sleep.There exists a close relationship between the host circadian rhythm and gut microbiota.In this work,a circadian disorder mouse model induced by constant darkness(CD)was constructed to investigate the regulating effects of capsaicin(CAP)on disturbances of metabolism homeostasis and gut microbiota in the respect of circadian rhythm-related mechanisms.Our results indicated that CAP reduced weight gain induced by circadian rhythm disorder in mice by inhibiting fat accumulation in liver and adipose tissue.The rhythmic expressions of circadian clock genes and lipid-metabolism related genes in liver were also recovered by CAP.Microbial study using 16S rRNA sequencing revealed that CAP modulated the gut microbiota richness,diversity and composition,and restored diurnal oscillations of gut microbes at the phylum and family level.These results indicated that CAP could alleviate CD-induced hepatic clock gene disruption and gut microbiota dysbiosis in mice,providing theoretical basis for CAP to be used as a muti-functional ingredient with great healthpromoting effects.

Proposal for a realtime Einstein-synchronization-defined satellite virtual clock

Realization of high performance satellite onboard clock is vital for various positioning, navigation, and timing applications. For further improvement of the synchronization-based satellite time and frequency references, we propose a geosynchronous(GEO) satellite virtual clock concept based on ground–satellite synchronization and present a beacon transponder structure for its implementation(scheduled for launch in 2025), which does not require atomic clocks to be mounted on the satellite. Its high performance relies only on minor modifications to the existing transponder structure of GEO satellites. We carefully model the carrier phase link and analyze the factors causing link asymmetry within the special relativity. Considering that performance of such synchronization-based satellite clocks is primarily limited by the link's random phase noise, which cannot be adequately modeled, we design a closed-loop experiment based on commercial GEO satellites for pre-evaluation. This experiment aims at extracting the zero-means random part of the ground-satellite Ku-band carrier phase via a feedback loop. Ultimately, we obtain a 1σ value of 0.633 ps(two-way link), following the Gaussian distribution. From this result, we conclude that the proposed real-time Einstein-synchronization-defined satellite virtual clock can achieve picosecond-level replication of onboard time and frequency.

A proposal for detecting weak electromagnetic waves around 2.6μm wavelength with Sr optical clock

Infrared signal detection is widely used in many fields.Due to the detection principle,however,the accuracy and range of detection are limited.Thanks to the ultra stability of the^(87)Sr optical lattice clock,external infrared electromagnetic wave disturbances can be responded to.Utilizing the ac Stark shift of the clock transition,we propose a new method to detect infrared signals.According to our calculations,the theoretical detection accuracy in the vicinity of its resonance band of 2.6μm can reach the order of 10-14W,while the minimum detectable signal of common detectors is on the order of 10^(-10)W.

Einstein’s Concept of Clock Synchronization Conflicts with the Second Relativity Postulate

Einstein defined clock synchronization whenever photon pulses with timetags traverse a fixed distance between two clocks with equal time spans ineither direction. Using the second relativity postulate, he found clocksmounted on a rod uniformly moving parallel with the rod’s length cannot besynchronized, but clocks attached to a stationary rod can. He dismissed thisdiscrepancy by claiming simultaneity and clock synchronization were not commonbetween inertial frames, but this paper proves with both Galilean and Lorentztransformations that simultaneity and clock synchronization are preservedbetween inertial frames. His derivation means moving clocks can never besynchronized in a “resting” inertial frame. Ultraprecise atomic clocks intimekeeping labs daily contradict his results. No algebraic error occurred inEinstein’s derivations. The two cases of clocksattached to a rod reveal three major conflicts with the currentsecond postulate. The net velocity between a photon source and detector plusthe “universal” velocity c is mathematically equivalent toEinstein’s clock synchronization method. As the ultraprecise timekeepingcommunity daily synchronizes atomic clocks on the moving Earth withultraprecise time uncertainty well below Einstein’s lowest limit ofsynchronization, the theoretical resolution of the apparent conflict isaccomplished by expanding the second relativity postulate to incorporate thenet velocity between the photon source and detector with the emitted velocity c as components of the total velocity c. This means the magnitudeof the total photon velocity can exceed the speed limit (299792458 m/s) set by the standard velocity c. .

