Adaptive gene expression of alternative splicing variants of PGC-1α regulates whole-body energy metabolism.

The transcriptional coactivator PGC-1α has been implicated in the regulation of multiple metabolic processes. However, the previously reported metabolic phenotypes of mice deficient in PGC-1α have been inconsistent. PGC-1α exists as multiple isoforms, including variants transcribed from an alternative first exon. We show here that alternative PGC-1α variants are the main entity that increases PGC-1α during exercise. These variants, unlike the canonical isoform of PGC-1α, are robustly upregulated in human skeletal muscle after exercise. Furthermore, the extent of this upregulation correlates with oxygen consumption. Mice lacking these variants manifest impaired energy expenditure during exercise, leading to the development of obesity and hyperinsulinemia. The alternative variants are also upregulated in brown adipose tissue in response to cold exposure, and mice lacking these variants are intolerant of a cold environment. Our findings thus indicate that an increase in PGC-1α expression, attributable mostly to upregulation of alternative variants, is pivotal for adaptive enhancement of energy expenditure and heat production and thereby essential for the regulation of whole-body energy metabolism.

Combined Effects of the Mobile Health (mHealth) Psychoeducation and Benson Relaxation Technique in Reducing the Caregiving Burden of Cancer Patients in Bangladesh: A Protocol for a Randomized Controlled Trial.

BACKGROUND: Chronic and noncommunicable diseases, including cancer, are a significant global public health concern. Family members or friends who serve as caregivers significantly contribute to supporting cancer patients without formal medical training. In most cases in Bangladesh, women perform caregiving activities with household responsibilities and lack adequate support from the family and healthcare systems; consequently, they face a significant burden as caregivers. This study aims to assess the effectiveness of combined mobile health (mHealth) psychoeducation and the Benson relaxation technique (BRT) on the caregiving burden among female informal caregivers of cancer patients in Bangladesh. METHODS: We shall conduct a prospective, open-label, two-arm (1:1), randomized controlled trial in a hospital, focusing on the burden of informal female caregivers of cancer patients in Bangladesh. The combined intervention will be delivered to the intervention group through mHealth starting April 2024 and will span six months. Participants' data will be collected through face-to-face interviews using the Zarit Burden Interview (ZBI), the Hospital Anxiety Depression Scale, and the World Health Organization Quality of Life Bangla Short Instrument. Outcomes will be assessed at the baseline, midline, and endline. We shall employ descriptive statistics such as frequencies, percentages, means, and standard deviations. The t-test or Mann-Whitney U test will be used to compare continuous variables. Additionally, a two-way repeated-measures analysis of variance will be employed to evaluate the outcomes. RESULTS: Participant enrollment began in January 2024, and recruitment is ongoing. The results of this study will be disseminated through publications and conferences. No external professional writers were involved in writing this manuscript. CONCLUSION: This study addresses the gap in the assessment of combined interventions for caregiver burden in Bangladesh. These outcomes may provide valuable insights into caregivers' well-being, caregiving responsibilities, and the potential for integrated interventions to reduce the burden, especially among women. If effective, we recommend the national integration of psychoeducation and BRT using mHealth.

Discriminant Accuracy of Standing Balance Tests for the Level of Gait Dependency in Hospitalized Patients with Alzheimer's Disease.

INTRODUCTION: When determining the level of gait independence in patients with Alzheimer's disease (AD), detailed functional assessment is difficult in some patients. The previous literature has suggested simple standing balance tests for patients with AD due to their ease of implementation in clinical practice and relevance to gait. However, their usefulness for discriminating the level of gait independence remains unclear. This study aimed to investigate the discrimination accuracy of a simple standing balance test in the level of gait independence among hospitalized patients with AD. METHODS: This cross-sectional study was a post hoc analysis of a study conducted on 63 inpatients with AD in a single hospital. Participants were divided into three groups according to their level of gait independence: independent, modified independent (independent, walking with walking aids), and dependent groups (supervision). Gait independence was determined using the Functional Independence Measure. Four standing balance tests were used - closed-leg, semi-tandem, tandem, and one-leg standings - and the discrimination accuracy of each test was calculated by receiver operating characteristic analysis. RESULTS: One-leg standing was best at discriminating between the independent and modified independent groups (positive predictive value = 80.0%, negative predictive value = 94.1%). Tandem standing was best at discriminating between the modified independent and dependent groups (positive predictive value = 74.1%, negative predictive value = 93.3%). CONCLUSION: A simple standing balance test may assist in the determining level of gait independence in patients with AD when it is difficult to perform a mobility assessment.

