Function (Oxford, England)最新文献

{"title":"Epigenetic Regulation of Autophagy in Bone Metabolism.","authors":"Yazhou Zhang, Qianqian Wang, Hongjia Xue, Yujin Guo, Shanshan Wei, Fengfeng Li, Linqiang Gong, Weiliang Pan, Pei Jiang","doi":"10.1093/function/zqae004","DOIUrl":"10.1093/function/zqae004","url":null,"abstract":"<p><p>The skeletal system is crucial for supporting bodily functions, protecting vital organs, facilitating hematopoiesis, and storing essential minerals. Skeletal homeostasis, which includes aspects such as bone density, structural integrity, and regenerative processes, is essential for normal skeletal function. Autophagy, an intricate intracellular mechanism for degrading and recycling cellular components, plays a multifaceted role in bone metabolism. It involves sequestering cellular waste, damaged proteins, and organelles within autophagosomes, which are then degraded and recycled. Autophagy's impact on bone health varies depending on factors such as regulation, cell type, environmental cues, and physiological context. Despite being traditionally considered a cytoplasmic process, autophagy is subject to transcriptional and epigenetic regulation within the nucleus. However, the precise influence of epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNA expression, on cellular fate remains incompletely understood. The interplay between autophagy and epigenetic modifications adds complexity to bone cell regulation. This article provides an in-depth exploration of the intricate interplay between these two regulatory paradigms, with a focus on the epigenetic control of autophagy in bone metabolism. Such an understanding enhances our knowledge of bone metabolism-related disorders and offers insights for the development of targeted therapeutic strategies.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"5 2","pages":"zqae004"},"PeriodicalIF":0.0,"publicationDate":"2024-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10935486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140133412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma of COVID-19 Patients Does Not Alter Electrical Resistance of Human Endothelial Blood-Brain Barrier In Vitro.","authors":"Agnė Pociūtė, Karolina Kriaučiūnaitė, Aida Kaušylė, Birutė Zablockienė, Tadas Alčauskas, Augustė Jelinskaitė, Akvilė Rudėnaitė, Ligita Jančorienė, Saulius Ročka, Alexei Verkhratsky, Augustas Pivoriūnas","doi":"10.1093/function/zqae002","DOIUrl":"10.1093/function/zqae002","url":null,"abstract":"<p><p>The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 instigated the most serious global health crisis. Clinical presentation of COVID-19 frequently includes severe neurological and neuropsychiatric symptoms. However, it is presently unknown whether and to which extent pathological impairment of blood-brain barrier (BBB) contributes to the development of neuropathology during COVID-19 progression. In the present study, we used human induced pluripotent stem cells-derived brain endothelial cells (iBECs) to study the effects of blood plasma derived from COVID-19 patients on the BBB integrity in vitro. We also performed a comprehensive analysis of the cytokine and chemokine profiles in the plasma of COVID-19 patients, healthy and recovered individuals. We found significantly increased levels of interferon γ-induced protein 10 kDa, hepatocyte growth factor, and interleukin-18 in the plasma of COVID-19 patients. However, blood plasma from COVID-19 patients did not affect transendothelial electrical resistance in iBEC monolayers. Our results demonstrate that COVID-19-associated blood plasma inflammatory factors do not affect BBB paracellular pathway directly and suggest that pathological remodeling (if any) of BBB during COVID-19 may occur through indirect or yet unknown mechanisms.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"5 2","pages":"zqae002"},"PeriodicalIF":0.0,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10935481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140133414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuromuscular Dysfunction Precedes Cognitive Impairment in a Mouse Model of Alzheimer's Disease.","authors":"Matthew H Brisendine, Anna S Nichenko, Aloka B Bandara, Orion S Willoughby, Niloufar Amiri, Zach Weingrad, Kalyn S Specht, Jacob M Bond, Adele Addington, Ronald G Jones, Kevin A Murach, Steven Poelzing, Siobhan M Craige, Robert W Grange, Joshua C Drake","doi":"10.1093/function/zqad066","DOIUrl":"10.1093/function/zqad066","url":null,"abstract":"<p><p>Alzheimer's disease (AD) develops along a continuum that spans years prior to diagnosis. Decreased muscle function and mitochondrial respiration occur years earlier in those that develop AD; however, it is unknown what causes these peripheral phenotypes in a disease of the brain. Exercise promotes muscle, mitochondria, and cognitive health and is proposed to be a potential therapeutic for AD, but no study has investigated how skeletal muscle adapts to exercise training in an AD-like context. Utilizing 5xFAD mice, an AD model that develops ad-like pathology and cognitive impairments around 6 mo of age, we examined in vivo neuromuscular function and exercise adapations (mitochondrial respiration and RNA sequencing) before the manifestation of overt cognitive impairment. We found 5xFAD mice develop neuromuscular dysfunction beginning as early as 4 mo of age, characterized by impaired nerve-stimulated muscle torque production and compound nerve action potential of the sciatic nerve. Furthermore, skeletal muscle in 5xFAD mice had altered, sex-dependent, adaptive responses (mitochondrial respiration and gene expression) to exercise training in the absence of overt cognitive impairment. Changes in peripheral systems, specifically neural communication to skeletal muscle, may be harbingers for AD and have implications for lifestyle interventions, like exercise, in AD.