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Nudix hydrolase NUDT19 regulates mitochondrial function and ATP production in murine hepatocytes
(2022)
Changes in intracellular CoA levels are known to contribute to the development of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2D) in human and rodents. However, the underlying genetic basis is still poorly understood.
Due to their diverse susceptibility towards metabolic diseases, mouse inbred strains have been proven to serve as powerful tools for the identification of novel genetic factors that underlie the patho-physiology of NAFLD and diabetes. Transcriptome analysis of mouse liver samples revealed the nucleoside diphosphate linked moiety X-type motif Nudt19 as novel candidate gene responsible for NAFLD and T2D development. Knockdown (KD) of Nudt19 increased mitochondrial and glycolytic ATP production rates in Hepa 1-6 cells by 41% and 10%, respectively.
The enforced utilization of glutamine or fatty acids as energy substrate reduced uncoupled respiration by 41% and 47%, respectively, in non-target (NT) siRNA transfected cells.
This reduction was prevented upon Nudt19 KD. Furthermore, incubation with palmitate or oleate respectively increased mitochondrial ATP production by 31% and 20%, and uncoupled respiration by 23% and 30% in Nudt19 KD cells, but not in NT cells.
The enhanced fatty acid oxidation in Nudt19 KD cells was accompanied by a 1.3-fold increased abundance of Pdk4.
This study is the first to describe Nudt19 as regulator of hepatic lipid metabolism and potential mediator of NAFLD and T2D development.
Background
In cystic fibrosis (CF), acute respiratory exacerbations critically enhance pulmonary destruction. Since these mainly occur outside regular appointments, they remain unexplored. We previously elaborated a protocol for home-based upper airway (UAW) sampling obtaining nasal-lavage fluid (NLF), which, in contrast to sputum, does not require immediate processing. The aim of this study was to compare UAW inflammation and pathogen colonization during stable phases and exacerbations in CF patients and healthy controls.
Methods
Initially, we obtained NLF by rinsing 10 ml of isotonic saline/nostril during stable phases. During exacerbations, subjects regularly collected NLF at home. CF patients directly submitted one aliquot for microbiological cultures. The remaining samples were immediately frozen until transfer on ice to our clinic, where PCR analyses were performed and interleukin (IL)-1 beta/IL-6/IL-8, neutrophil elastase (NE), matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1 were assessed.
Results
Altogether, 49 CF patients and 38 healthy controls (HCs) completed the study, and 214 NLF samples were analyzed. Of the 49 CF patients, 20 were at least intermittently colonized with P. aeruginosa and received azithromycin and/or inhaled antibiotics as standard therapy. At baseline, IL-6 and IL-8 tended to be elevated in CF compared to controls. During infection, inflammatory mediators increased in both cohorts, reaching significance only for IL-6 in controls (p=0.047). Inflammatory responses tended to be higher in controls [1.6-fold (NE) to 4.4-fold (MMP-9)], while in CF, mediators increased only moderately [1.2-1.5-fold (IL-6/IL-8/NE/TIMP-1/MMP-9)]. Patients receiving inhalative antibiotics or azithromycin (n=20 and n=15, respectively) revealed lower levels of IL-1 beta/IL-6/IL-8 and NE during exacerbation compared to CF patients not receiving those antibiotics. In addition, CF patients receiving azithromycin showed MMP-9 levels significantly lower than CF patients not receiving azithromycin at stable phase and exacerbation. Altogether, rhinoviruses were the most frequently detected virus, detected at least once in n=24 (49.0%) of the 49 included pwCF and in n=26 (68.4%) of the 38 healthy controls over the 13-month duration of the study. Remarkably, during exacerbation, rhinovirus detection rates were significantly higher in the HC group compared to those in CF patients (65.8% vs. 22.4%; p<0.0001).
Conclusion
Non-invasive and partially home-based UAW sampling opens new windows for the assessment of inflammation and pathogen colonization in the unified airway system.