大负荷运动后骨骼肌核心时钟基因Bmal1/Clock、Cry1/Per1的节律性振荡变化趋势

目的:探讨大负荷运动对骨骼肌核心时钟基因节律性表达的影响。方法:将208只8周龄SD大鼠随机分为对照(control,C)组与运动(Exercise,E)组,E组予以一次大负荷运动训练。每6 h取各组比目鱼肌,采用透射电镜观察骨骼肌纤维超微结构,通过实时荧光定量PCR实验测定骨骼肌核心时钟基因Bmal1、Clock、Cry1、Per1表达量,并使用余弦分析软件circacompare(R package)获取拟合余弦曲线参数,分析其节律性振荡的变化趋势。结果:1)C组Bmal1、Clock、Cry1、Per1 mRNA在72 h内呈现3个完整近日节律周期;E组Bmal1 mRNA、Cry1和Per1mRNA在0~24 h、Clock mRNA在0~72 h近日节律消失。2)与C组相比,E组Bmal1 mRNA在0、6、12和18 h显著升高,Clock mRNA在0 h时显著升高;Cry1、Per1 mRNA在0、12 h显著降低。3)C组各时相肌纤维超微结构正常,E组0、24和48 h均出现不同程度肌小节结构破坏、线粒体肿胀及聚集等改变,72 h有所缓解。结论:一次大负荷运动可诱发骨骼肌核心时钟基因Bmal1/Clock、Cry1/Per1节律振荡紊乱,其变化趋势与肌纤维超微结构损伤时相基本一致。

电针对昼夜节律紊乱C57BL/6J小鼠肝脏基因Clock、Bmal1表达的影响

目的 观察电针肝俞对昼夜节律紊乱小鼠外周时钟基因的影响,分析各实验条件下,不同时间点Clock、Bmal1基因的分布规律,为外周生物钟基因时间分布提供参考,并探讨电针治疗睡眠节律紊乱的潜在机制。方法 将72只C57BL/6J小鼠按随机数字表法分成空白组、模型组、肝俞组和非经非穴组,每组18只。空白组常规饲养;其余3组采取光暗交替法L(光)∶D(暗)=2 h∶2 h造模法持续5 d,模型组只捆绑不针刺;肝俞组针刺肝俞穴;非经非穴组选取非经非穴部位进行针刺。电针干预5 d后,于第6天02∶00开始,每组每4 h取材1次,共取材6次。采用PCR法以及Western blot法检测各组小鼠肝脏内的Clock和Bmal1基因mRNA的表达水平和蛋白表达含量,同时用余弦函数计算出各组基因的节律性。结果 与模型组比较,肝俞组中Clock与Bmal1基因表达恢复时间节律(P<0.05)。与模型组比较,非经非穴组内Clock与Bmal1基因表达无时序性(P>0.05);肝俞组Clock、Bmal1的蛋白表达量较模型组明显降低且恢复节律性(P<0.05)。结论 小鼠肝脏中Clock和Bmal1时钟基因呈时序性变化,电针肝俞穴可改善小鼠睡眠,其机制可能与调节时钟基因Clock和Bmal1,降低两种基因及蛋白表达,恢复正常睡眠节律有关。

CLOCK inhibits the proliferation of porcine ovarian granulosa cells by targeting ASB9

Background Clock circadian regulator(CLOCK)is a core factor of the mammalian biological clock system in regulat-ing female fertility and ovarian physiology.However,CLOCK’s specific function and molecular mechanism in porcine granulosa cells(GCs)remain unclear.In this study,we focused on CLOCK’s effects on GC proliferation.Results CLOCK significantly inhibited cell proliferation in porcine GCs.CLOCK decreased the expression of cell cycle-related genes,including CCNB1,CCNE1,and CDK4 at the mRNA and protein levels.CDKN1A levels were upregulated by CLOCK.ASB9 is a newly-identified target of CLOCK that inhibits GC proliferation;CLOCK binds to the E-box element in the ASB9 promoter.Conclusions These findings suggest that CLOCK inhibits the proliferation of porcine ovarian GCs by increasing ASB9 level.

Clock基因多态性与不同发情模式绵羊产羔数的关联分析

本研究旨在探究绵羊Clock基因g.70873128G>A、g.70875941C>T和g.70885750G>T位点多态性与绵羊产羔数之间的关系,以期为绵羊高繁殖力分子育种提供新的遗传标记。利用Sequenom MassARRAY?SNP技术对常年发情绵羊品种(小尾寒羊、湖羊和策勒黑羊)和季节性发情绵羊品种(滩羊、苏尼特羊和草原型藏羊)Clock基因3个多态位点多态性进行检测,并与小尾寒羊产羔数进行关联分析。分型结果表明:g.70873128G>A位点存在AA、AG和GG 3种基因型,g.70875941C>T位点存在TT、TC和CC 3种基因型,g.70885750G>T位点存在GG、GT和TT 3种基因型。群体遗传学分析表明:3个位点基因型频率和等位基因频率在2种发情模式绵羊品种间均达到差异极显著水平。g.70873128G>A位点在滩羊和草原型藏羊中表现为中度多态(0.25T位点和g.70885750G>T位点在策勒黑羊和滩羊中表现为中度多态(0.25A位点在策勒黑羊和滩羊中处于哈代-温伯格不平衡状态(P<0.05),g.70875941C>T位点在苏尼特羊中处于哈代-温伯格不平衡状态(P<0.05),g.70885750G>T位点在6个绵羊品种中处于哈代-温伯格平衡状态(P>0.05)。关联分析表明,3个多态位点与小尾寒羊第1、第2以及第3胎产羔数均无显著关联。综上,Clock基因g.70873128G>A、g.70875941C>T和g.70885750G>T位点可能都不是影响小尾寒羊产羔数的关键位点。