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"5 1","pages":"zqad066"},"PeriodicalIF":5.1,"publicationDate":"2023-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10727840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138814640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac Timeless Trans-Organically Regulated by miR-276 in Adipose Tissue Modulates Cardiac Function.","authors":"Chao Tang, Qiufang Li, Xiaoya Wang, Zhengwen Yu, Xu Ping, Yi Qin, Yang Liu, Lan Zheng","doi":"10.1093/function/zqad064","DOIUrl":"10.1093/function/zqad064","url":null,"abstract":"<p><p>The interconnection between cardiac function and circadian rhythms is of great importance. While the role of the biological clock gene Timeless (Tim) in circadian rhythm has been extensively studied, its impact on cardiac function remains largely been unexplored. Previous research has provided experimental evidence for the regulation of the heart by adipose tissue and the targeting of miR-276a/b on Timeless. However, the extent to which adipose tissue regulates cardiac Timeless genes trans-organically through miR-276a/b, and subsequently affects cardiac function, remains uncertain. Therefore, the objective of this study was to investigate the potential trans-organ modulation of the Timeless gene in the heart by adipose tissue through miR-276a/b. We found that cardiac-specific Timeless knockdown and overexpression resulted in a significant increase in heart rate (HR) and a significant decrease in Heart period (HP), diastolic intervals (DI), systolic intervals (SI), diastolic diameter (DD), and systolic diameter (SD). miR-276b systemic knockdown resulted in a significant increase in DI, arrhythmia index (AI), and fractional shortening (FS) significantly increased and SI, DD and SD significantly decreased. Adipose tissue-specific miR-276a/b knockdown and miR-276a overexpression resulted in a significant increase in HR and a significant decrease in DI and SI, which were improved by exercise intervention. This study presents a novel finding that highlights the significance of the heart circadian clock gene Timeless in heart function. Additionally, it demonstrates that adipose tissue exerts trans-organ modulation on the expression of the heart Timeless gene via miR-276a/b.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"5 1","pages":"zqad064"},"PeriodicalIF":5.1,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138500701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming Confounding to Characterize the Effects of Calcium Channel Blockers.","authors":"Sudarshan Rajagopal, Paul B Rosenberg","doi":"10.1093/function/zqad054","DOIUrl":"10.1093/function/zqad054","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad054"},"PeriodicalIF":5.1,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41241712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Reappraisal of the Effects of L-type Ca²⁺ Channel Blockers on Store-Operated Ca²⁺ Entry and Heart Failure.","authors":"Gary S Bird, Diane D'Agostin, Safaa Alsanosi, Stefanie Lip, Sandosh Padmanabhan, Anant B Parekh","doi":"10.1093/function/zqad047","DOIUrl":"10.1093/function/zqad047","url":null,"abstract":"<p><p>Dihydropyridines such as amlodipine are widely used as antihypertensive agents, being prescribed to ∼70 million Americans and >0.4 billion adults worldwide. Dihydropyridines block voltage-gated Ca²⁺ channels in resistance vessels, leading to vasodilation and a reduction in blood pressure. Various meta-analyses show that dihydropyridines are relatively safe and effective in reducing hypertension. The use of dihydropyridines has recently been called into question as these drugs appear to activate store-operated Ca²⁺ entry in fura-2-loaded nonexcitable cells, trigger vascular remodeling, and increase heart failure, leading to the questioning of their clinical use. Given that hypertension is the dominant \"silent killer\" across the globe affecting ∼1.13 billion people, removal of Ca²⁺ channel blockers as antihypertensive agents has major health implications. Here, we show that amlodipine has marked intrinsic fluorescence, which further increases considerably inside cells over an identical excitation spectrum as fura-2, confounding the ability to measure cytosolic Ca²⁺. Using longer wavelength Ca²⁺ indicators, we find that concentrations of Ca²⁺ channel blockers that match therapeutic levels in serum of patients do not activate store-operated Ca²⁺ entry. Antihypertensive Ca²⁺ channel blockers at pharmacological concentrations either have no effect on store-operated channels, activate them indirectly through store depletion or inhibit the channels. Importantly, a meta-analysis of published clinical trials and a prospective real-world analysis of patients prescribed single antihypertensive agents for 6 mo and followed up 1 yr later both show that dihydropyridines are not associated with increased heart failure or other cardiovascular disorders. Removal of dihydropyridines for treatment of hypertension cannot therefore be recommended.