The physiological changes caused by the decline in estrogen levels due to menopause are linked to an increased risk of depression. This study investigated the antidepressant effects of hyperoside ...(HYP), a natural flavonol glycoside, and its associated molecular mechanisms in primary hippocampal neurons and ovariectomized (OVX) mice. HYP treatment increased nitric oxide (NO) production and neuronal nitric oxide synthase (nNOS) expression in primary hippocampal neurons; additionally, it upregulated the expression of brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin receptor kinase B (TrkB). In OVX mice, HYP treatment significantly improved depression-like behaviors in an open field test to a level comparable to estrogen treatment. Furthermore, HYP treatment upregulated OVX-induced decreased nNOS expression and BDNF-TrkB signaling in the hippocampus. Therefore, this study suggests that HYP exhibits antidepressant potential by addressing estrogen deficiency-induced alterations, specifically by restoring nNOS expression, promoting NO production, and concurrently enhancing BDNF-TrkB signaling in OVX mice.
Perturbed cellular protein homeostasis (proteostasis) and mitochondrial dysfunction play an important role in neurodegenerative diseases, however, the interplay between these two phenomena remains ...unclear. Mitochondrial dysfunction leads to a delay in mitochondrial protein import, causing accumulation of non-imported mitochondrial proteins in the cytosol and challenging proteostasis. Cells respond by increasing proteasome activity and molecular chaperones in yeast and C. elegans. Here, we demonstrate that in human cells mitochondrial dysfunction leads to the upregulation of a chaperone HSPB1 and, interestingly, an immunoproteasome-specific subunit PSMB9. Moreover, PSMB9 expression is dependent on the translation elongation factor EEF1A2. These mechanisms constitute a defense response to preserve cellular proteostasis under mitochondrial stress. Our findings define a mode of proteasomal activation through the change in proteasome composition driven by EEF1A2 and its spatial regulation, and are useful to formulate therapies to prevent neurodegenerative diseases.
The study aimed to identify critical factors associated with the surgical stability of pogonion (Pog) by applying machine learning (ML) to predict relapse following two-jaw orthognathic surgery ...(2 J-OGJ). The sample set comprised 227 patients (110 males and 117 females, 207 training and 20 test sets). Using lateral cephalograms taken at the initial evaluation (T0), pretreatment (T1), after (T2) 2 J-OGS, and post treatment (T3), 55 linear and angular skeletal and dental surgical movements (T2-T1) were measured. Six ML modes were utilized, including classification and regression trees (CART), conditional inference tree (CTREE), and random forest (RF). The training samples were classified into three groups; highly significant (HS) (≥ 4), significant (S) (≥ 2 and < 4), and insignificant (N), depending on Pog relapse. RF indicated that the most important variable that affected relapse rank prediction was ramus inclination (RI), CTREE and CART revealed that a clockwise rotation of more than 3.7 and 1.8 degrees of RI was a risk factor for HS and S groups, respectively. RF, CTREE, and CART were practical tools for predicting surgical stability. More than 1.8 degrees of CW rotation of the ramus during surgery would lead to significant Pog relapse.
Oviedomycin is one among several polyketides known for their potential as anticancer agents. The biosynthetic gene cluster (BGC) for oviedomycin is primarily found in Streptomyces antibioticus. ...However, because this BGC is usually inactive under normal laboratory conditions, it is necessary to employ systematic metabolic engineering methods, such as heterologous expression, refactoring of BGCs, and optimization of precursor biosynthesis, to allow efficient production of these compounds. Oviedomycin BGC was captured from the genome of Streptomyces antibioticus by a newly constructed plasmid, pCBA, and conjugated into the heterologous strain, S. coelicolor M1152. To increase the production of oviedomycin, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system was utilized in an in vitro setting to refactor the native promoters within the ovm BGC. The target promoters of refactoring were selected based on examination of factors such as transcription levels and metabolite profiling. Furthermore, genome-scale metabolic simulation was applied to find overexpression targets that could enhance the biosynthesis of precursors or cofactors related to oviedomycin production. The combined approach led to a significant increase in oviedomycin production, reaching up to 670 mg/L, which is the highest titer reported to date. This demonstrates the potential of the approach undertaken in this study. The metabolic engineering approach used in this study led to the successful production of a valuable polyketide, oviedomycin, via BGC cloning, promoter refactoring, and gene manipulation of host metabolism aided by genome-scale metabolic simulation. This approach can be also useful for the efficient production of other secondary molecules encoded by 'silent' BGCs.