Assessment of psychological distress and its associated factors among patients with cancer undergoing chemotherapy in rural Bangladesh.

Background: Psychological distress may worsen during cancer treatment and affect well-being. Information on the prevalence of distress and its associated variables in cancer patients undergoing chemotherapy in rural Bangladesh has not been thoroughly explored. To address this, we aimed to assess psychological distress and its associated factors in patients with cancer undergoing chemotherapy. Methods: This cross-sectional study was conducted at a tertiary care hospital in rural Bangladesh. Only adult patients with cancer who were receiving chemotherapy were enrolled in this study. The validated Depression Anxiety Stress Scale was used to assess psychological distress. Frequency and percentages were used in descriptive analysis, and logistic regression analysis was performed to investigate potential associated factors for depression, anxiety, and stress. Results: Participants comprised 415 patients with a mean age of 46.3 years. The prevalence of depression, anxiety, and stress was 61.5%, 55.4%, and 22.0%, respectively. In the multivariate logistic regression analysis, patients with more than five family members and smokeless tobacco users had a significant association with depression, anxiety, and stress. In contrast, participants aged >60 years had a protective association with depression. Conclusions: Our findings show that patients with cancer receiving chemotherapy experience a high prevalence of depression and anxiety and that the use of smokeless tobacco and having six or more family members are associated with psychological distress. These findings will aid health professionals and policymakers in establishing and implementing improved care programs to ensure the greater mental health of cancer survivors, particularly in resource-limited settings.

The Japanese Breast Cancer Society clinical practice guidelines for epidemiology and prevention of breast cancer, 2022 edition.

The Japanese Breast Cancer Society Clinical Practice Guidelines for Epidemiology and Prevention of Breast Cancer, 2022 Edition.

An intact pituitary vasopressin system is critical for building a robust circadian clock in the suprachiasmatic nucleus.

The circadian clock is a biological timekeeping system that oscillates with a circa-24-h period, reset by environmental timing cues, especially light, to the 24-h day-night cycle. In mammals, a "central" clock in the hypothalamic suprachiasmatic nucleus (SCN) synchronizes "peripheral" clocks throughout the body to regulate behavior, metabolism, and physiology. A key feature of the clock's oscillation is resistance to abrupt perturbations, but the mechanisms underlying such robustness are not well understood. Here, we probe clock robustness to unexpected photic perturbation by measuring the speed of reentrainment of the murine locomotor rhythm after an abrupt advance of the light-dark cycle. Using an intersectional genetic approach, we implicate a critical role for arginine vasopressin pathways, both central within the SCN and peripheral from the anterior pituitary.

Combining Physical and Cognitive Functions to Discriminate Level of Gait Independence in Hospitalized Patients with Alzheimer's Disease.

INTRODUCTION: Both physical and cognitive functions are required to be assessed to determine the level of gait independence in patients with Alzheimer's disease (AD); nonetheless, a method to achieve this assessment has not been established. This study aimed to investigate the accuracy of an assessment method that combined muscle strength, balance ability, and cognitive function parameters in discriminating the level of gait independence in a real-world setting in hospitalized patients with AD. METHODS: In this cross-sectional study, 63 patients with AD (mean age: 86.1 ± 5.8 years) were classified into three groups according to their gait level: independent, modified independent (independent walking with walking aids), and dependent groups. Discrimination accuracy was calculated for single items of muscle strength, balance ability, and cognitive function tests and for combinations of each. RESULTS: The combined accuracy of muscle strength, balance ability, and cognitive function had a positive predictive value of 100.0% and a negative predictive value of 67.7% between the independent and modified independent groups. The positive and negative predictive values were 100.0% and 72.4%, respectively, between the modified independent and dependent groups. CONCLUSION: This study emphasizes the importance of assessing the level of gait independence in a real-world setting in patients with AD from the perspective of both physical and cognitive functions and proposes a novel method for discriminating an optimal state.

Factors Associated with Long-term Medication Adherence in Patients Who Participated in a Short-term Group Psychoeducation Program for Bipolar Disorder.

