Decoding the role of gut microbiota in Alzheimer’s pathogenesis and envisioning future therapeutic avenues

Alzheimer’s disease (AD) emerges as a perturbing neurodegenerative malady, with a profound comprehension of its underlying pathogenic mechanisms continuing to evade our intellectual grasp. Within the intricate tapestry of human health and affliction, the enteric microbial consortium, ensconced within the milieu of the human gastrointestinal tract, assumes a role of cardinal significance. Recent epochs have borne witness to investigations that posit marked divergences in the composition of the gut microbiota between individuals grappling with AD and those favored by robust health. The composite vicissitudes in the configuration of the enteric microbial assembly are posited to choreograph a participatory role in the inception and progression of AD, facilitated by the intricate conduit acknowledged as the gut-brain axis. Notwithstanding, the precise nature of this interlaced relationship remains enshrouded within the recesses of obscurity, poised for an exhaustive revelation. This review embarks upon the endeavor to focalize meticulously upon the mechanistic sway exerted by the enteric microbiota upon AD, plunging profoundly into the execution of interventions that govern the milieu of enteric microorganisms. In doing so, it bestows relevance upon the therapeutic stratagems that form the bedrock of AD’s management, all whilst casting a prospective gaze into the horizon of medical advancements

Comparative analysis of the effect of electromyogram to bispectral index and 95% spectral edge frequency under remimazolam and propofol anesthesia: a prospective, randomized, controlled clinical trial

BackgroundBispectral index (BIS), an index used to monitor the depth of anesthesia, can be interfered with by the electromyogram (EMG) signal. The 95% spectral edge frequency (SEF95) also can reflect the sedation depth. Remimazolam in monitored anesthesia care results in higher BIS values than propofol, though in the same sedation level assessed by Modified Observers Assessment of Alertness and Sedation (MOAA/S). Our study aims to illustrate whether EMG is involved in remimazolam causing higher BIS value than propofol preliminarily and to explore the correlations among BIS, EMG, and SEF95 under propofol and remimazolam anesthesia.Patients and methodsTwenty-eight patients were randomly divided into propofol (P) and remimazolam (RM) groups. Patients in the two groups received alfentanil 10 μg/kg, followed by propofol 2 mg/kg and remimazolam 0.15 mg/kg. Blood pressure (BP), heart rate (HR), and oxygen saturation (SpO2) were routinely monitored. The BIS, EMG, and SEF95 were obtained through BIS VISTATM. The primary outcomes were BIS, EMG, and the correlation between BIS and EMG in both groups. Other outcomes were SEF95, the correlation between BIS and SEF95, and the correlation between EMG and SEF95. And all the statistical and comparative analysis between these signals was conducted with SPSS 26.0 and GraphPad Prism 8.ResultsBIS values, EMG, and SEF95 were significantly higher in the RM group than in the P group (all p < 0.001). There was a strong positive correlation between BIS and EMG in the RM group (r = 0.416). Nevertheless, the BIS in the P group showed a weak negative correlation with EMG (r = −0.219). Both P (r = 0.787) and RM group (r = 0.559) had a reasonably significant correlation coefficient between BIS and SEF95. SEF95 almost did not correlate with EMG in the RM group (r = 0.101).ConclusionBispectral index can be interfered with high EMG intensity under remimazolam anesthesia. However, EMG can hardly affect the accuracy of BIS under propofol anesthesia due to low EMG intensity and a weak negative correlation between EMG and BIS. Moreover, SEF95 may have a great application prospect in predicting the sedation condition of remimazolam

Combined network analysis and interpretable machine learning reveals the environmental adaptations of more than 10,000 ruminant microbial genomes

BackgroundThe ruminant gastrointestinal contains numerous microbiomes that serve a crucial role in sustaining the host’s productivity and health. In recent times, numerous studies have revealed that variations in influencing factors, including the environment, diet, and host, contribute to the shaping of gastrointestinal microbial adaptation to specific states. Therefore, understanding how host and environmental factors affect gastrointestinal microbes will help to improve the sustainability of ruminant production systems.ResultsBased on a graphical analysis perspective, this study elucidates the microbial topology and robustness of the gastrointestinal of different ruminant species, showing that the microbial network is more resistant to random attacks. The risk of transmission of high-risk metagenome-assembled genome (MAG) was also demonstrated based on a large-scale survey of the distribution of antibiotic resistance genes (ARG) in the microbiota of most types of ecosystems. In addition, an interpretable machine learning framework was developed to study the complex, high-dimensional data of the gastrointestinal microbial genome. The evolution of gastrointestinal microbial adaptations to the environment in ruminants were analyzed and the adaptability changes of microorganisms to different altitudes were identified, including microbial transcriptional repair.ConclusionOur findings indicate that the environment has an impact on the functional features of microbiomes in ruminant. The findings provide a new insight for the future development of microbial resources for the sustainable development in agriculture

HIPK1 Inhibition Protects against Pathological Cardiac Hypertrophy by Inhibiting the CREB-C/EBPβ Axis

