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Sleep constitutes a third of human life and it is increasingly recognized as important for health. Over the past several decades, numerous genes have been identified to be involved in sleep regulation in animal models, but most of these genes when disturbed impair not only sleep but also health and physiological functions. Human natural short sleepers are individuals with lifelong short sleep and no obvious adverse outcomes associated with the lack of sleep. These traits appear to be heritable, and thus characterization of the genetic basis of natural short sleep provides an opportunity to study not only the genetic mechanism of human sleep but also the relationship between sleep and physiological function. This review focuses on the current understanding of mutations associated with the natural short sleep trait and the mechanisms by which they contribute to this trait.

High temperatures severely affect plant growth and pose a threat to global crop production. Heat causes the accumulation of misfolded proteins in the endoplasmic reticulum(ER), as well as triggering the heat-shock response (HSR) in the cytosol and the unfolded protein response (UPR) in the ER. Excessive misfolded proteins undergo further degradation through ER-associated degradation (ERAD). Although much research on the plant heat stress response has been conducted, the regulation of ER-localized proteins has not been well-studied thus far. We isolated the microsome fraction from heat-treated and untreated maize seedlings and performed proteome and ubiquitylome analyses. Of the 8306 total proteins detected in the proteomics analysis, 1675 proteins were significantly up-regulated and 708 proteins were significantly down-regulated. Global ubiquitination analysis revealed 1780 proteins with at least one ubiquitination site. Motif analysis revealed that alanine and glycine are the preferred amino acids upstream and downstream of ubiquitinated lysine sites. ERAD components were found to be hyper-ubiquitinated after heat treatment, implying the feedback regulation of ERAD activity through protein degradation.

Circadian clock drives the 24h rhythm in our behavior and physiology. Previously, we have shown that inner nuclear membrane protein Lamin B receptor (LBR) regulates circadian rhythm in human cells andDrosophila, while the underlying mechanism is unclear (Lin et al., 2014). A very recent study reported that the circadian clock protein PERIOD is organized into discrete foci at the nuclear envelope in fly circadian neurons, which is believed to be important for controlling the subcellular localization of clock genes. Loss of LBR leads to disruption of these foci, but how they are regulated is yet unknown. Here we found that LBR likely facilitates PER foci accumulation by destabilizing the catalytic subunit of protein phosphatase 2A, MICROTUBULE STAR (MTS). MTS is known to dephosphorylate PER and hampers the accumulation of PER foci. On the other hand, the circadian kinase DOUBLETIME (DBT) which phosphorylates PER enhances the accumulation of the foci. These foci are likely phase-separated condensates, the formation of which mediated by intrinsically disordered region in PER. Taken together, here we demonstrate a key role for phosphorylation in promoting the accumulation of PER foci, while LBR modulates this process by impinging on the circadian phosphatase MTS.

High-fat diet (HFD)-induced obesity is a growing epidemic and major health concern. While excessive daytime sleepiness (EDS) is a common symptom of HFD-induced obesity, preliminary findings suggest that reduced wakefulness could be improved with time-restricted feeding (TRF). At present, however, the underlying neural mechanisms remain largely unknown. The paraventricular thalamic nucleus (PVT) plays a role in maintaining wakefulness. We found that chronic HFD impaired the activity of PVT neurons. Notably, inactivation of the PVT was sufficient to reduce and fragment wakefulness during the active phase in lean mice, similar to the sleep–wake alterations observed in obese mice with HFD-induced obesity. On the other hand, enhancing PVT neuronal activity consolidated wakefulness in mice with HFD-induced obesity. We observed that the fragmented wakefulness could be eliminated and reversed by TRF. Furthermore, TRF prevented the HFD-induced disruptions on synaptic transmission in the PVT, in a feeding duration-dependent manner. Collectively, our findings demonstrate that ad libitum access to a HFD results in inactivation of the PVT, which is critical to impaired nocturnal wakefulness and increased sleep, while TRF can prevent and reverse diet-induced PVT dysfunction and excessive sleepiness. We establish a link between TRF and neural activity, through which TRF can potentially serve as a lifestyle intervention against diet/obesity-related EDS.