Background
Malnutrition plays an essential role in the mechanism of pathogenesis for sarcopenia. In late life, both food consumption and energy intakes decline. One of key factors for reduced energy ...intakes is anorexia of ageing. The aim of this study is to examine the association between anorexia of ageing and sarcopenia among community‐dwelling elderly Japanese individuals.
Methods
This uses population‐based, cross‐sectional cohort study of elderly Japanese individuals. Anorexia of ageing was assessed via a simplified nutritional appetite questionnaire. Handgrip strength and walking speed were tested, and skeletal muscle mass was assessed using a bio‐impedance analysis device. Subjects with sarcopenia were defined as those who met the criteria of the Asian Working Group for Sarcopenia. The association between anorexia of ageing and sarcopenia was then analysed via multiple regression analysis.
Results
In total, 9,496 elderly Japanese individuals were evaluated (mean age 74.1 ± 5.4 years; male, 47.0%). The prevalence of anorexia of ageing was 9.8% (n = 927) in the present study. The prevalence of sarcopenia in men was 1.1%, 1.8%, 6.1%, 10.1%, and 21.2% and was 1.6%, 3.3%, 3.6%, 4.8%, and 7.4% in women aged 65–69, 70–74, 75–79, 80–84, and 85 years and older, respectively. The prevalence of anorexia also showed an age‐dependent increase in both sexes (P < 0.001, respectively). The prevalence of anorexia in men was 8.3%, 6.3%, 9.8%, 13.6%, and 12.9% and was 7.9%, 9.4%, 10.5%, 17.6%, and 17.1% in women aged 65–69, 70–74, 75–79, 80–84, and 85 years and older, respectively. In multivariable logistic regression model adjusted for the covariates except for albumin, anorexia of ageing was independently associated with sarcopenia (OR: 1.45, 95% CI: 1.07 to 1.95; P = 0.015). This significant association remained even after adjusting for all covariates including nutritional status (OR: 1.42, 95% CI: 1.06 to 1.92, P = 0.020).
Conclusions
Anorexia of ageing is associated with sarcopenia among Japanese elderly individuals. Further studies are needed to determine whether a causal association exists between anorexia and sarcopenia.
We investigated the physiological changes during the fattening period and production characteristics in Japanese Black steers bred and raised using the typical feeding system in Japan. Here, 21 ...Japanese Black steers aged 12 months were used, with experimental period divided into early (12-14 months of age), middle (15-22 months), and late fattening phases (23-30 months). The liver transcriptome, blood metabolites, hormones, and rumen fermentation characteristics were analyzed. Blood triglyceride and non-esterified fatty acid concentrations increased, whereas blood ketone levels decreased, with fattening phases. Blood insulin increased with fattening phases and was positively correlated with carcass weight and marbling in late fattening phases. Rumen fermentation characteristics showed high propionate levels and low butyrate levels in late fattening phases, likely due to increased energy intake. Genes related to glucose metabolism, such as SESN3, INSR, LEPR, and FOXO3, were down-regulated in late fattening phases. Genes related to lipid metabolism, such as FABP4, were up-regulated, whereas FADS1 and FADS2 were down-regulated. These findings suggest that the physiological changes resulted from changes in the energy content and composition of diets. Liver metabolism changed with changes in fat metabolism. Insulin was strongly associated with physiological changes and productivity in Japanese Black cattle.
The triple oxygen isotopes (16O, 17O, and 18O) are very useful in hydrological and climatological studies because of their sensitivity to environmental conditions. This review presents an overview of ...the published literature on the potential applications of 17O in hydrological studies. Dual-inlet isotope ratio mass spectrometry and laser absorption spectroscopy have been used to measure 17O, which provides information on atmospheric conditions at the moisture source and isotopic fractionations during transport and deposition processes. The variations of δ17O from the developed global meteoric water line, with a slope of 0.528, indicate the importance of regional or local effects on the 17O distribution. In polar regions, factors such as the supersaturation effect, intrusion of stratospheric vapor, post-depositional processes (local moisture recycling through sublimation), regional circulation patterns, sea ice concentration and local meteorological conditions determine the distribution of 17O-excess. Numerous studies have used these isotopes to detect the changes in the moisture source, mixing of different water vapor, evaporative loss in dry regions, re-evaporation of rain drops during warm precipitation and convective storms in low and mid-latitude waters. Owing to the large variation of the spatial scale of hydrological processes with their extent (i.e., whether the processes are local or regional), more studies based on isotopic composition of surface and subsurface water, convective precipitation, and water vapor, are required. In particular, in situ measurements are important for accurate simulations of atmospheric hydrological cycles by isotope-enabled general circulation models.
