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Ca2+ overload-induced mitochondrial dysfunction is considered a contributing factor alcohol-associated liver disease pathogenesis. Here the authors report that PDK4 promotes Ca2 + -channelling complex formation at the endoplasmic reticulum-mitochondria contact sites, which contributes to the pathogenesis of alcohol-associated liver disease in studies with male mouse and hepatocyte models.

Summary: Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer’s disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.

Abstract Background Muscle atrophy, leading to muscular dysfunction and weakness, is an adverse outcome of sustained period of glucocorticoids usage. However, the molecular mechanism underlying this detrimental condition is currently unclear. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscle and has been implicated in the pathogenesis of several diseases. The current study was designed to investigated and delineate the role of PDK4 in the context of muscle atrophy, which could be identified as a potential therapeutic avenue to protect against dexamethasone‐induced muscle wasting. Methods The dexamethasone‐induced muscle atrophy in C2C12 myotubes was evaluated at the molecular level by expression of key genes and proteins involved in myogenesis, using immunoblotting and qPCR analyses. Muscle dysfunction was studied in vivo in wild‐type and PDK4 knockout mice treated with dexamethasone (25 mg/kg body weight, i.p., 10 days). Body weight, grip strength, muscle weight and muscle histology were assessed. The expression of myogenesis markers were analysed using qPCR, immunoblotting and immunoprecipitation. The study was extended to in vitro human skeletal muscle atrophy analysis. Results Knockdown of PDK4 was found to prevent glucocorticoid‐induced muscle atrophy and dysfunction in C2C12 myotubes, which was indicated by induction of myogenin (0.3271 ± 0.102 vs 2.163 ± 0.192, ****P

Age-related macular degeneration (AMD), especially neovascular AMD with choroidal neovascularization (CNV), is the leading cause of blindness in the elderly. Although matrix metalloproteinases (MMPs) are involved in pathological ocular angiogenesis, including CNV, the cellular origin of MMPs in AMD remains unknown. The present study investigated the role of microglial MMPs in CNV. MMP activities were analyzed by gelatin zymography in aqueous humor samples from patients with CNV and laser-induced CNV mice. Active MMP-9 was increased in the aqueous humor samples from neovascular AMD patients compared with control subjects. In the retinal pigment epithelium (RPE)/choroid from CNV mice, active MMP-9 increased, beginning 1 h post-CNV induction, and remained upregulated until Day 7. In RPE/choroid from CNV mice, active MMP-9 was suppressed by minocycline, a known microglial inhibitor, at 6 h and 1-day post-CNV induction. Flow cytometry revealed that the proportion of activated microglia increased very early, beginning at 1 h post-CNV induction, and was maintained until Day 7. Similarly, immunohistochemistry revealed increased microglial activation and MMP-9 expression on CNV lesions at 6 h and 1-day post-CNV induction. SB-3CT, an MMP inhibitor, decreased vascular leakage and lesion size in laser-induced CNV mice. These findings indicated nearly immediate recruitment of activated microglia and very early MMP-9 activation in the RPE/choroid. The present study newly identified a potential role for early microglial MMP-9 expression in CNV, and furthermore that modulating microglial MMP expression is a novel putative therapeutic for CNV.

Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.

More and more devices are equipped with global positioning system (GPS). However, those handheld devices with consumer-grade GPS receivers usually have low accuracy in positioning. A position correction algorithm is therefore useful in this case. In this paper, we proposed an evolutionary computation based technique to generate a correction function by two GPS receivers and a known reference location. Locating one GPS receiver on the known location and combining its longitude and latitude information and exact poisoning information, the proposed technique is capable of evolving a correction function by such. The proposed technique can be implemented and executed on handheld devices without hardware reconfiguration. Experiments are conducted to demonstrate performance of the proposed technique. Positioning error could be significantly reduced from the order of 10 m to the order of 1 m.

