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Autophagy is an evolutionarily conserved catabolic process that involves the invagination and degradation of cytoplasmic components through an autophagosomelysosome track. Autophagy functions as a quality control of cellular milieu and is implicated in a wide variety of pathological conditions. However, excessive or imbalanced autophagic flux may also be associated with cellular toxicity and may potentially contribute to the development of pathological conditions. Just as all membrane trafficking systems need to constantly strike a balance in their level of activation and inhibition to ensure proper spatial and temporal delivery of their cargo, autophagy must also be tightly regulated. Here, we provide an overview of the current knowledge regarding the negative regulation of mammalian autophagy in an effort to understand its physiological relevance and potential clinical importance.

Despite the recognized impact of intrinsic capacity (IC) impairment on healthy aging, international comparisons in different sociocultural contexts are scarce. This study aimed to compare IC impairment among community-dwelling older adults in Japan and Taiwan to explore the context of healthy aging in different countries. Comparative observational study. National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) in Japan and Longitudinal Aging Study of Taipei (LAST) in Taiwan. 794 individuals (age range, 60.0–86.5 years) from NILS-LSA and 1,358 (60.0–96.7 years) from LAST. IC impairment was evaluated across the domains of locomotion, cognition, vitality, sensory capacity, and psychological well-being. Participants were categorized as having impaired IC or healthy. We investigated associations between IC impairment, falls, and all-cause mortality. IC impairment was present in 54.9% and 37.3% of participants in the NILS-LSA and LAST cohorts, respectively. Male NILS-LSA participants with impaired IC (odds ratio [OR]:1.50, 95% confidence interval [CI]:1.03–2.20), with hearing loss (OR:1.98, 95% CI:1.00–3.90) were more likely to fall. In LAST, impaired locomotion (OR:2.14, 95% CI:1.46–3.14) increased the risk of falls. Men with impaired IC (hazard ratio [HR]; 2.14, 95% CI.10–4.15) and visual impairment (HR:2.21, 95% CI:1.15–4.25) and women with impaired psychological well-being (HR:4.94, 95% CI:1.28–18.97) in the NILS-LSA cohort had greater risk for all-cause mortality; however, this was not shown for LAST participants. The prevalence and distribution of IC impairment and associated biomarkers differed significantly between participants in Japan and Taiwan. However, the associations with adverse outcomes remained similar, emphasizing the need for tailored interventions for healthy aging.

Prohibitin (PHB) is indispensable for Ras-induced Raf-1 activation, cell migration and growth; however, the exact role of PHB in the molecular pathogenesis of cancer metastasis remains largely unexamined. Here, we found a positive correlation between plasma membrane-associated PHB and the clinical stages of cancer. The level of PHB phosphorylated at threonine 258 (T258) and tyrosine 259 (Y259) in human cancer-cell membranes correlated with the invasiveness of cancer cells. Overexpression of phosphorylated PHB (phospho-PHB) in the lipid-raft domain of the cell membrane enhanced cell migration/invasion through PI3K/Akt and Raf-1/ERK activation. It also enhanced epithelial–mesenchymal transition, matrix metalloproteinase-2 activity and invasiveness of cancer cells in vitro . Immunoprecipitation analysis demonstrated that phospho-PHB associated with Raf-1, Akt and Ras in the membrane and was essential for the activation of Raf-1 signaling by Ras. Mice implanted with cancer cells stably overexpressing PHB in the plasma membrane showed enlarged cervical tumors, enhanced metastasis and shorter survival time compared with mice implanted with cancer cells without PHB overexpression. Dephosphorylation of PHB at T258 by site-directed mutagenesis diminished the in vitro and in vivo effects of PHB. These results suggest that increase in phospho-PHB T258 in the raft domain of the plasma membrane has a role in the Ras-driven activation of PI3K/Akt and Raf-1/ERK-signaling cascades and results in the promotion of cancer metastasis.