Inhibition of pathological cardiac hypertrophy is recognized as an important therapeutic strategy for heart failure, although effective targets are still lacking in clinical practice. Homeodomain interacting protein kinase 1 (HIPK1) is a conserved serine/threonine kinase that can respond to different stress signals, however, whether and how HIPK1 regulates myocardial function is not reported. Here, it is observed that HIPK1 is increased during pathological cardiac hypertrophy. Both genetic ablation and gene therapy targeting HIPK1 are protective against pathological hypertrophy and heart failure in vivo. Hypertrophic stress-induced HIPK1 is present in the nucleus of cardiomyocytes, while HIPK1 inhibition prevents phenylephrine-induced cardiomyocyte hypertrophy through inhibiting cAMP-response element binding protein (CREB) phosphorylation at Ser271 and inactivating CCAAT/enhancer-binding protein β (C/EBPβ)-mediated transcription of pathological response genes. Inhibition of HIPK1 and CREB forms a synergistic pathway in preventing pathological cardiac hypertrophy. In conclusion, HIPK1 inhibition may serve as a promising novel therapeutic strategy to attenuate pathological cardiac hypertrophy and heart failure

Long Noncoding RNA ANPODRT Overexpression Protects Nucleus Pulposus Cells from Oxidative Stress and Apoptosis by Activating Keap1-Nrf2 Signaling

Oxidative stress and subsequent nucleus pulposus (NP) cell apoptosis are important contributors to the development of intervertebral disc degeneration (IDD). Emerging evidences show that long noncoding RNAs (lncRNAs) play a role in the pathogenesis of IDD. In this study, we investigated the role of lncRNA ANPODRT (anti-NP cell oxidative damage-related transcript) in oxidative stress and apoptosis in human NP cells. We found that ANPODRT was downregulated in degenerative NP tissues and in NP cells treated with tert-butyl hydroperoxide (TBHP, the oxidative stress inducer). ANPODRT overexpression alleviated oxidative stress and apoptosis in NP cells exposed to TBHP, while ANPODRT knockdown exerted opposing effects. Mechanistically, ANPODRT facilitated nuclear factor E2-related factor 2 (Nrf2) accumulation and nuclear translocation and activated its target genes by disrupting the kelch-like ECH-associated protein 1- (Keap1-) Nrf2 association in NP cells. Nrf2 knockdown abolished the antioxidative stress and antiapoptotic effects of ANPODRT in NP cells treated with TBHP. Collectively, our findings suggest that ANPODRT protects NP cells from oxidative stress and apoptosis, at least partially, by activating Nrf2 signaling, implying that ANPODRT may be a potential therapeutic target for IDD

SMAX1-LIKE7 Signals from the Nucleus to Regulate Shoot Development in Arabidopsis via Partially EAR Motif-Independent Mechanisms.

Strigolactones (SLs) are hormonal signals that regulate multiple aspects of shoot architecture, including shoot branching. Like many plant hormonal signaling systems, SLs act by promoting ubiquitination of target proteins and their subsequent proteasome-mediated degradation. Recently, SMXL6, SMXL7, and SMXL8, members of the SMAX1-LIKE (SMXL) family of chaperonin-like proteins, have been identified as proteolytic targets of SL signaling in Arabidopsis thaliana However, the mechanisms by which these proteins regulate downstream events remain largely unclear. Here, we show that SMXL7 functions in the nucleus, as does the SL receptor, DWARF14 (D14). We show that nucleus-localized D14 can physically interact with both SMXL7 and the MAX2 F-box protein in a SL-dependent manner and that disruption of specific conserved domains in SMXL7 affects its localization, SL-induced degradation, and activity. By expressing and overexpressing these SMXL7 protein variants, we show that shoot tissues are broadly sensitive to SMXL7 activity, but degradation normally buffers the effect of increasing SMXL7 expression. SMXL7 contains a well-conserved EAR (ETHYLENE-RESPONSE FACTOR Amphiphilic Repression) motif, which contributes to, but is not essential for, SMXL7 functionality. Intriguingly, different developmental processes show differential sensitivity to the loss of the EAR motif, raising the possibility that there may be several distinct mechanisms at play downstream of SMXL7.European Research Council (Grant ID: 294514– EnCoDe), Gatsby Foundation (Grant ID: GAT3272C), Chinese Government Scholarship PhD Program (Sichuan Agriculture University)This is the author accepted manuscript. The final version is available from the American Society of Plant Biologists via http:/​/​dx.​doi.​org/​10.1105/tpc.16.0028

Association between Bullying Victimization and Symptoms of Depression among Adolescents: A Moderated Mediation Analysis

Background: Bullying victimization and its effect on symptoms of depression have received attention from researchers, but few studies have considered the potential mechanism. The aim of this study was to examine a moderated mediation model for the association between bullying victimization and depressive symptoms in terms of it being mediated by social anxiety, and investigated whether sleep duration would show moderating effects in this relationship. Methods: In this study, there were 2956 students, who completed three questionnaires, including a bullying victimization scale, as well as a social anxiety and epidemiologic studies depression scale. Results: Bullying victimization’s effects on depressive symptoms were mediated by social anxiety. Furthermore, sleep duration moderated the relationship between bullying victimization and depressive symptoms. Conclusions: The research contributes by clarifying the mechanisms underlying the relationship between bullying victimization and depressive symptoms