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The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here, we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including C4b and C3 , in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERBα, and deletion of REV-ERBα causes increased expression of C4b transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERBα deletion increased microglial phagocytosis of synapses and synapse loss in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis which was antiphase to REV-ERBα expression. This daily variation in microglial synaptic phagocytosis was abrogated by global REV-ERBα deletion, which caused persistently elevated synaptic phagocytosis. This work uncovers the BMAL1-REV-ERBα axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.

Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after α-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD.

Purpose Left atrial (LA) volume and strain parameters have been associated with cardiovascular outcomes in several cardiac pathologies, yet their role in predicting major adverse cardiovascular events (MACE) in kidney transplant (KT) recipients has not been explored. Methods We retrospectively reviewed the records of adult KT recipients from our institution (2015–2024). We utilized baseline echocardiograms routinely acquired during KT workup to measure LA volumetrics and strain. MACE was the study’s primary endpoint, defined as cardiovascular death, nonfatal myocardial infarction, stroke, major arrhythmias or heart failure hospitalization. Logistic regression, Kaplan-Meier and Cox proportional hazards regression were performed to evaluate the association between LA parameters and MACE. Results Of 518 patients who underwent kidney transplant, 377 were in sinus rhythm with an acceptable quality echocardiogram (male, 56.7%; mean age 53.7 ± 13.1 years). Over a median follow up duration of 5.3 ± 2.3 years from KT, 82 patients reached the study endpoint. Kaplan-Meier analysis showed significantly lower MACE-free survival in patients with abnormal LA strain. After adjusting for confounding variables in the Cox Proportional Hazards model, of all LA parameters, lower LAScd (HR 0.94, 95% CI 0.89–0.98, p  = 0.003), and LASr (HR 0.97, 95% CI 0.94–0.995, p  = 0.02) were independently associated with MACE. Conclusion In this retrospective single center study, LA strain parameters particularly LASr and LAScd were independently associated with MACE after KT. LA strain might have a role in risk stratification in this population.

The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here, we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including C4b and C3, in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERB[alpha], and deletion of REV-ERB[alpha] causes increased expression of C4b transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERB[alpha] deletion increased microglial phagocytosis of synapses and synapse loss in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis which was antiphase to REV-ERB[alpha] expression. This daily variation in microglial synaptic phagocytosis was abrogated by global REV-ERB[alpha] deletion, which caused persistently elevated synaptic phagocytosis. This work uncovers the BMAL1-REV-ERB[alpha] axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.

The circadian clock has been shown to regulate various aspects of brain health including microglial and astrocyte activation. Here we report that deletion of the master clock protein BMAL1 induces robust increases in the expression of complement genes such as C3, C4b and C1q in the hippocampus. Loss of downstream REV-ERBα-mediated transcriptional repression led to increases in C4b in neurons and astrocytes as well as C3 protein in microglia and astrocytes. REV-ERBα deletion induced complement C3/C4b gene expression and increased microglial phagocytosis of synapses in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis in wild type mice which was abrogated by REV-ERBα deletion. This work uncovers the BMAL1-REV-ERBα axis as a regulator of complement expression and synaptic phagocytosis in the brain, thereby illuminating a novel mechanism of synaptic regulation by the circadian clock.

The circadian clock has been shown to regulate various aspects of brain health including microglial and astrocyte activation. Here we report that deletion of the master clock protein BMAL1 induces robust increases in the expression of complement genes such as C3, C4b and C1q in the hippocampus. Loss of downstream REV-ERBalpha-mediated transcriptional repression led to increases in C4b in neurons and astrocytes as well as C3 protein in microglia and astrocytes. REV-ERBalpha deletion induced complement C3/C4b gene expression and increased microglial phagocytosis of synapses in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis in wild type mice which was abrogated by REV-ERBalpha deletion. This work uncovers the BMAL1-REV-ERBalpha axis as a regulator of complement expression and synaptic phagocytosis in the brain, thereby illuminating a novel mechanism of synaptic regulation by the circadian clock. Competing Interest Statement The authors have declared no competing interest.

Compares differences in the presentation and management of acute coronary syndrome (ACS) patients presenting to interventional versus non-interventional NZ hospitals. Assesses the data collected by the New Zealand Cardiac Society ACS Audit Group over 14 days from each hospital in NZ (n=36) that admits ACS patients. Compares patient management at intervention centres (5 public, 3 private) with non-intervention centres (28 public). Attributes investigations and revascularisation procedures performed on transferred patients to the referring centre. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.