Passive transit-signal priority (TSP) is an effective approach to improve the operational efficiency of transit systems on arterial roads. This paper presents an integrated TSP model that benefits ...both transit vehicles and other road users. The proposed model uses the random arrival characteristics of transit vehicles related to their stochastic dwell times at near-side stops. Thus, it enables not only two-way bandwidth maximization within subsystems but also the combined optimization of adjacent subsystems. To minimize any negative impact on side-street traffic, this study, unlike previous research, considers the influential area by the introduction of TSP. Case studies on 15 intersections in Sejong, Korea, verify the superior performance of the proposed model for both transit and general vehicles.
Formalin-fixed, paraffin-embedded (FFPE) tissue specimens are routinely used in pathological diagnosis, but their large number of artifactual mutations complicate the evaluation of companion ...diagnostics and analysis of next-generation sequencing data. Identification of variants with low allele frequencies is challenging because existing FFPE filtering tools label all low-frequency variants as artifacts. To address this problem, we aimed to develop DEEPOMICS FFPE, an AI model that can classify a true variant from an artifact. Paired whole exome sequencing data from fresh frozen and FFPE samples from 24 tumors were obtained from public sources and used as training and validation sets at a ratio of 7:3. A deep neural network model with three hidden layers was trained with input features using outputs of the MuTect2 caller. Contributing features were identified using the SHapley Additive exPlanations algorithm and optimized based on training results. The performance of the final model (DEEPOMICS FFPE) was compared with those of existing models (MuTect filter, FFPolish, and SOBDetector) by using well-defined test datasets. We found 41 discriminating properties for FFPE artifacts. Optimization of property quantification improved the model performance. DEEPOMICS FFPE removed 99.6% of artifacts while maintaining 87.1% of true variants, with an F1-score of 88.3 in the entire dataset not used for training, which is significantly higher than those of existing tools. Its performance was maintained even for low-allele-fraction variants with a specificity of 0.995, suggesting that it can be used to identify subclonal variants. Different from existing methods, DEEPOMICS FFPE identified most of the sequencing artifacts in the FFPE samples while retaining more of true variants, including those of low allele frequencies. The newly developed tool DEEPOMICS FFPE may be useful in designing capture panels for personalized circulating tumor DNA assay and identifying candidate neoepitopes for personalized vaccine design. DEEPOMICS FFPE is freely available on the web ( http://deepomics.co.kr/ffpe ) for research.
The formation of epithelial tissues containing lumens requires not only the apical-basolateral polarization of cells, but also the coordinated orientation of this polarity such that the apical ...surfaces of neighboring cells all point toward the central lumen. Defects in extracellular matrix (ECM) signaling lead to inverted polarity so that the apical surfaces face the surrounding ECM. We report a molecular switch mechanism controlling polarity orientation. ECM signals through a β1-integrin/FAK/p190RhoGAP complex to downregulate a RhoA/ROCK/Ezrin pathway at the ECM interface. PKCβII phosphorylates the apical identity-promoting Podocalyxin/NHERF1/Ezrin complex, removing Podocalyxin from the ECM-abutting cell surface and initiating its transcytosis to an apical membrane initiation site for lumen formation. Inhibition of this switch mechanism results in the retention of Podocalyxin at the ECM interface and the development instead of collective front-rear polarization and motility. Thus, ECM-derived signals control the morphogenesis of epithelial tissues by controlling the collective orientation of epithelial polarization.
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•β1-integrin suppresses RhoA activity at the ECM interface•RhoA promotes collective front-rear polarity and motility•PKCβII antagonizes apical domain formation at the ECM interface•Apical domain components are restabilized at the lumen initiation site
Bryant et al. uncover a pathway controlling apical-basal polarity orientation in 3D culture. Beta1-integrins sense ECM to control the spatiotemporal RhoA activity. Inappropriate RhoA activity at the ECM interface causes stabilization of apical proteins at the ECM interface and collective front-rear polarity, rather than forming a lumen in 3D culture.