SummaryA considerable proportion of stroke survivors are prescribed with proton pump inhibitors (PPIs). Our study indicated that PPI use is associated with an increased risk of osteoporosis, hip fracture, and vertebral fracture in stroke patients. The risk tends to increase as the cumulative doses of PPIs increase.IntroductionA considerable proportion of stroke survivors are prescribed with proton pump inhibitors (PPIs). Our study investigated the association between PPI use and the risk of osteoporosis and fracture among stroke survivors.MethodsA population-based propensity-matched retrospective cohort study was conducted using the National Health Insurance Research Database in Taiwan. Patients diagnosed with a new stroke between 2000 and 2012 were identified. After propensity score matching, 10,596 patients were enrolled, and 5298 patients were each assigned to the PPI user and non-user groups. Hazard ratios (HRs) were calculated for the risk of osteoporosis, hip fracture, and vertebral fractures according to PPI use or non-use. Sensitivity analyses were conducted to evaluate the dose effects of PPI.ResultsPPI use after stroke was associated with an increased risk of osteoporosis, hip fracture, or vertebral fracture, with an adjusted HR (aHR) of 1.28 (P < 0.001). The aHRs were also significant for each outcome: osteoporosis, 1.26 (P < 0.001); hip fracture, 1.18 (P = 0.048); vertebral fracture, 1.33 (P < 0.001). A pattern of dose effect was identified. For any event (osteoporosis/hip fracture/vertebral fracture), the aHR for PPI use of 1–90, 91–365, and > 365 cDDDs was 1.22 (P < 0.001), 1.27 (P < 0.001), and 1.66 (P < 0.001), respectively. For each outcome, the highest dose was associated with the highest risk, with aHR of 1.79 (P < 0.001), 1.41 (P = 0.039), and 1.82 (P < 0.001) for osteoporosis, hip fracture, and vertebral fracture, respectively. Age- and sex-stratified analyses revealed similar patterns.ConclusionsPPI use is associated with an increased risk of osteoporosis, hip fracture, and vertebral fracture in stroke patients.

Maximizing the power delivered by a thermoelectric generator (TEG) (with an internal resistance R TE ) can be achieved by optimizing its design taking into account the external load (with a resistance of R L ). In the present work, the evolution of the thermoelectric (TE) properties of the materials along the leg was considered. By considering a fixed heat rate on the hot side, the powers delivered by various TEGs were assessed by varying the length of the legs. After that, analytical approach was detailed based on the mathematical formulas governing the thermal and electrical transports. This approach revealed that the ratio m  =  R L /R TE is between the most commonly claimed values (1 and (1 +  zT ) 1/2 ). Our variable properties model reveals that the optimal design requires lower cost than that considered by equaling R TE and R L ( m  = 1). This finding turns out to be more and more valid for materials which present a linear variation of temperature with position.

Background Accurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients’ treatment. The current heavy workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on daily image analyses. Methods Based on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC diagnosis using weakly labeled pathological whole-slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, > 14,680 WSIs, from > 9631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, the USA, and Germany. Results Our innovative AI tool consistently and nearly perfectly agreed with (average Kappa statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multicenters. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.988 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells. Conclusions This first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. It will drastically alleviate the heavy clinical burden of daily pathology diagnosis and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.

This study aims to assess the effectiveness of a multidomain intervention program on the change in functional status of hospitalized older adults. This single-arm, prospective, non-randomized interventional study investigates the efficacy of a multidomain interventional program including cognitive stimulation activity, simple exercises, frailty education, and nutrition counseling. At a tertiary hospital in southern Taiwan, 352 eligible patients were sequentially enrolled. Included patients were aged ≥65 years (mean age, 79.6 ± 9.0 years; 62% male), scored 3–7 on the Clinical Frailty Scale (CFS), and were hospitalized in the geriatric acute ward. Those receiving standard care (physical rehabilitation and nutrition counseling) during January–July 2019 composed the historical control group. Those receiving the multidomain intervention during August–December 2019 composed the intervention group. The primary outcome was the change in activities of daily life (ADL) and frailty status, as assessed by Katz Index and Clinical Frailty Scale, with using the generalized estimating equation model. The length of hospital stay, medical costs, and re-admission rates were secondary outcomes. Participants undergoing intervention (n = 101; 27.9%) showed greater improvements in the ADL and CFS during hospitalization (ADL adjusted estimate, 0.61; 95% CI, 0.11–1.11; p = 0.02; CFS adjusted estimate, −1.11; 95% CI, −1.42–−0.80; p < 0.01), shorter length of hospital stay (adjusted estimate, -5.00; 95% CI, −7.99–−2.47; p < 0.01), lower medical costs (adjusted estimate, 0.58; 95% CI, 0.49–0.69; p < 0.01), and lower 30- and 90-day readmission rates (30-day adjusted OR [aOR], 0.12; 95% CI, 0.27–0.50; p < 0.01; 60-day aOR, 0.04; 95% CI, 0.01–0.33; p < 0.01) than did controls. Participation in the multidomain intervention program during hospitalization improved the functional status and decreased the hospital stay length, medical costs, and readmission rates of frail older people.