Improving adherence to medication and quality of life is a challenge in treating bipolar disorder. Therefore, psychoeducation plays an important role. This study examined factors associated with long-term medication adherence in patients with bipolar disorder who participated in a short-term psychoeducation program. Additionally, the relationships between medication adherence and medication attitudes and quality of life (QOL) were assessed. Multiple regression analysis was conducted on 67 inpatients and outpatients using medication adherence (Brief Evaluation for Medication Influences and Beliefs [BEMIB] score) as the dependent variable and clinical and demographic variables before and after the program as explanatory variables, one year after completion of the program. Pearson's correlation coefficients were calculated for associations between patients' BEMIB score and medication attitudes (Drug Attitude Inventory-10 [DAI-10]) and QOL (World Health Organization QOL-26 [WHOQOL-26] score) before and after the program and one year after program completion. The results showed that the CSQ-8 J (Client Satisfaction Questionnaire-8 Japanese) and DAI-10 scores immediately after the program were significantly related to the BEMIB score one year after program completion. Both the BEMIB and DAI-10 showed significant positive correlations with several items of the WHOQOL-26, both after the program and one year after completion of the program. The results suggest that medication attitudes acquired through psychoeducation and program satisfaction impact long-term medication adherence. The study also indicates that medication attitudes and medication adherence after a psychoeducation program are associated with QOL. Thus, patients' subjective views after a psychoeducation program can play an important role in long-term medication adherence and QOL.

Prefrontal activation during dual-task seated stepping and walking performed by subacute stroke patients with hemiplegia.

Objectives: This study examined prefrontal cortex (PFC) activation during dual-task seated stepping and walking performed by subacute stroke patients with hemiplegia and evaluated the relationship between PFC activation, frontal lobe functions, and dual-task interference. Methods: Patients with functional ambulation category (FAC) scores ≤ 2 comprised the seated stepping task group. Those with FAC scores > 2 comprised the walking task group. There were 11 patients in the seated stepping task group (mean age, 65.3±12.2 years; age range, 55-73.5 years; 7 male and 4 female patients; time since stroke onset, 45.7±9.9 days) and 11 patients in the walking task group (mean age, 65.6±15.2 years; age range, 49.5-74.5 years; 7 male and 4 female patients; time since stroke onset, 57.5±18.3 days). Both groups completed the Frontal Assessment Battery (FAB). The seated stepping task group performed the following three tasks: cognitive task (CT), normal seated stepping (NSS), and dual-task seated stepping (DTSS). The walking task group completed the following tasks: CT, normal walking (NW), and dual-task walking (DTW). The CT was a letter fluency task; this letter fluency task was simultaneously performed during seated stepping (DTSS) and walking (DTW). Changes in the oxygenated hemoglobin (O2Hb) concentration and deoxygenated hemoglobin concentration during the tasks were measured using near-infrared spectroscopy (Pocket NIRS HM; Dynasense Inc., Japan). The number of steps, walking speed, and percentage of correct responses to the CT were recorded. Results: The results showed that DTSS activated the PFC significantly more than performing a single task and that NSS was associated with a significantly higher difference in the hemoglobin concentration when compared to that associated with the CT, which was a single task. In the walking task group, PFC activation was significantly higher during DTW, NW, and CT (in that order), and O2Hb concentrations were significantly higher in the contralesional hemisphere than in the ipsilesional hemisphere during all tasks. Associations between PFC activation, FAB scores, and dual-task interference in the seated task group indicated significant positive correlations between FAB scores and cognitive performance with dual-task interference. Conclusion: DTSS may be an effective means of activating the PFC of patients with difficulty walking.

Alcohol consumption and breast cancer prognosis after breast cancer diagnosis: a systematic review and meta­analysis of the Japanese Breast Cancer Society Clinical Practice Guideline, 2022 edition.