Human NaV1.9 (hNaV1.9), encoded by SCN11A, is preferentially expressed in nociceptors, and its mutations have been linked to pain disorders. NaV1.9 could be a promising drug target for pain relief. However, the modulation of NaV1.9 activity has remained elusive. Here, we identified a new candidate NaV1.9-interacting partner, protein arginine methyltransferase 7 (PRMT7). Whole-cell voltage-clamp recordings showed that coelectroporation of human SCN11A and PRMT7 in dorsal root ganglion (DRG) neurons of Scn11a-/- mice increased the hNaV1.9 current density. By contrast, a PRMT7 inhibitor (DS-437) reduced mNaV1.9 currents in Scn11a+/+ mice. Using the reporter molecule CD4, we observed an increased distribution of hLoop1 on the cell surface of PRMT7-overexpressing HKE293T cells. Furthermore, we found that PRMT7 mainly binds to residues 563 to 566 within the first intracellular loop of hNaV1.9 (hLoop1) and methylates hLoop1 at arginine residue 519. Moreover, overexpression of PRMT7 increased the number of action potential fired in DRG neurons of Scn11a+/+ mice but not Scn11a-/- mice. However, DS-437 significantly inhibited the action potential frequency of DRG neurons and relieved pain hypersensitivity in Scn11aA796G/A796G mice. In summary, our observations revealed that PRMT7 modulates neuronal excitability by regulating NaV1.9 currents, which may provide a potential method for pain treatment.

Pilomatricoma, a benign skin appendage tumor, also known as calcifying epithelioma, consists of islands of epithelial cells histologically that contain anucleated cells in the center surrounded by basophilic cells and partial calcification. Sporadic pilomatricomas commonly have somatic mutations in the gene CTNNB1, but causative genes from germline and the underlying pathophysiology are unclear. In this study, we identified a germline missense variant of PLCD1 encoding PLCδ1, c.1186G>A (p.Glu396Lys), in a large Chinese family with autosomal dominant multiple pilomatricomas. Phospholipase C, a key enzyme playing critical roles in intracellular signal transduction, is essential for epidermal barrier integrity. The p.Glu396Lys variant increased the enzymatic activity of PLCδ1, leading to protein kinase C/protein kinase D/extracellular signal–regulated kinase1/2 pathway activation and TPRV6 channel closure, which not only resulted in excessive proliferation of keratinocytes in vitro and in vivo but also induced local accumulation of calcium in the pilomatricoma-like tumor that developed spontaneously in the skin of Plcd1E396K/E396K mice. Our results implicate this p.Glu396Lys variant of PLCD1 from germline leading to gain-of-function of PLCδ1 as a causative genetic defect in familial multiple pilomatricomas.

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Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders, including Huntington disease [caused by expanded CAG repeats (CAGr) in the HTT gene], and amyotrophic lateral sclerosis [ALS, possibly caused by expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene], of which the molecular mechanisms remain unclear. Here, we demonstrated that lowering the Drosophila homologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and the shortened life-span in Drosophila expressing expanded CAGr or expanded G4C2r. Expression of human tau (htau4R) restored the disease-related phenotypes that had been mitigated by the loss of dtau, suggesting an evolutionarily-conserved role of tau in neurodegeneration. We further revealed that G4C2r expression increased tau accumulation by inhibiting autophagosome–lysosome fusion, possibly due to lowering the level of BAG3, a regulator of autophagy and tau. Taken together, our results reveal a novel mechanism by which expanded G4C2r causes neurodegeneration via an evolutionarily-conserved mechanism. Our findings provide novel autophagy-related mechanistic insights into C9ORF72-ALS and possible entry points to disease treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12264-020-00518-2) contains supplementary material, which is available to authorized users.