Science teachers use a large number of visual representations and models in science classes to guide students to understand complex phenomena and to learn to conduct scientific inquiry. Fluent formation and use of visual representation involves metavisualization, which is a process related to metacognition and visualization. However, what kinds of knowledge and skills are involved and interact during successful metavisualization need further research. Moreover, teachers' metavisualization should be a focus of research since teachers play a mediating role in guiding students to become proficient performers of visualization in science. Therefore, in this study, we investigated how an experienced science teacher performed metavisualization via qualitative data collection techniques including think-aloud tasks and a follow-up retrospective interview. We identified the relevant knowledge and skills that were involved in the teacher's metavisualization. Moreover, by focusing on the interaction among the knowledge and skills, we observed three aspects of the teacher's performance that were salient to her metavisualization, including the use of metavisual strategies, judgement criteria, and the encountered critical points. Drawing upon previous perspectives and this study's findings, we propose a model of metavisualization by extending an existing model for further research. The findings also provide insight into teacher professional development programs.

Insomnia is a common sleep disorder with significant societal and economic impacts. Current pharmacotherapies for insomnia are often accompanied by side effects, necessitating the development of new therapeutic drugs. In this study, the hypnotic effects and mechanisms of Sedum kamtschaticum 30% ethanol extract (ESK) and one of its active compounds, myricitrin, were investigated using pentobarbital-induced sleep experiments, immunohistochemistry (IHC), receptor binding assays, and enzyme-linked immunosorbent assay (ELISA). The pentobarbital-induced sleep experiments revealed that ESK and myricitrin reduced sleep latency and prolonged total sleep time in a dose-dependent manner. Based on c-Fos immunostaining, ESK, and myricitrin enhanced the GABAergic neural activity in sleep-promoting ventrolateral preoptic nucleus (VLPO) GABAergic. By measuring the level of GABA released from VLPO GABAergic neurons, ESK and myricitrin were found to increase GABA release in the hypothalamus. These effects were significantly inhibited by SCH. Moreover, ESK exhibited a concentration-dependent binding affinity for the adenosine A2A receptors (A2AR). In conclusion, ESK and myricitrin have hypnotic effects, and their underlying mechanisms may be related to the activation of A2AR. [ABSTRACT FROM AUTHOR]

The process of impinging-jet atomization involves the collision of multiple liquid jets to create atomization. This study specifically focuses on a system that utilizes impinging atomization with multiple jets. The injectors used in this study are arranged in either a planar configuration for doublet injectors or a stereoscopic configuration for quadruplet injectors, both designed to facilitate impinging atomization. The angle at which the jets collide is set at 90°, with injector intersection angles of either 60° or 120°. The diameter of the jets ranges from 0.8 to 1.1 mm, while the length–diameter ratio of the pipe remains fixed at 10. To investigate the atomization process, experiments were conducted by varying flow rates (ranging from 30 to 130 mL/min) from each injector using pure water as the working fluid. This resulted in a range of Weber numbers spanning from 4 to 206 and Reynolds numbers ranging from 578 to 3443. Four atomization regimes were observed in the impinging atomization flow field: closed-rim mode, periodic drop mode, open rim mode, and fully developed mode. The experiment utilized a high-speed camera to observe the formation and breakup of the liquid sheet. However, increasing the number of jets and altering the impingement configuration had minimal impact on the liquid sheet patterns as the Weber number increased. Compared to traditional double jet atomization, quadruplet jet atomization resulted in the wider extension of liquid sheets and similar atomization patterns. This study is useful for designing jet impingement-atomization systems for confined spaces. [ABSTRACT FROM AUTHOR]