Recent theories suggest a shift from model-based goal-directed to model-free habitual decision-making in obsessive-compulsive disorder (OCD). However, it is yet unclear, whether this shift in the decision process is heritable. We investigated 32 patients with OCD, 27 unaffected siblings (SIBs) and 31 healthy controls (HCs) using the two-step task. We computed behavioral and reaction time analyses and fitted a computational model to assess the balance between model-based and model-free control. 80 subjects also underwent structural imaging. We observed a significant ordered effect for the shift towards model-free control in the direction OCD>SIB>HC in our computational parameter of interest. However less directed analyses revealed no shift towards model-free control in OCDs. Nonetheless, we found evidence for reduced model-based control in OCDs compared to HCs and SIBs via 2nd stage reaction time analyses. In this measure SIBs also showed higher levels of model-based control than HCs. Across all subjects these effects were associated with the surface area of the left medial/right dorsolateral prefrontal cortex. Moreover, correlations between bilateral putamen/right caudate volumes and these effects varied as a function of group: they were negative in SIBs and OCDs, but positive in HCs. Associations between fronto-striatal regions and model-based reaction time effects point to a potential endophenotype for OCD.
Symptom Checker Applications (SCA) are mobile applications often designed for the end-user to assist with symptom assessment and self-triage. SCA are meant to provide the user with easily accessible information about their own health conditions.
However, SCA raise questions regarding ethical, legal, and social aspects (ELSA), for example, regarding fair access to this new technology.
The aim of this scoping review is to identify the ELSA of SCA in the scientific literature. A scoping review was conducted to identify the ELSA of SCA. Ten databases (e.g., Web of Science and PubMed) were used. Studies on SCA that address ELSA, written in English or German, were included in the review.
The ELSA of SCA were extracted and synthesized using qualitative content analysis. A total of 25,061 references were identified, of which 39 were included in the analysis. The identified aspects were allotted to three main categories: (1) Technology; (2) Individual Level; and (3) Healthcare system.
The results show that there are controversial debates in the literature on the ethical and social challenges of SCA usage. Furthermore, the debates are characterised by a lack of a specific legal perspective and empirical data.
The review provides an overview on the spectrum of ELSA regarding SCA. It offers guidance to stakeholders in the healthcare system, for example, patients, healthcare professionals, and insurance providers and could be used in future empirical research to investigate the perspectives of those affected, such as users.
Background
Depression is a leading cause of disability worldwide and a significant contributor to the global burden of disease. Altered leptin levels are known to be associated with depressive symptoms, however discrepancies in the results of increased or decreased levels exist. Due to various limitations associated with commonly used antidepressant drugs, alternatives such as exercise therapy are gaining more importance. Therefore, the current study investigates whether depressed patients have higher leptin levels compared to healthy controls and if exercise is efficient to reduce these levels.
Methods
Leptin levels of 105 participants with major depressive disorder (MDD; 45.7% female, age mean ± SEM: 39.1 ± 1.0) and 34 healthy controls (HC; 61.8% female, age mean ± SEM: 36.0 ± 2.0) were measured before and after a bicycle ergometer test. Additionally, the MDD group was separated into three groups: two endurance exercise intervention groups (EX) differing in their intensities, and a waiting list control group (WL). Leptin levels were measured pre and post a 12-week exercise intervention or the waiting period.
Results
Baseline data showed no significant differences in leptin levels between the MDD and HC groups. As expected, correlation analyses displayed significant relations between leptin levels and body weight (HC: r = 0.474, p = 0.005; MDD: r = 0.198, p = 0.043) and even more with body fat content (HC: r = 0.755, p < 0.001; MDD: r = 0.675, p < 0.001). The acute effect of the bicycle ergometer test and the 12-week training intervention showed no significant changes in circulating leptin levels.
Conclusion
Leptin levels were not altered in patients with major depression compared to healthy controls and exercise, both the acute response and after 12 weeks of endurance training, had no effect on the change in leptin levels.
Trial registration
The study was registered at the German register for clinical studies (DRKS) and the International Clinical Trials Registry Platform of the World Health Organization https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00008869 on 28/07/2015.
The ability to catalyze diverse reactions with relevance for chemical and pharmaceutical research and industry has led to an increasing interest in fungal enzymes.
There is still an enormous potential considering the sheer amount of new enzymes from the huge diversity of fungi.
Most of these fungal enzymes have not been characterized yet due to the lack of high throughput synthesis and analysis methods.
This bottleneck could be overcome by means of cell-free protein synthesis. In this study, cell-free protein synthesis based on eukaryotic cell lysates was utilized to produce a functional glycoside hydrolase (GH78) from the soft-rot fungus Xylaria polymorpha (Ascomycota).
The enzyme was successfully synthesized under different reaction conditions.