CLOCK氧化还原修饰介导内源性H_(2)O_(2)对小鼠细胞呼吸的调节作用

目的探究生物钟核心转录因子昼夜节律运动输出周期蛋白(CLOCK)介导内源性过氧化氢(H_(2)O_(2))对细胞呼吸的调节作用和机制。方法利用Seahorse细胞能量代谢分析仪检测Clock^(C195S)小鼠胚胎成纤维细胞(MEFs)和成体成纤维细胞(MAFs)细胞氧耗能力和糖酵解能力;通过q-PCR检测细胞呼吸关键代谢酶基因表达水平;MEFs进行抗氧化剂Trolox处理后,用Amplex■ Red试剂盒检测内源性H_(2)O_(2)的含量,并通过生物素碘乙酰胺(BIAM)探针标记检测CLOCK蛋白氧化还原修饰的改变,进一步检测处理后的细胞氧耗能力和细胞呼吸关键代谢酶基因表达水平。结果Clock^(C195S)细胞氧耗能力和糖酵解能力下降,烟酰胺腺嘌呤二核苷酸(NAD)合成关键酶烟酰胺单核苷酸腺苷转移酶(NMNAT2)表达降低(P<0.05),NAD含量下降;Trolox处理导致细胞内源性H_(2)O_(2)含量降低,Clock wt MEFs氧耗能力降低而Clock^(C195S) MEFs变化无统计学意义。结论CLOCK蛋白可以通过195位点半胱氨酸氧化还原修饰介导内源性H_(2)O_(2)对细胞呼吸的调节作用。

奶牛生物钟基因CLOCK的真核表达载体构建、生物信息学分析及其组织表达谱

旨在克隆奶牛昼夜运动输出周期(circadian locomotor output cycles kaput,CLOCK)基因的蛋白编码区序列(coding sequence,CDS),构建该基因的真核表达载体,检测CLOCK基因在奶牛不同组织的相对表达丰度,并预测分析奶牛CLOCK蛋白的高级结构、理化性质及其功能特征。以奶牛肝脏组织cDNA为模板,通过PCR扩增奶牛CLOCK基因CDS区片段,利用同源重组法将其连接至pcDNA3.1-Puro-N-3HA载体;经酶切与测序鉴定后,将鉴定正确的质粒命名为pcDNA3.1-Puro-N-3HA-bCLOCK;将pcDNA3.1-Puro-N-3HA空质粒和pcDNA3.1-Puro-N-3HA-bCLOCK重组质粒分别转染至HEK293T细胞,通过蛋白质免疫印迹(Western blot)检测CLOCK蛋白的过表达效率;提取奶牛的心、肝、脾、肺等10个组织的总RNA并反转录为cDNA,以此为模板通过实时定量PCR(real-time quantitative PCR,qPCR)检测CLOCK基因在奶牛不同组织的表达变化;同时,利用生物信息学软件对奶牛CLOCK基因及其编码蛋白进行功能预测分析。琼脂糖凝胶电泳结果显示,成功克隆了奶牛CLOCK基因全长CDS区片段。酶切与测序结果显示,pcDNA3.1-Puro-N-3HA-bCLOCK真核表达载体构建成功。Western blot结果表明,该真核表达载体在HEK293T细胞中成功表达HA-CLOCK融合蛋白。qPCR结果表明,CLOCK基因在心、肝、脾、肺等10个组织中均有表达,其中在心脏表达最高,在小肠表达最低。生物信息学分析结果表明,奶牛CLOCK基因的CDS区与绵羊、山羊、骆驼的相似性较高;奶牛CLOCK蛋白由845个氨基酸组成,分子质量为95.12 kDa,无跨膜结构域与信号肽,为亲水性蛋白,二级结构中富含α-螺旋;奶牛CLOCK蛋白的三级结构与绵羊、人和小鼠的差异极小。结论:本研究成功克隆了奶牛CLOCK基因全长CDS区片段并构建了其真核表达载体,qPCR检测CLOCK基因在奶牛不同组织的表达谱,通过生物信息学预测分析CLOCK蛋白的结构与功能特性,为进一步探究奶牛CLOCK基因的生物学功能提供理论依据。