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad047"},"PeriodicalIF":5.1,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41241710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How Do We Clean Up the Scientific Record?","authors":"Alexei Verkhratsky, Ole H Petersen","doi":"10.1093/function/zqad055","DOIUrl":"10.1093/function/zqad055","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad055"},"PeriodicalIF":5.1,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41241711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breathing and Oxygen Carrying Capacity in Ts65Dn and Down Syndrome.","authors":"Lara R DeRuisseau, Candace N Receno, Caitlin Cunningham, Melissa L Bates, Morgan Goodell, Chen Liang, Brianna Eassa, Jessica Pascolla, Keith C DeRuisseau","doi":"10.1093/function/zqad058","DOIUrl":"10.1093/function/zqad058","url":null,"abstract":"<p><p>Individuals with Down syndrome (Ds) are at increased risk of respiratory infection, aspiration pneumonia, and apnea. The Ts65Dn mouse is a commonly used model of Ds, but there have been no formal investigations of awake breathing and respiratory muscle function in these mice. We hypothesized that breathing would be impaired in Ts65Dn vs. wild-type (WT), and would be mediated by both neural and muscular inputs. Baseline minute ventilation was not different at 3, 6, or 12 mo of age. However, <i>V_T/T_i</i>, a marker of the neural drive to breathe, was lower in Ts65Dn vs. WT and central apneas were more prevalent. The response to breathing hypoxia was not different, but the response to hypercapnia was attenuated, revealing a difference in carbon dioxide sensing, and/or motor output in Ts65Dn. Oxygen desaturations were present in room air, demonstrating that ventilation may not be sufficient to maintain adequate oxygen saturation in Ts65Dn. We observed no differences in arterial <i>P</i>_O2 or <i>P</i>_CO2, but Ts65Dn had lower hemoglobin and hematocrit. A retrospective medical record review of 52,346 Ds and 52,346 controls confirmed an elevated relative risk of anemia in Ds. We also performed eupneic in-vivo electromyography and in-vitro muscle function and histological fiber typing of the diaphragm, and found no difference between strains. Overall, conscious respiration is impaired in Ts65Dn, is mediated by neural mechanisms, and results in reduced hemoglobin saturation. Oxygen carrying capacity is reduced in Ts65Dn vs. WT, and we demonstrate that individuals with Ds are also at increased risk of anemia.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad058"},"PeriodicalIF":0.0,"publicationDate":"2023-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89721633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breast Milk Epidermal Growth Factor Confers Paracellular Calcium Absorption in the Infant Small Intestine.","authors":"Andreanna Burman, Izumi Kaji","doi":"10.1093/function/zqad057","DOIUrl":"10.1093/function/zqad057","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad057"},"PeriodicalIF":0.0,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1a/d5/zqad057.PMC10583193.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49685762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Striatal Dopamine Signals and Reward Learning.","authors":"Pol Bech,&nbsp;Sylvain Crochet,&nbsp;Robin Dard,&nbsp;Parviz Ghaderi,&nbsp;Yanqi Liu,&nbsp;Meriam Malekzadeh,&nbsp;Carl C H Petersen,&nbsp;Mauro Pulin,&nbsp;Anthony Renard,&nbsp;Christos Sourmpis","doi":"10.1093/function/zqad056","DOIUrl":"10.1093/function/zqad056","url":null,"abstract":"Abstract We are constantly bombarded by sensory information and constantly making decisions on how to act. In order to optimally adapt behavior, we must judge which sequences of sensory inputs and actions lead to successful outcomes in specific circumstances. Neuronal circuits of the basal ganglia have been strongly implicated in action selection, as well as the learning and execution of goal-directed behaviors, with accumulating evidence supporting the hypothesis that midbrain dopamine neurons might encode a reward signal useful for learning. Here, we review evidence suggesting that midbrain dopaminergic neurons signal reward prediction error, driving synaptic plasticity in the striatum underlying learning. We focus on phasic increases in action potential firing of midbrain dopamine neurons in response to unexpected rewards. These dopamine neurons prominently innervate the dorsal and ventral striatum. In the striatum, the released dopamine binds to dopamine receptors, where it regulates the plasticity of glutamatergic synapses. The increase of striatal dopamine accompanying an unexpected reward activates dopamine type 1 receptors (D1Rs) initiating a signaling cascade that promotes long-term potentiation of recently active glutamatergic input onto striatonigral neurons. Sensorimotor-evoked glutamatergic input, which is active immediately before reward delivery will thus be strengthened onto neurons in the striatum expressing D1Rs. In turn, these neurons cause disinhibition of brainstem motor centers and disinhibition of the motor thalamus, thus promoting motor output to reinforce rewarded stimulus-action outcomes. Although many details of the hypothesis need further investigation, altogether, it seems likely that dopamine signals in the striatum might underlie important aspects of goal-directed reward-based learning.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 6","pages":"zqad056"},"PeriodicalIF":0.0,"publicationDate":"2023-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10572094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41241713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}