Aims: Cleft lip with or without cleft palate (CL/P) is a common birth defect with an average prevalence of 1/700 to 1/1000. Almost 70% of CL/P cases are nonsyndromic CL/P (NSCL/P). The aim of this study was to identify the underlying cause of a four-generation Chinese family with autosomal dominant NSCL/P. Methods: Genomic DNA was extracted from peripheral blood leukocytes, and whole-exome sequencing was carried out to identify the underlying genetic cause of the disorder. The mutation was confirmed by Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Western blotting and coimmunoprecipitation were used to analyze the protein expression level and adhesive dimerization of the CDH1 mutants. Slow aggregation assays were conducted to investigate the cell-cell adhesion ability. Results: A novel missense mutation (c.468G>C/p.Trp156Cys) of CDH1 was identified in the proband and the mutation was shown to cosegregate with the phenotype in the family. Furthermore, we found that the p.Trp156Cys mutation led to decreased E-cadherin dimerization and cell-cell adhesion ability. Conclusions: Our findings identified a novel CDH1 variant (c.468G>C/p.Trp156Cys) responsible for NSCL/P in a Chinese family, which expanded the mutational spectrum of the CDH1 gene and may contribute to understanding the molecular basis of NSCL/P.

Affective disorders are often accompanied by circadian rhythm disruption and the major symptoms of mental illness occur in a rhythmic manner. Chronotype, also known as circadian preference for rest or activity, is believed to exert a substantial influence on mental health. Here, we review the connection between chronotypes and affective disorders, and discuss the potential underlying mechanisms between these two phenomena.

Shift work is known to be associated with an increased risk of neurological and psychiatric diseases, but how it contributes to the development of these diseases remains unclear. Chronic jet lag (CJL) induced by shifting light-dark cycles repeatedly is a commonly used protocol to mimic the environmental light/dark changes encountered by shift workers. Here we subjected wildtype mice to CJL and performed positron emission tomography imaging of glucose metabolism to monitor brain activities. We also conducted RNA sequencing using prefrontal cortex and nucleus accumbens tissues from these animals, which are brain regions strongly implicated in the pathology of various neurological and psychiatric conditions. Our results reveal the alterations of brain activities and systematic reprogramming of gene expression in brain tissues under CJL, building hypothesis for how CJL increases the susceptibility to neurological and psychiatric diseases., Measurement(s) brain measurement • sleep duration • sleep quality • fragments per kilobase of exon per million mapped reads Technology Type(s) positron emission tomography • animal activity monitoring system • RNA sequencing Factor Type(s) chronic jet lag Sample Characteristic - Organism Mus musculus Sample Characteristic - Environment laboratory environment Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.12924248

Most organisms on the earth exhibit circadian rhythms in behavior and physiology, which are driven by endogenous clocks. Phosphorylation plays a central role in timing the clock, but how this contributes to overt rhythms is unclear. Here we conduct phosphoproteomics in conjunction with transcriptomic and proteomic profiling using fly heads. By developing a pipeline for integrating multi-omics data, we identify 789 (~17%) phosphorylation sites with circadian oscillations. We predict 27 potential circadian kinases to participate in phosphorylating these sites, including 7 previously known to function in the clock. We screen the remaining 20 kinases for effects on circadian rhythms and find an additional 3 to be involved in regulating locomotor rhythm. We re-construct a signal web that includes the 10 circadian kinases and identify GASKET as a potentially important regulator. Taken together, we uncover a circadian kinome that potentially shapes the temporal pattern of the entire circadian molecular landscapes., Phosphorylation plays an important role in the regulation of molecular circadian clocks. Here the authors utilize multi-omics data from flies to describe the circadian kinome and identify GASKET as a potentially important regulator within the circadian kinase network.

Host rock samples and deposits collected from the upper Yangtze River and the Dadu River, which both drained the southeastern Tibet Plateau and nature electron spin resonance (ESR) signals of quartz E' center were determined with ESR spectrometry. Statistical analyses of the results show that nature signal intensity of quartz E' center as a new indicator can be used to fingerprint the source of detrital quartz in modern river sediments. Firstly, nature signal intensities of quartz E' center both in bedrocks and its deposits show lower values (less than 11 s. u.) in granitic drainages than those in metamorphic drainage and sedimentary drainage (more than 19 s. u.). Secondly, nature signal intensities of quartz E' center in deposits will be enhanced by sunlight bleaching from source to sink. Thirdly, with the increasing of transportation distance accumulation nature signal intensities of quartz E' center in deposits are changed according to the different mixture ratios of samples which attributed the different types of host rocks. The researches indicate that nature signal intensities of quartz E' center have a significantly dependence on lithology both in bedrocks and in deposits, and nature signal intensities of quartz E' center can reflect the mixture ratio of deposits with different types of sourced bedrocks.