We characterized its enzymatic activities and immobilized the protein via FLAG-Tag interaction. Alteration of several conditions including reaction temperature, template design and lysate supplementation had an influence on the activity of cell-free synthesized GH78.
Consequently this led to a production of purified GH78 with a specific activity of 15.4 U mg? 1.
The results of this study may be foundational for future high throughput fungal enzyme screenings, including substrate spectra analysis and mutant screenings.
Introduction
Elderly patients after hospitalisation for acute events on account of age-related diseases (eg, joint or heart valve replacement surgery) are often characterised by a remarkably reduced functional health. Multicomponent rehabilitation (MR) is considered an appropriate approach to restore the functioning of these patients. However, its efficacy in improving functioning-related outcomes such as care dependency, activities of daily living (ADL), physical function and health-related quality of life (HRQL) remains unclarified. We outline the research framework of a scoping review designed to map the available evidence of the effects of MR on the independence and functional capacity of elderly patients hospitalised for age-related diseases in four main medical specialties beyond geriatrics.
Methods and analysis
The biomedical databases (PubMed, Cochrane Library, ICTRP Search Platform, ClinicalTrials) and additionally Google Scholar will be systematically searched for studies comparing centre-based MR with usual care in patients ≥75 years of age, hospitalised for common acute events due to age-related diseases (eg, joint replacement, stroke) in one of the specialties of orthopaedics, oncology, cardiology or neurology. MR is defined as exercise training and at least one additional component (eg, nutritional counselling), starting within 3 months after hospital discharge. Randomised controlled trials as well as prospective and retrospective controlled cohort studies will be included from inception and without language restriction. Studies investigating patients <75 years, other specialties (eg, geriatrics), rehabilitation definition or differently designed will be excluded. Care dependency after at least a 6-month follow-up is set as the primary outcome. Physical function, HRQL, ADL, rehospitalisation and mortality will be additionally considered. Data for each outcome will be summarised, stratified by specialty, study design and type of assessment. Furthermore, quality assessment of the included studies will be performed.
Ethics and dissemination
Ethical approval is not required. Findings will be published in a peer-reviewed journal and presented at national and/or international congresses.
Functional near-infrared spectroscopy (fNIRS) allows for a reliable assessment of oxygenated blood flow in relevant brain regions. Recent advancements in immersive virtual reality (VR)-based technology have generated many new possibilities for its application, such as in stroke rehabilitation. In this study, we asked whether there is a difference in oxygenated hemoglobin (HbO2) within brain motor areas during hand/arm movements between immersive and non-immersive VR settings. Ten healthy young participants (24.3 ± 3.7, three females) were tested using a specially developed VR paradigm, called “bus riding”, whereby participants used their hand to steer a moving bus. Both immersive and non-immersive conditions stimulated brain regions controlling hand movements, namely motor cortex, but no significant differences in HbO2 could be found between the two conditions in any of the relevant brain regions. These results are to be interpreted with caution, as only ten participants were included in the study.
Background: Socially assistive devices (care robots, companions, smart screen assistants) have been advocated as a promising tool in elderly care in Western healthcare systems. Ethical debates indicate various challenges. One of the most prevalent arguments in the debate is the double-benefit argument claiming that socially assistive devices may not only provide benefits for autonomy and well-being of their users but might also be more efficient than other caring practices and might help to mitigate scarce resources in healthcare. Against this background, we used a subset of comparative empirical studies from a comprehensive systematic review on effects and perceptions of human-machine interaction with socially assistive devices to gather and appraise all available evidence supporting this argument from the empirical side.
Methods: Electronic databases and additional sources were queried using a comprehensive search strategy which generated 9851 records. Studies were screened independently by two authors. Methodological quality of studies was assessed. For 39 reports using a comparative study design, a narrative synthesis was performed.
Results: The data shows positive evidential support to claim that some socially assistive devices (Paro) might be able to contribute to the well-being and autonomy of their users. However, results also indicate that these positive findings may be heavily dependent on the context of use and the population. In addition, we found evidence that socially assistive devices can have negative effects on certain populations. Evidence regarding the claim of efficiency is scarce. Existing results indicate that socially assistive devices can be more effective than standard of care but are far less effective than plush toys or placebo devices.
Discussion: We suggest using the double-benefit argument with great caution as it is not supported by the currently available evidence. The occurrence of potentially negative effects of socially assistive devices requires more research and indicates a more complex ethical calculus than suggested by the double-benefit argument.