Alcohol consumption is internationally recognized as one of the compelling risk factors for breast cancer, but it does not necessarily correlate with the prognosis of breast cancer patients. Alcohol consumption in breast cancer patients was addressed in the 2022 Breast Cancer Clinical Practice Guidelines. A systematic review and meta-analysis of epidemiological studies on alcohol consumption and breast cancer recurrence, breast cancer-related mortality, all-cause mortality, and cardiovascular disease mortality in breast cancer patients was performed. The PubMed, Cochrane Library, and Ichushi-Web databases were searched for relevant publications reporting cohort or case-control studies published until March 2021. A total of 33 studies (32 cohort studies and 1 case-control study) met the eligibility criteria; 4638 cases of recurrence, 12,209 cases of breast cancer-specific mortality, and 21,945 cases of all-cause mortality were observed. With regard to breast cancer recurrence, 7 studies assessed pre-diagnosis alcohol consumption (relative risk (RR) 1.02, 95% confidence interval (95% CI) 0.77-1.37, p = 0.88) and 3 studies assessed post-diagnosis alcohol consumption (RR 0.96, 95% CI 0.85-1.10, p = 0.57), and no significant increase or decrease in risk was observed. With regard to breast cancer-related mortality, 19 studies assessed pre-diagnosis alcohol consumption (RR 1.02, 95% CI 0.93-1.11, p = 0.69), 9 studies assessed post-diagnosis alcohol consumption (RR 0.96, 95% CI 0.77-1.19, p = 0.70), and no significant increase or decrease in risk was observed. With regard to all-cause mortality, 18 studies assessed pre-diagnosis alcohol consumption (RR 0.90, 95% CI 0.82-0.99, p = 0.02), 8 studies assessed post-diagnosis alcohol consumption (RR 0.88, 95% CI 0.74-1.02, p = 0.08), and pre-diagnosis alcohol consumption was associated with a significantly decreased risk. With regard to cardiovascular disease mortality and alcohol consumption, 2 studies assessed it, and the RRwas 0.47 (95% CI 0.28-0.79, p = 0.005), showing that alcohol consumption was associated with a significantly decreased risk. The limitations of this study are that drinking status was mainly based on a questionnaire survey, which is somewhat inaccurate and has many confounding factors, and the cut-off value for the maximum alcohol intake in many studies was low, and it is possible that the actual intake was only an appropriate amount. In many countries, a standard drinking amount is set, and wise decisions are required.

Minimal upstream open reading frame of Per2 mediates phase fitness of the circadian clock to day/night physiological body temperature rhythm.

Body temperature in homeothermic animals does not remain constant but displays a regular circadian fluctuation within a physiological range (e.g., 35°C-38.5°C in mice), constituting a fundamental systemic signal to harmonize circadian clock-regulated physiology. Here, we find the minimal upstream open reading frame (uORF) encoded by the 5' UTR of the mammalian core clock gene Per2 and reveal its role as a regulatory module for temperature-dependent circadian clock entrainment. A temperature shift within the physiological range does not affect transcription but instead increases translation of Per2 through its minimal uORF. Genetic ablation of the Per2 minimal uORF and inhibition of phosphoinositide-3-kinase, lying upstream of temperature-dependent Per2 protein synthesis, perturb the entrainment of cells to simulated body temperature cycles. At the organismal level, Per2 minimal uORF mutant skin shows delayed wound healing, indicating that uORF-mediated Per2 modulation is crucial for optimal tissue homeostasis. Combined with transcriptional regulation, Per2 minimal uORF-mediated translation may enhance the fitness of circadian physiology.

A scoping review of cognitive assessment tools and domains for chemotherapy-induced cognitive impairments in cancer survivors.

Backgrounds: Cancer survivors suffer from specific symptoms known as chemotherapy-induced cognitive impairments (CICIs). CICIs are difficult to capture with existing assessments such as the brief screening test for dementia. Although recommended neuropsychological tests (NPTs) exist, international consensus and shared cognitive domains of assessment tools are unknown. The aim of this scoping review was as follows: (1) to identify studies that assess CICIs in cancer survivors; (2) to identify shared cognitive assessment tools and domains by mapping the domains reported in studies using the International Classification of Functioning, Disability and Health (ICF) framework. Methods: The study followed the recommendations made by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. We searched the following three databases through October 2021: PubMed, CINAHL, and Web of Science. Prospective longitudinal or cross-sectional studies were selected to determine CICI-specific assessment tools for adult cancer survivors. Results: Sixty-four prospective studies (36 longitudinal studies and 28 cross-sectional studies) were included after checking for eligibility. The NPTs were divided into seven main cognitive domains. The specific mental functions were often used in the order of memory, attention, higher-level cognitive functions, and psychomotor functions. Perceptual functions were used less frequently. In some ICF domains, shared NPTs were not clearly identified. In some different domains, the same NPTs were used, such as the trail making test and the verbal fluency test. When the association between the publishing year and the amount of NPT use was examined, it was found that the amount of tool use tended to decline over the publication years. The Functional Assessment of Cancer Therapy-Cognitive function (FACT-Cog) was a shared consensus tool among the patient-reported outcomes (PROs). Conclusion: Chemotherapy-induced cognitive impairments are currently gaining interest. Shared ICF domains such as memory and attention were identified for NPTs. There was a gap between the publicly recommended tools and the tools actually used in the studies. For PROs, a clearly shared tool, FACT-Cog, was identified. Mapping the domains reported in studies using the ICF can help in the process of reviewing consensus on which NPTs may be used to target cognitive domains. Systematic review registration: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000053710, identifier UMIN000047104.

