Neurons have adapted mechanisms to traffic RNA and protein into distant dendritic and axonal arbors. Taking a biochemical approach, we reveal that forebrain synaptic transcript accumulation shows ...overwhelmingly daily rhythms, with two-thirds of synaptic transcripts showing time-of-day-dependent abundance independent of oscillations in the soma. These transcripts formed two sharp temporal and functional clusters, with transcripts preceding dawn related to metabolism and translation and those anticipating dusk related to synaptic transmission. Characterization of the synaptic proteome around the clock demonstrates the functional relevance of temporal gating for synaptic processes and energy homeostasis. Unexpectedly, sleep deprivation completely abolished proteome but not transcript oscillations. Altogether, the emerging picture is one of a circadian anticipation of messenger RNA needs in the synapse followed by translation as demanded by sleep-wake cycles.
The circadian clock drives daily changes of physiology, including sleep-wake cycles, through regulation of transcription, protein abundance, and function. Circadian phosphorylation controls cellular ...processes in peripheral organs, but little is known about its role in brain function and synaptic activity. We applied advanced quantitative phosphoproteomics to mouse forebrain synaptoneurosomes isolated across 24 hours, accurately quantifying almost 8000 phosphopeptides. Half of the synaptic phosphoproteins, including numerous kinases, had large-amplitude rhythms peaking at rest-activity and activity-rest transitions. Bioinformatic analyses revealed global temporal control of synaptic function through phosphorylation, including synaptic transmission, cytoskeleton reorganization, and excitatory/inhibitory balance. Sleep deprivation abolished 98% of all phosphorylation cycles in synaptoneurosomes, indicating that sleep-wake cycles rather than circadian signals are main drivers of synaptic phosphorylation, responding to both sleep and wake pressures.
Distilling insomnia genome-wide association study (GWAS) variants, Palermo and colleagues identified several genes that participate in sleep regulation in two different model organisms. This workflow ...sets off an innovative strategy to extract biological relevance from large human genomic databases.
The gut microbiome is well known to impact host physiology and health. Given widespread control of physiology by circadian clocks, we asked how the microbiome interacts with circadian rhythms in the
...gut. The microbiome did not cycle in flies fed ad libitum, and timed feeding (TF) drove limited cycling only in clockless
flies. However, TF and loss of the microbiome influenced the composition of the gut cycling transcriptome, independently and together. Moreover, both interventions increased the amplitude of rhythmic gene expression, with effects of TF at least partly due to changes in histone acetylation. Contrary to expectations, timed feeding rendered animals more sensitive to stress. Analysis of microbiome function in circadian physiology revealed that germ-free flies reset more rapidly with shifts in the light:dark cycle. We propose that the microbiome stabilizes cycling in the host gut to prevent rapid fluctuations with changing environmental conditions.
Daily rhythms of behavior and neurophysiology are integral to the circadian clocks of all animals. Examples of circadian clock regulation in the human brain include daily rhythms in sleep-wake, ...cognitive function, olfactory sensitivity, and risk for ischemic stroke, all of which overlap with symptoms displayed by many COVID-19 patients. Motivated by the relatively unexplored, yet pervasive, overlap between circadian functions and COVID-19 neurological symptoms, this perspective piece uses daily variations in the sense of smell and the timing of sleep and wakefulness as illustrative examples. We propose that time-stamping clinical data and testing may expand and refine diagnosis and treatment of COVID-19.
Microglia interact with neurons to facilitate synapse plasticity; however, signal(s) contributing to microglia activation for synapse elimination in pathology are not fully understood. Here, using in ...vitro organotypic hippocampal slice cultures and transient middle cerebral artery occlusion (MCAO) in genetically engineered mice in vivo, we report that at 24 hours after ischemia, microglia release brain-derived neurotrophic factor (BDNF) to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the cornu ammonis 1 (CA1) in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75 neurotrophin receptor (p75
) and tropomyosin receptor kinase B (TrkB) receptors, respectively. After MCAO, we report that in the peri-infarct area and in the corresponding contralateral hemisphere, similar neuroplasticity occurs through microglia activation and gephyrin phosphorylation at serine-268 and serine-270 in vivo. Targeted deletion of the
gene in microglia or
S268A/S270A (phospho-null) point mutations protects against ischemic brain damage, neuroinflammation, and synapse downregulation after MCAO.
Purpose
To analyze the prognostic factors of recurrence and overall survival in rare histotypes of vulvar cancer.
Methods
An international multicenter retrospective study including patients diagnosed ...with vulvar cancer was performed. One hundred centers participated in the study and 2453 vulvar cancer cases were enrolled from January 2001 until December 2005. After exclusion of squamous vulvar cancer, Paget´s disease and vulvar melanoma 112 tumors were analyzed for the present study.
Results
The mean age at diagnosis was 64.9 ± 17.2 years. 99 (88.4%) patients had a single lesion, in 25 (22.3%) cases the vulvar tumor involved the midline, and only 13 (11.5%) patients had clinically positive inguinal lymph nodes. The mean size of the lesion was 33.8 ± 33.9 mm. Regarding the surgical treatment, 2 (1.8%) patients underwent skinning vulvectomy, 63 (56.3%) local excision, 41 (36.6%) vulvectomy, 3 (2.7%) exenteration and 3 (2.7%) did not receive any surgical treatment. The mean free surgical margin was 8.2 ± 9 mm and 7 (6.2%) patients presented positive inguinal nodes. Radiotherapy was administered in 22 (19.6%) patients and it was performed postoperatively in all cases; 14 (12.5%) patients received adjuvant chemotherapy. The mean overall follow-up time was 44.1 ± 35.7 months. The risk factors associated with overall survival were chemotherapy and radiotherapy, tumor size and stromal invasion (
p
< 0.05). The only independent factor significantly associated with global recurrence and absence of metastasis was radiotherapy (
p
= 0.02 and
p
= 0.002, respectively).
Conclusion
Postoperative radiotherapy seems to be the only independent factor associated with recurrence and overall survival in uncommon types of vulvar cancer.
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