impaired

摘要： Mitochondria dysfunction occurs in the aging brain as well as in several neurodegenerative disorders and predisposes neuronal cells to enhanced sensitivity to neurotoxins.In particular,defects in any of the mitochondria respiratory chain complexes lead to impaired adenosine triphosphate production resulting in diseases that often affect the central nervous system.For instance,innate deficits in succinate dehydrogenase(SDH)mitochondria respiratory chain complex II activity caused by genetic mutations in SDH subunits lead to early-onset neurodegeneration(Jain-Ghai et al.,2013),while several adult-onset genetic neurodegenerative disorders are associated with variable levels of complex II deficiency in the central nervous system(Túnez et al.,2010).Also,chemically induced complex II deficiency leads to neurodegeneration.

摘要： The brain has a high metabolic rate and consumes approximately 20%of the total energy in the body at any given time.Although it requires a large amount of energy to function,the brain cannot store significant amounts of energy making it exquisitely dependent on constant nutrient supply via blood flow.When blood flow to the brain is impaired,such as during stroke,there are rapid and severe consequences for the neurons that depend on this constant energy supply.

摘要： Dear editor,Necrotizing fasciitis is a relatively rare,rapidly advancing,infectious disease with high lethality.[1]It is characterized by subcutaneous and fascial tissue necrosis and can even extend to involve skin and muscle.[2]The initial spread along fascial planes with little visual evidence impedes the crucial early diagnosis.Patients often report minor or major trauma preceding the infection,yet in some cases,the disease develops idiopathically.[3]Risk factors,including older age,diabetes,chronic renal failure,and obesity,predispose to impaired immunity and loss of physiological barriers.[2]

摘要： A German couple who have helped China’s hearing-impaired for 20 years.AT the start of every work day, Uwe Brutzer writes down the quantity and ingredients required for making the bread and desserts of that day on a board in the kitchen of his Bach’s Bakery. During work hours, amid the sounds of the machines, the bakery kitchen is especially orderly and quiet.

摘要： BACKGROUND Mutation in the titin gene(TTN)in left ventricular noncompaction(LVNC)has been reported with a highly heterogeneous prevalence,and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacteri-zed.In the present study,we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies.METHODS The whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autoso-mal dominant LVNC cardiomyopathy.The clustered regularly interspaced short palindromic repeats associated protein 9(CRISPR/Cas9)technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro,in which functional studies were carried out and characterized in comparison to its wild-type counterpart.RESULTS A novel truncating mutation TTN p.R2021X was identified as the only plausible disease-causing variant that segreg-ated with disease among the five surviving affected individuals,with an interrogation of the entire genome excluding other po-tential causes.Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haplo-insufficient disease mechanism in titin truncation mutation cardiomyocytes.Further functional studies suggested mitochondrial abnormities in the presence of mutation,including decreased oxygen consumption rate,reduced adenosine triphosphate produc-tion,impaired activity of electron translation chain,and abnormal mitochondrial structure on electron microscopy.Impaired aut-ophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p.R2021X truncation mutation cardiomyocytes.CONCLUSIONS The TTN p.R2021X mutation has a function in the cause of a highly penetrant familial LVNC.These findings expand the spectrum of titin’s roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.

摘要： Anorexia and fasting are host adaptations to acute infection, inducing a metabolic switch towards ketogenesis and the production of ketone bodies, including β-hydroxybutyrate (BHB) 1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we report impaired production of BHB in humans with SARS-CoV-2-induced but not influenza-induced acute respiratory distress syndrome (ARDS). CD4^(+) T cell function is impaired in COVID-19 and BHB promotes both survival and production of Interferon-γ from CD4^(+) T cells. Using metabolic tracing analysis, we uncovered that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but can be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality.

摘要： Mutations of the ADAR1 gene encoding an RNA deaminase cause severe diseases associated with chronic activation of type I interferon(IFN)responses,including Aicardi-Goutières syndrome and bilateral striatal necrosis1-3.The IFN-inducible p150 isoform of ADAR1 contains a Zαdomain that recognizes RNA with an alternative left-handed double-helix structure,termed Z-RNA4,5.Hemizygous ADAR1 mutations in the Zαdomain cause type I IFN-mediated pathologies in humans2,3 and mice6-8;however,it remains unclear how the interaction of ADAR1 with Z-RNA prevents IFN activation.Here we show that Z-DNA-binding protein 1(ZBP1),the only other protein in mammals known to harbour Zαdomains9,promotes type I IFN activation and fatal pathology in mice with impaired ADAR1 function.ZBP1 deficiency or mutation of its Zαdomains reduced the expression of IFN-stimulated genes and largely prevented early postnatal lethality in mice with hemizygous expression of ADAR1 with mutated Zαdomain(Adar1mZα/-mice).Adar1mZα/-mice showed upregulation and impaired editing of endogenous retroelement-derived complementary RNA reads,which represent a likely source of Z-RNAs activating ZBP1.