It has been known for many years that genetic influences account for some of the individual differences in human sleep parameters, but the underlying molecular mechanisms remain unclear. With major advances of molecular biology and the recognition of heritable sleep behaviors in humans over the past 30years, a number of genetic variants have been identified to be associated with human sleep timing, duration and quality, both in healthy individuals and under pathological conditions. Some of these variants were further validated and characterized in animal models, shedding light on the mechanism of how these variants likely alter sleep in humans, which may provide new insights into developing more effective treatments to improve human sleep.

Various computational super-resolution methods are available based on the analysis of fluorescence fluctuation behind acquired frames. However, dilemmas often exist in the balance of fluorophore characteristics, computation cost, and achievable resolution. Here we present an approach that uses a super-resolution radial fluctuations (SRRF) image to guide the Bayesian analysis of fluorophore blinking and bleaching (3B) events, allowing greatly accelerated localization of overlapping fluorophores with high accuracy. This radial fluctuation Bayesian analysis (RFBA) approach is also extended to three dimensions for the first time and combined with light-sheet fluorescence microscopy, to achieve super-resolution volumetric imaging of thick samples densely labeled with common fluorophores. For example, a 700-nm thin Bessel plane illumination is developed to optically section the Drosophila brain, providing a high-contrast 3D image of rhythmic neurons. RFBA analyzes 30 serial volumes to reconstruct a super-resolved 3D image at 4-times higher resolutions (~70 and 170 nm), and precisely resolve the axon terminals. The computation is over 2-orders faster than conventional 3B analysis microscopy. The capability of RFBA is also verified through dual-color imaging of cell nucleus in live Drosophila brain. The spatial co-localization patterns of the nuclear envelope and DNA in a neuron deep inside the brain can be precisely extracted by our approach.

Background Circadian rhythm, regulated by both internal and external environment of the body, is a multi-scale biological oscillator of great complexity. On the molecular level, thousands of genes exhibit rhythmic transcription, which is both organ- and species-specific, but it remains a mystery whether some common factors could potentially explain their rhythmicity in different organs. In this study we address this question by analyzing the transcriptome data in 12 mouse organs to determine such major impacting factors. Results We found a strong positive correlation between the transcriptional level and rhythmic amplitude of circadian rhythmic genes in mouse organs. Further, transcriptional level could explain over 70% of the variation in amplitude. In addition, the functionality and tissue specificity were not strong predictors of amplitude, and the expression level of rhythmic genes was linked to the energy consumption associated with transcription. Conclusion Expression level is a single major factor impacts the behavior of rhythmic genes in mouse organs. This single determinant implicates the importance of rhythmic expression itself on the design of the transcriptional system. So, rhythmic regulation of highly expressed genes can effectively reduce the energetic cost of transcription, facilitating the long-term adaptive evolution of the entire genetic system.

Additional file 6: Figure S5. Relationship between transcriptional level of rhythmic genes and the number of rhythmically expressed tissues.

Almost all organisms exhibit ~24-h rhythms, or circadian rhythms, in a plentitude of biological processes. These rhythms are driven by endogenous molecular clocks consisting of a series of transcriptional and translational feedback loops. Previously, we have shown that the inner nuclear membrane protein MAN1 regulates this clock and thus the locomotor rhythm in flies, but the mechanism remains unclear. Here, we further confirmed the previous findings and found that knocking down MAN1 in the pacemaker neurons of adult flies is sufficient to lengthen the period of the locomotor rhythm. Molecular analysis revealed that knocking down MAN1 led to reduced mRNA and protein levels of the core clock gene period (per), likely by reducing its transcription. Over-expressing per rescued the long period phenotype caused by MAN1 deficiency whereas per mutation had an epistatic effect on MAN1, indicating that MAN1 sets the pace of the clock by targeting per. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12264-019-00404-6) contains supplementary material, which is available to authorized users.