Prolonged Light Exposure Induces Circadian Impairment in Aquaporin-4-Knockout Mice.

Astrocytes are densely present in the suprachiasmatic nucleus (SCN), which is the master circadian oscillator in mammals, and are presumed to play a key role in circadian oscillation. However, specific astrocytic molecules that regulate the circadian clock are not yet well understood. In our study, we found that the water channel aquaporin-4 (AQP4) was abundantly expressed in SCN astrocytes, and we further examined its circadian role using AQP4-knockout mice. There was no prominent difference in circadian behavioral rhythms between Aqp4-/- and Aqp4+/+ mice subjected to light-dark cycles and constant dark conditions. However, exposure to constant light induced a greater decrease in the Aqp4-/- mice rhythmicity. Although the damped rhythm in long-term constant light recovered after transfer to constant dark conditions in both genotypes, the period until the reappearance of original rhythmicity was severely prolonged in Aqp4-/- mice. In conclusion, AQP4 absence exacerbates the prolonged light-induced impairment of circadian oscillations and delays their recovery to normal rhythmicity.

Interventions focusing on learning pre-transfer wheelchair manipulation in a patient with severe Alzheimer's disease: a case report.

BACKGROUND: Independence of transfer is important for the daily activities of wheelchair users. A critical step in performing this transfer includes a pre-transfer wheelchair manipulation, and patients with Alzheimer's disease (AD) experience difficulties in learning these tasks. In this report, we present the results of a treatment focused on learning pre-transfer wheelchair manipulation and its learning course in a patient with severe AD. CASE DESCRIPTION: The patient was a 92-year-old woman with severe AD during hospitalization in a long-term care ward. Since her cognitive function was highly compromised, she required assistance for pre-transfer wheelchair manipulation. Physiotherapists implemented a treatment plan that incorporated post-behavioral praise into a practice combining errorless learning and spaced retrieval training for pre-transfer wheelchair manipulation. OUTCOMES: The patient was able to accurately perform pre-transfer wheelchair manipulation in the seventh treatment session and achieved transfer independence after 12 physiotherapy sessions. CONCLUSION: This case report suggests that practicing combined errorless learning, spaced retrieval training, and post-behavioral praise was helpful as a treatment modality for an individual with severe AD for wheelchair manipulation learning before transfer.

Nmu/Nms/Gpr176 Triple-Deficient Mice Show Enhanced Light-Resetting of Circadian Locomotor Activity.

The suprachiasmatic nucleus (SCN) is the master circadian clock in mammals and is properly entrained by environmental light cycle. However, the molecular mechanism(s) determining the magnitude of phase shift by light is still not fully understood. The orphan G-protein-coupled receptor Gpr176 is enriched in the SCN, controls the pace (period) of the circadian rhythm in behavior but is not apparently involved in the light entrainment; Gpr176-/- animals display a shortened circadian period in constant darkness but their phase-resetting responses to light are normal. Here, we performed microarray analysis and identified enhanced mRNA expression of neuromedin U (Nmu) and neuromedin S (Nms) in the SCN of Gpr176-/- mice. By generating C57BL/6J-backcrossed Nmu/Nms/Gpr176 triple knockout mice, we noted that the mutant mice had a greater magnitude of phase shift in response to early subjective night light than wildtype mice, while Nmu/Nms double knockout mice as well as Gpr176 knockout mice are normal in the phase shifts induced by light. At the molecular level, Nmu-/-Nms-/-Gpr176-/- mice had a reduced induction of Per1 and cFos mRNA expression in the SCN by light and mildly upregulated circadian expression of Per2, Prok2, Rgs16, and Rasl11b. These expressional changes may underlie the phenotype of the Nmu/Nms/Gpr176 knockout mice. Our data argue that there is a mechanism requiring Nmu, Nms, and Gpr176 for the proper modulation of light-induced phase shift in mice. Simultaneous modulation of Nmu/Nms/Gpr176 may provide a potential target option for modulating the circadian clock.

Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity.

The epidermis is the outermost layer of the skin and the body's primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.

Factors Associated with Caregiver Burden and Depressive States among Family Caregivers of Patients Admitted due to Behavioral and Psychological Symptoms of Dementia.