摘要： A new study has demonstrated that the microbiome in the gastrointestinal system has a massive influence on the likelihood of getting a risk of serious complications,sometimes including autoimmune disorders,metabolic syndrome,impaired glucose tolerance,cerebrovascular disease,and various cancers[1].A growing body of evidence suggests that the microbiome develops in large part as a result of the foods we eat,with experiments showing that even small changes in diet may have major and short-lived effects on bacteria.Again,because of this deeper connection,altering the microbial community structure via a diet program just might have a significant positive impact on clinical effectiveness[2].Specialists became particularly inclined to reassess the effect food provided might have on the microbiome of the hypervisor by quickly assessing and evaluating the microbial communities ubiquitous in the human digestive system.

摘要： Mechanical stimulation plays an important role in bone remodeling. Exercise-induced mechanical loading enhances bone strength,whereas mechanical unloading leads to bone loss. Increasing evidence has demonstrated that long noncoding RNAs(lnc RNAs) play key roles in diverse biological, physiological and pathological contexts. However, the roles of lnc RNAs in mechanotransduction and their relationships with bone formation remain unknown. In this study, we screened mechanosensing lnc RNAs in osteoblasts and identified Neat1, the most clearly decreased lnc RNA under simulated microgravity. Of note, not only Neat1 expression but also the specific paraspeckle structure formed by Neat1 was sensitive to different mechanical stimulations, which were closely associated with osteoblast function. Paraspeckles exhibited small punctate aggregates under simulated microgravity and elongated prolate or larger irregular structures under mechanical loading. Neat1 knockout mice displayed disrupted bone formation, impaired bone structure and strength, and reduced bone mass. Neat1 deficiency in osteoblasts reduced the response of osteoblasts to mechanical stimulation. In vivo, Neat1 knockout in mice weakened the bone phenotypes in response to mechanical loading and hindlimb unloading stimulation. Mechanistically, paraspeckles promoted nuclear retention of E3 ubiquitin ligase Smurf1 m RNA and downregulation of their translation, thus inhibiting ubiquitination-mediated degradation of the osteoblast master transcription factor Runx2, a Smurf1 target. Our study revealed that Neat1 plays an essential role in osteoblast function under mechanical stimulation, which provides a paradigm for the function of the lnc RNA-assembled structure in response to mechanical stimulation and offers a therapeutic strategy for long-term spaceflight-or bedrest-induced bone loss and age-related osteoporosis.

摘要： Periodontal ligament stem cells(PDLSCs) are a key cell type for restoring/regenerating lost/damaged periodontal tissues, including alveolar bone, periodontal ligament and root cementum, the latter of which is important for regaining tooth function. However,PDLSCs residing in an inflammatory environment generally exhibit compromised functions, as demonstrated by an impaired ability to differentiate into cementoblasts, which are responsible for regrowing the cementum. This study investigated the role of mitochondrial function and downstream long noncoding RNAs(lnc RNAs) in regulating inflammation-induced changes in the cementogenesis of PDLSCs. We found that the inflammatory cytokine-induced impairment of the cementogenesis of PDLSCs was closely correlated with their mitochondrial function, and lnc RNA microarray analysis and gain/loss-of-function studies identified GACAT2 as a regulator of the cellular events involved in inflammation-mediated mitochondrial function and cementogenesis.Subsequently, a comprehensive identification of RNA-binding proteins by mass spectrometry(Ch IRP-MS) and parallel reaction monitoring(PRM) assays revealed that GACAT2 could directly bind to pyruvate kinase M1/2(PKM1/2), a protein correlated with mitochondrial function. Further functional studies demonstrated that GACAT2 overexpression increased the cellular protein expression of PKM1/2, the PKM2 tetramer and phosphorylated PKM2, which led to enhanced pyruvate kinase(PK) activity and increased translocation of PKM2 into mitochondria. We then found that GACAT2 overexpression could reverse the damage to mitochondrial function and cementoblastic differentiation of PDLSCs induced by inflammation and that this effect could be abolished by PKM1/2 knockdown. Our data indicated that by binding to PKM1/2 proteins, the lnc RNA GACAT2 plays a critical role in regulating mitochondrial function and cementogenesis in an inflammatory environment.