Psychiatric diseases are often accompanied by circadian disruptions, but the molecular underpinnings remain largely unclear. To address this, we screened genes that have been previously reported to be associated with psychiatric diseases and found that TRRAP, a gene associated with schizophrenia, is involved in circadian rhythm regulation. Knocking down Nipped-A, the Drosophila homolog of human TRRAP, leads to lengthened period of locomotor rhythms in flies. Molecular analysis demonstrates that NIPPED-A sets the pace of the clock by increasing the mRNA and protein levels of core clock genes timeless (tim) and Par domain protein 1e (Pdp1e). Furthermore, we found that NIPPED-A promotes the transcription of tim and Pdp1e possibly by facilitating deubiquitination of histone H2B via the deubiquitination module of the transcription co-activator Spt-Ada-Gcn5 acetyltransferase complex. Taken together, these findings reveal a novel role for NIPPED-A in epigenetic regulation of the clock.

The aim of this study was to evaluate the diagnostic value of the sarcopenia index (serum creatinine [mg/dl]/cystatin C [mg/dl] × 100) for estimating low muscle mass and sarcopenia in community-dwelling older adults. We included 371 older adults (≥60 years) with normal kidney function. Four common diagnostic criteria (the European Working Group on Sarcopenia in Older People (EWGSOP), Asia Working Group for Sarcopenia (AWGS), International Working Group on Sarcopenia (IWGS), and Foundation for the National Institutes of Health (FNIH) criteria) were separately applied as the “gold standard”. The receiver operating characteristic (ROC) curves and the area under the ROC curves (AUC) were applied to evaluate the overall diagnostic accuracy. For identifying low muscle mass, the AUC ranged from 0.505 (95% confidence interval [CI] 0.453–0.557) to 0.558 (95% CI 0.506–0.609). For identifying sarcopenia, the AUC ranged from 0.555 (95% CI 0.503–0.606) to 0.618 (95% CI 0.566–0.668). Subgroup analyses according to gender showed similar results. In conclusion, the sarcopenia index based on serum creatinine and cystatin C may not serve as biomarkers of either low muscle mass or sarcopenia in urban community-dwelling older people with normal kidney function.

Adequate sleep is essential for physical and mental health. We previously identified a missense mutation in the human DEC2 gene (BHLHE41) leading to the familial natural short sleep behavioral trait. DEC2 is a transcription factor regulating the circadian clock in mammals, although its role in sleep regulation has been unclear. Here we report that prepro-orexin, also known as hypocretin (Hcrt), gene expression is increased in the mouse model expressing the mutant hDEC2 transgene (hDEC2-P384R). Prepro-orexin encodes a precursor protein of a neuropeptide producing orexin A and B (hcrt1 and hcrt2), which is enriched in the hypothalamus and regulates maintenance of arousal. In cell culture, DEC2 suppressed prepro-orexin promoter-luc (ore-luc) expression through cis-acting E-box elements. The mutant DEC2 has less repressor activity than WT-DEC2, resulting in increased orexin expression. DEC2-binding affinity for the prepro-orexin gene promoter is decreased by the P384R mutation, likely due to weakened interaction with other transcription factors. In vivo, the decreased immobility time of the mutant transgenic mice is attenuated by an orexin receptor antagonist. Our results suggested that DEC2 regulates sleep/wake duration, at least in part, by modulating the neuropeptide hormone orexin.

Objective The Mini Sarcopenia Risk Assessment (MSRA), a new sarcopenia screening tool, has 2 versions: MSRA-7 (full version, 7 items) and MSRA-5 (short version, 5 items). We aimed to compare the diagnostic values of MSRA-7 and MSRA-5 to SARC-F for screening sarcopenia. Design A diagnostic accuracy study. Setting A community in Chengdu, China. Participants Older adults. Measurements Muscle mass, strength, and physical performance were tested using a bioimpedance analysis (BIA) device, handgrip strength, and walking speed, respectively. Using the Asian Working Group for Sarcopenia (AWGS) criteria as the gold standard, the sensitivity/specificity analyses of the 3 scales were assessed. Receiver operating characteristic (ROC) curves and area under the ROC curves (AUC) were used to compare the overall diagnostic accuracy of the 3 scales. Results We recruited 384 participants. Against the AWGS criteria, SARC-F had a sensitivity of 29.5% and a specificity of 98.1%, and the MSRA-7 had a sensitivity of 86.9% and a specificity of 39.6%, whereas the MSRA-5 had a sensitivity of 90.2% and a specificity of 70.6%. The AUCs of SARC-F, MSRA-7, and MSRA-5 were 0.89 [95% confidence interval (CI), 0.86-0.92], 0.70 (95% CI, 0.65-0.74), and 0.85 (95% CI, 0.81-0.89), respectively. The differences in AUCs between SARC-F and MSRA-7 and in those between MSRA-7 and MSRA-5 were statistically significant (P Conclusion MSRA-5 may serve as a novel screening tool for sarcopenia in Chinese community-dwelling older adults. SARC-F, a class screening tool, is also suitable for this population. MSRA-5 and SARC-F demonstrated a similar diagnostic accuracy in our study population. MSRA-5 has better sensitivity, whereas SARC-F has better specificity. However, the diagnostic value of MSRA needs to be further validated in different populations.