Objectives: Coronavirus disease 2019 (COVID‐19) is associated with mortality in persons with comorbidities. The aim of this study was to evaluate in‐hospital outcomes in patients with COVID‐19 with and without epilepsy. Methods: We conducted a retrospective study of patients with COVID‐19 admitted to a multicenter health system between March 15, 2020, and May 17, 2021. Patients with epilepsy were identified using a validated International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM)/ICD‐10‐CM case definition. Logistic regression models and Kaplan–Meier analyses were conducted for mortality and non‐routine discharges (i.e., not discharged home). An ordinary least‐squares regression model was fitted for length of stay (LOS). Results: We identified 9833 people with COVID‐19 including 334 with epilepsy. On univariate analysis, people with epilepsy had significantly higher ventilator use (37.70% vs 14.30%, p <.001), intensive care unit (ICU) admissions (39.20% vs 17.70%, p <.001) mortality rate (29.60% vs 19.90%, p <.001), and longer LOS (12 days vs 7 days, p <.001). and fewer were discharged home (29.64% vs 57.37%, p <.001). On multivariate analysis, only non‐routine discharge (adjusted odds ratio [aOR] 2.70, 95% confidence interval [CI] 2.00–3.70; p <.001) and LOS (32.50% longer, 95% CI 22.20%–43.60%; p <.001) were significantly different. Factors associated with higher odds of mortality in epilepsy were older age (aOR 1.05, 95% CI 1.03–1.08; p <.001), ventilator support (aOR 7.18, 95% CI 3.12–16.48; p <.001), and higher Charlson comorbidity index (CCI) (aOR 1.18, 95% CI 1.04–1.34; p =.010). In epilepsy, admissions between August and December 2020 or January and May 2021 were associated with a lower odds of non‐routine discharge and decreased LOS compared to admissions between March and July 2020, but this difference was not statistically significant. Significance: People with COVID‐19 who had epilepsy had a higher odds of non‐routine discharge and longer LOS but not higher mortality. Older age (≥65), ventilator use, and higher CCI were associated with COVID‐19 mortality in epilepsy. This suggests that older adults with epilepsy and multimorbidity are more vulnerable than those without and should be monitored closely in the setting of COVID‐19. [ABSTRACT FROM AUTHOR]

Abstract Background An increasing number of people are using multiple medications each day, named polypharmacy. This is driven by an ageing population, increasing multimorbidity, and single disease-focussed guidelines. Medications carry obvious benefits, yet polypharmacy is also linked to adverse consequences including adverse drug events, drug-drug and drug-disease interactions, poor patient experience and wasted resources. Problematic polypharmacy is ‘the prescribing of multiple medicines inappropriately, or where the intended benefits are not realised’. Identifying people with problematic polypharmacy is complex, as multiple medicines can be suitable for people with several chronic conditions requiring more treatment. Hence, polypharmacy is often potentially problematic, rather than always inappropriate, dependent on clinical context and individual benefit vs risk. There is a need to improve how we identify and evaluate these patients by extending beyond simple counts of medicines to include individual factors and long-term conditions. Aim To produce a Polypharmacy Assessment Score to identify a population with unusual levels of prescribing who may be at risk of potentially problematic polypharmacy. Methods Analyses will be performed in three parts: 1. A prediction model will be constructed using observed medications count as the dependent variable, with age, gender and long-term conditions as independent variables. A ‘Polypharmacy Assessment Score’ will then be constructed through calculating the differences between the observed and expected count of prescribed medications, thereby highlighting people that have unexpected levels of prescribing. Parts 2 and 3 will examine different aspects of validity of the Polypharmacy Assessment Score: 2. To assess ‘construct validity’, cross-sectional analyses will evaluate high-risk prescribing within populations defined by a range of Polypharmacy Assessment Scores, using both explicit (STOPP/START criteria) and implicit (Medication Appropriateness Index) measures of inappropriate prescribing. 3. To assess ‘predictive validity’, a retrospective cohort study will explore differences in clinical outcomes (adverse drug reactions, unplanned hospitalisation and all-cause mortality) between differing scores. Discussion Developing a cross-cutting measure of polypharmacy may allow healthcare professionals to prioritise and risk stratify patients with polypharmacy using unusual levels of prescribing. This would be an improvement from current approaches of either using simple cutoffs or narrow prescribing criteria.

Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca2+-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD. Ca2+ overload-induced mitochondrial dysfunction is considered a contributing factor alcohol-associated liver disease pathogenesis. Here the authors report that PDK4 promotes Ca2 + -channelling complex formation at the endoplasmic reticulum-mitochondria contact sites, which contributes to the pathogenesis of alcohol-associated liver disease in studies with male mouse and hepatocyte models. [ABSTRACT FROM AUTHOR]