INTRODUCTION: Among those caring for people with dementia (PwD) at home, more than 60% feel a caregiver burden (CB), and one in three are depressed. Reducing feelings of burden and depressive states in caregiving families will improve the living environment for PwD. However, very few studies have focused on effective methods and reducing feelings of burden and depressive states of caregivers. Thus, using data from a previous study, we aimed to determine the factors associated with perceived CB and depressive states experienced by caregivers for PwD with behavioral and psychological symptoms of dementia (BPSD) at home. METHODS: We performed single regression analysis on 285 participants' data to determine the association between each item and the Zarit Caregiver Burden Interview and Center for Epidemiologic Studies-Depression Scale scores. We performed multiple regression analysis with variables considered in the single regression analysis as independent variables. RESULTS: Severity of BPSD, caregivers' subjective health status (SHS), time of caregiving, and depressive states were related to CB, and caregivers' SHS and CB were related to depressive states. CONCLUSIONS: Similar to previous studies, we identified an association between family caregivers' perceived CB and BPSD in PwD. Additionally, we found that caregivers' SHS is commonly associated with both perceived CB and depressive states. This is a new finding. Our results suggest that interventions focusing on family caregivers' health status can help not only to reduce family caregivers' CB and depressive states but also stabilize patients' symptoms and provide home-based care for a longer time.

CNOT1 regulates circadian behaviour through Per2 mRNA decay in a deadenylation-dependent manner.

Circadian clocks are an endogenous internal timekeeping mechanism that drives the rhythmic expression of genes, controlling the 24 h oscillatory pattern in behaviour and physiology. It has been recently shown that post-transcriptional mechanisms are essential for controlling rhythmic gene expression. Controlling the stability of mRNA through poly(A) tail length modulation is one such mechanism. In this study, we show that Cnot1, encoding the scaffold protein of the CCR4-NOT deadenylase complex, is highly expressed in the suprachiasmatic nucleus, the master timekeeper. CNOT1 deficiency in mice results in circadian period lengthening and alterations in the mRNA and protein expression patterns of various clock genes, mainly Per2. Per2 mRNA exhibited a longer poly(A) tail and increased mRNA stability in Cnot1+/- mice. CNOT1 is recruited to Per2 mRNA through BRF1 (ZFP36L1), which itself oscillates in antiphase with Per2 mRNA. Upon Brf1 knockdown, Per2 mRNA is stabilized leading to increased PER2 expression levels. This suggests that CNOT1 plays a role in tuning and regulating the mammalian circadian clock.

A light-induced small G-protein gem limits the circadian clock phase-shift magnitude by inhibiting voltage-dependent calcium channels.

Calcium signaling is pivotal to the circadian clockwork in the suprachiasmatic nucleus (SCN), particularly in rhythm entrainment to environmental light-dark cycles. Here, we show that a small G-protein Gem, an endogenous inhibitor of high-voltage-activated voltage-dependent calcium channels (VDCCs), is rapidly induced by light in SCN neurons via the calcium (Ca2+)-mediated CREB/CRE transcriptional pathway. Gem attenuates light-induced calcium signaling through its interaction with VDCCs. The phase-shift magnitude of locomotor activity rhythms by light, at night, increases in Gem-deficient (Gem-/-) mice. Similarly, in SCN slices from Gem-/- mice, depolarizing stimuli induce larger phase shifts of clock gene transcription rhythms that are normalized by the application of an L-type VDCC blocker, nifedipine. Voltage-clamp recordings from SCN neurons reveal that Ca2+ currents through L-type channels increase in Gem-/- mice. Our findings suggest that transcriptionally activated Gem feeds back to suppress excessive light-evoked L-type VDCC activation, adjusting the light-induced phase-shift magnitude to an appropriate level in mammals.

Excess S-adenosylmethionine inhibits methylation via catabolism to adenine.

The global dietary supplement market is valued at over USD 100 billion. One popular dietary supplement, S-adenosylmethionine, is marketed to improve joints, liver health and emotional well-being in the US since 1999, and has been a prescription drug in Europe to treat depression and arthritis since 1975, but recent studies questioned its efficacy. In our body, S-adenosylmethionine is critical for the methylation of nucleic acids, proteins and many other targets. The marketing of SAM implies that more S-adenosylmethionine is better since it would stimulate methylations and improve health. Previously, we have shown that methylation reactions regulate biological rhythms in many organisms. Here, using biological rhythms to assess the effects of exogenous S-adenosylmethionine, we reveal that excess S-adenosylmethionine disrupts rhythms and, rather than promoting methylation, is catabolized to adenine and methylthioadenosine, toxic methylation inhibitors. These findings further our understanding of methyl metabolism and question the safety of S-adenosylmethionine as a supplement.