Daily rhythms of behavior and physiology arise from endogenous circadian clocks. At the molecular level, the circadian clock consists of intricate transcriptional and post-transcriptional feedback loops that drive 24h rhythms in a vast repertoire of basic cellular processes. The nuclear envelope, as a fundamental component of the cell, has been shown to function as a global transcriptional regulatory machinery. Recently we found that nuclear envelope proteins regulate the circadian clock both in the mammalian system and in fruit flies. One of these proteins, MAN1, impinges on the clock by binding to the promoter region of the core clock gene BMAL1 and enhances its transcription. Here we discuss about other potential mechanisms employed by nuclear envelope proteins to regulate the circadian clock and possible biological relevance of these modulations.

PiT2 is a member of the inorganic phosphate transporter family, and is extensively expressed in the nervous system. It was found that loop7 domain of PiT2 is not required for retroviral recognition and transport function. The exact functions of loop7 remain poorly understood. Here we show that loop7 of PiT2 is necessary for the transport of PiT2 protein to the cell surface. Further, loop7 is also related to the outgrowth of neurite in Neuro2A cells interacts with the light chain 1 of microtubule-associated protein 1B (MAP1B). PiT2 with mutated MAP1B binding sites affect neurite outgrowth whereas Pi transport function deficient mutants of PiT2 do not. We also show that Drosophila dPiT interacts with microtubule-associated protein Futsch, and dPiT is crucial for the normal development of neuromuscular junctions (NMJs). These results indicate that PiT2 might participate in the regulation of neuronal outgrowth by interacting with MAP1B and independently of its Pi transport function in the nervous system.

Objective To identify the causative gene of autosomal dominant paroxysmal kinesigenic dyskinesia and benign familial infantile seizures (PKD/BFIS) in a large Chinese family and explore the potential pathogenic mechanism of a PRRT2 (proline-rich transmembrane protein 2) variant. Methods Genetic testing was performed via whole exome sequencing. Western blotting and immunofluorescence were used to analyze the protein expression level and subcellular localization of the PRRT2 mutant in HeLa cells and N2A cells. Coimmunoprecipitation was conducted to investigate the interaction of the PRRT2 mutant with syntaxin 1B (STX1B). Results In a large Chinese family with autosomal dominant PKD/BFIS showing wide phenotypic heterogeneity, including patients suffering from PKD, BFIS, or epilepsy and asymptomatic variant carriers, a c.621dupA variant in PRRT2 was identified in the proband and was shown to cosegregate with the phenotype in this family. This variant results in premature termination at codon 224, producing a truncated protein (p.Ser208Ilefs*17) in which the two conserved hydrophobic segments and the cytoplasmic loop are missing. Both the expression and subcellular localization of PRRT2 are strongly affected by the c.621dupA variant. In addition, we found that PRRT2 directly interacts with STX1B, a SNARE protein critical for neurotransmitter release, whereas the truncated variant p.Ser208Ilefs*17 lacking the helix-loop-helix domain fails to bind to STX1B. Significance Our findings identified a PRRT2 variant in a family with PKD/BFIS and confirmed STX1B as a new binding partner of PRRT2, which suggested that the loss of the interaction between PRRT2 and STX1B may contribute to the pathogenesis of PKD/BFIS.

In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes.