To discern the diagnostic accuracy between the updated diagnostic consensus of the Asian Working Group for Sarcopenia (AWGS) in 2019 (AWGS 2019) and the previous AWGS 2014 guidelines. A prospective population-based cohort study. The study included 731 older community-dwelling adults aged ≥ 65 years who participated in face-to-face interviews and were followed up for 11-year mortality until 31 Mar 2022. We utilized a handgrip strength dynamometer to measure participants' muscle strength, while their walking speed was determined by a timed 6-meter walk test at their usual pace. Additionally, muscle mass was measured using dual-energy X-ray absorptiometry scanning. Sarcopenia was defined as the presence of low muscle mass in combination with weakness and/or slowness both by AWGS 2014 and 2019 criteria. The present study followed 731 participants (mean age 73.4 ± 5.4 years, men predominant 52.8%) over a period of 11 years, yielding 5927 person-years and 159 deaths. Prevalence of sarcopenia defined by AWGS 2019 and 2014 criteria were 8.5% and 6.8%, respectively. Sarcopenia defined by AWGS 2019 (HR 1.62, 95% CI 1.04–2.54, p=0.034) but not AWGS 2014 was significantly associated with mortality in community-living older adults after adjusting for potential confounders such as age, sex, education, drinking, disease burden and serum level of testosterone. The study also found that the AWGS 2019 criteria had a better model fitness than AWGS 2014 criteria in predicting mortality. AWGS 2019 criteria outperformed AWGS 2014 in identifying sarcopenia risk and predicting mortality. Screening for sarcopenia in older adults may improve health outcomes by identifying those at increased mortality risk.

Dengue virus (DENV) infection is a major cause of acute febrile illness in Indonesia. Diagnostic inaccuracy may occur due to its varied and non-specific presentation. Characterization of DENV epidemiology, clinical presentation, and virology will facilitate appropriate clinical management and public health policy. A multicenter observational cohort study was conducted in Indonesia to assess causes of acute fever requiring hospitalization. Clinical information and specimens were collected at enrollment, 14-28 days, and 3 months from 1,486 children and adults. Total of 468 (31.9%) cases of DENV infection were confirmed by reference laboratory assays. Of these, 414 (88.5%) were accurately diagnosed and 54 had been misdiagnosed as another infection by sites. One hundred initially suspected dengue cases were finally classified as 'non-dengue'; other pathogens were identified in 58 of those cases. Mortality of DENV infection was low (0.6%). Prior DENV exposure was found in 92.3% of subjects >12 years. DENV circulated year-round in all cities, with higher incidence from January to March. DENV-3 and DENV-1 were the predominant serotypes. This study identified DENV-1 with TS119(C→T) substitution in the serotyping primer annealing site, leading to failure of serotype determination. DENV is a common etiology of acute febrile illness requiring hospitalization in Indonesia. Diagnostic accuracy at clinical sites merits optimization since misdiagnosis of DENV infection and over-estimation of dengue can negatively impact management and outcomes. Mutation at the annealing site of the serotyping primer may confound diagnosis. Clinicians should consider following diagnostic algorithms that include DENV confirmatory testing. Policy-makers should prioritize development of laboratory capacity for diagnosis of DENV.

The organic matter of living plants is the precursor material of the organic matter stored in terrestrial soil ecosystems. Although a great deal of knowledge exists on the carbon turnover processes of plant material, some of the processes of soil organic matter (SOM) formation, in particular from microbial necromass, are still not fully understood. Recent research showed that a larger part of the original plant matter is converted into microbial biomass, while the remaining part in the soil is modified by extracellular enzymes of microbes. At the end of its life, microbial biomass contributes to the microbial molecular imprint of SOM as necromass with specific properties. Next to appropriate environmental conditions, heterotrophic microorganisms require energy-containing substrates with C, H, O, N, S, P, and many other elements for growth, which are provided by the plant material and the nutrients contained in SOM. As easily degradable substrates are often scarce resources in soil, we can hypothesize that microbes optimize their carbon and energy use. Presumably, microorganisms are able to mobilize biomass building blocks (mono and oligomers of fatty acids, amino acids, amino sugars, nucleotides) with the appropriate stoichiometry from microbial necromass in SOM. This is in contrast to mobilizing only nutrients and consuming energy for new synthesis from primary metabolites of the tricarboxylic acid cycle after complete degradation of the substrates. Microbial necromass is thus an important resource in SOM, and microbial mining of building blocks could be a life strategy contributing to priming effects and providing the resources for new microbial growth cycles. Due to the energy needs of microorganisms, we can conclude that the formation of SOM through microbial biomass depends on energy flux. However, specific details and the variability of microbial growth, carbon use and decay cycles in the soil are not yet fully understood and linked to other fields of soil science. Here, we summarize the current knowledge on microbial energy gain, carbon use, growth, decay, and necromass formation for relevant soil processes, e. g. the microbial carbon pump, C storage, and stabilization. We highlight the factors controlling microbial necromass contribution to SOM and the implications for soil carbon use efficiency (CUE) and we identify research needs for process-based SOM turnover modelling and for understanding the variability of these processes in various soil types under different climates.