Temporally restricted feeding (RF) can phase reset the circadian clocks in numerous tissues in mammals, contributing to altered timing of behavioral and physiological rhythms. However, little is known regarding the underlying molecular mechanism. Here we demonstrate a role for the gamma isotype of protein kinase C (PKCγ) in food-mediated entrainment of behavior and the molecular clock. We found that daytime RF reduced late-night activity in wild-type mice but not mice homozygous for a null mutation of PKCγ ( PKCγ −/− ). Molecular analysis revealed that PKCγ exhibited RF-induced changes in activation patterns in the cerebral cortex and that RF failed to substantially phase shift the oscillation of clock gene transcripts in the absence of PKCγ. PKCγ exerts effects on the clock, at least in part, by stabilizing the core clock component brain and muscle aryl hydrocarbon receptor nuclear translocator like 1 (BMAL1) and reducing its ubiquitylation in a deubiquitination-dependent manner. Taken together, these results suggest that PKCγ plays a role in food entrainment by regulating BMAL1 stability.

A 3-item SARC-F (termed SARC-F-3 in our study) was recently suggested as a screening tool for sarcopenia. The aim of this study was to compare the diagnostic value of SARC-F-3 to SARC-F in community-dwelling older people. We conducted a diagnostic accuracy study in an urban community in Chengdu, China. People aged 60 years or older were included. Muscle mass, strength, and physical performance were measured by a bio-impedance analysis (BIA) device, handgrip strength, and gait speed test, respectively. The Asia Working Group for Sarcopenia (AWGS) criteria were applied as the “gold reference.” The sensitivity/specificity analyses of SARC-F and SARC-F-3 were performed. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were applied to compare the overall accuracy of SARC-F and SARC-F-3. The cut-off points of SARC-F-3 for sarcopenia were determined using the Youden index method. A total of 384 older people aged 71.5 ± 5.8 years were included. On the basis of the AWGS criteria, the prevalence of sarcopenia in our study population was 15.9%. The optimal cut-off point of SARC-F-3 for identifying sarcopenia was a total score of ≥ 2. In the whole study population, the sensitivity and specificity of SARC-F were 29.5% [95% confidence interval (95% CI): 18.5–42.6] and 98.1% (95% CI: 96.0–99.3), respectively, whereas the sensitivity and specificity of SARC-F-3 were 13.1% (95% CI: 5.8–24.2) and 97.8% (95% CI: 95.6–99.1), respectively. The AUCs of SARC-F and SARC-F-3 were 0.894 (95% CI: 0.859–0.923) and 0.676 (95% CI: 0.627–0.723), respectively (P

Objectives To compare the diagnostic value of the 5-component questionnaire that measures strength, assistance walking, rise from a chair, climb stairs, and falls (SARC-F) and SARC-F combined with calf circumference (SARC-CalF) for screening sarcopenia in community-dwelling older adults. Design A diagnostic accuracy study. Setting A community in Chengdu, China. Participants Older adults aged 60 years or older. Measurements Muscle mass, muscle strength, and physical performance were estimated using a bioimpedance analysis device, handgrip strength, and gait speed, respectively. Four commonly used diagnostic criteria [European Working Group on Sarcopenia in Older People (EWGSOP), Asian Working Group for Sarcopenia (AWGS), International Working Group on Sarcopenia (IWGS), and Foundation for the National Institutes of Health (FNIH) criteria] were applied as the reference standard, separately. The sensitivity/specificity analyses of the SARC-F and SARC-CalF methods were evaluated. The receiver operating characteristics curves and the area under the receiver operating characteristics curves were used to compare the overall diagnostic accuracy of the SARC-F and SARC-CalF for identifying sarcopenia. Results We included 160 men and 224 women. Based on the 4 diagnostic criteria, the prevalence of sarcopenia ranged from 11.7% to 25.0%. Using the AWGS criteria as the reference standard, the SARC-CalF had a sensitivity of 60.7% and a specificity of 94.7% in the whole study population, whereas the SARC-F had a sensitivity of 29.5% and a specificity of 98.1%. The area under the receiver operating characteristics curves for SARC-CalF and SARC-F were 0.92 (95% confidence interval 0.89‒0.94) and 0.89 (95% confidence interval 0.86‒0.92), respectively (P = .003). We obtained similar results when using the other 3 criteria as the reference standard. Subgroup analyses revealed similar results in both men and women. Conclusions SARC-CalF significantly improves the sensitivity and overall diagnostic accuracy of SARC-F for screening sarcopenia in community-dwelling older adults.