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Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control. However, the mechanisms by which Parkin connects mitochondrial homeostasis with cellular metabolism in adipose tissue remain unclear. Here, we demonstrate that Park2 gene (encodes Parkin) deletion specifically from adipose tissue protects mice against high-fat diet and aging-induced obesity. Despite a mild reduction in mitophagy, mitochondrial DNA content and mitochondrial function are increased in Park2 deficient white adipocytes. Moreover, Park2 gene deletion elevates mitochondrial biogenesis by increasing Pgc1α protein stability through mitochondrial superoxide-activated NAD(P)H quinone dehydrogenase 1 (Nqo1). Both in vitro and in vivo studies show that Nqo1 overexpression elevates Pgc1α protein level and mitochondrial DNA content and enhances mitochondrial activity in mouse and human adipocytes. Taken together, our findings indicate that Parkin regulates mitochondrial homeostasis by balancing mitophagy and Pgc1α-mediated mitochondrial biogenesis in white adipocytes, suggesting a potential therapeutic target in adipocytes to combat obesity and obesity-associated disorders. Parkin plays a role in mitophagy and has been shown to control adipose tissue browning and thermogenesis. Here the authors report that Parkin coordinates mitophagy with Pgc1α-mediated mitochondrial biogenesis in white adipocytes to regulate adiposity.

Small-conductance Ca 2+ -activated K + channels (SK channels) influence the induction of synaptic plasticity at hippocampal CA3–CA1 synapses. We find that in mice, SK channels are localized to dendritic spines, and their activity reduces the amplitude of evoked synaptic potentials in an NMDA receptor (NMDAR)-dependent manner. Using combined two-photon laser scanning microscopy and two-photon laser uncaging of glutamate, we show that SK channels regulate NMDAR-dependent Ca 2+ influx within individual spines. SK channels are tightly coupled to synaptically activated Ca 2+ sources, and their activity reduces the amplitude of NMDAR-dependent Ca 2+ transients. These effects are mediated by a feedback loop within the spine head; during an excitatory postsynaptic potential (EPSP), Ca 2+ influx opens SK channels that provide a local shunting current to reduce the EPSP and promote rapid Mg 2+ block of the NMDAR. Thus, blocking SK channels facilitates the induction of long-term potentiation by enhancing NMDAR-dependent Ca 2+ signals within dendritic spines.

Fibrils and oligomers are the aggregated protein agents of neuronal dysfunction in ALS diseases. Whereas we now know much about fibril architecture, atomic structures of disease-related oligomers have eluded determination. Here, we determine the corkscrew-like structure of a cytotoxic segment of superoxide dismutase 1 (SOD1) in its oligomeric state. Mutations that prevent formation of this structure eliminate cytotoxicity of the segment in isolation as well as cytotoxicity of the ALS-linked mutants of SOD1 in primary motor neurons and in a Danio rerio (zebrafish) model of ALS. Cytotoxicity assays suggest that toxicity is a property of soluble oligomers, and not large insoluble aggregates. Our work adds to evidence that the toxic oligomeric entities in protein aggregation diseases contain antiparallel, out-of-register β-sheet structures and identifies a target for structure-based therapeutics in ALS.

Mitochondria have distinct architectural features and biochemical functions consistent with cell-specific bioenergetic needs. However, as imaging and isolation techniques advance, heterogeneity amongst mitochondria has been observed to occur within the same cell. Moreover, mitochondrial heterogeneity is associated with functional differences in metabolic signaling, fuel utilization, and triglyceride synthesis. These phenotypic associations suggest that mitochondrial subpopulations and heterogeneity influence the risk of metabolic diseases. This review examines the current literature regarding mitochondrial heterogeneity in the pancreatic beta-cell and renal proximal tubules as they exist in the pathological and physiological states; specifically, pathological states of glucolipotoxicity, progression of type 2 diabetes, and kidney diseases. Emphasis will be placed on the benefits of balancing mitochondrial heterogeneity and how the disruption of balancing heterogeneity leads to impaired tissue function and disease onset.

The aggregation and colloidal stability of three, commercially-available, gamma-aluminum oxide nanoparticles (γ-Al2O3 NPs) (nominally 5, 10, and 20–30 nm) were systematically examined as a function of pH, ionic strength, humic acid (HA) or clay minerals (e.g., montmorillonite) concentration using dynamic light scattering and transmission electron microscopy techniques. NPs possess pH-dependent surface charges, with a point of zero charge (PZC) of pH 7.5 to 8. When pH < PZC, γ-Al2O3 NPs are colloidally stable up to 100 mM NaCl and 30 mM CaCl2. However, significant aggregation of NPs is pronounced in both electrolytes at high ionic strength. In mixed systems, both HA and montmorillonite enhance NP colloidal stability through electrostatic interactions and steric hindrance when pH ≤ PZC, whereas their surface interactions are quite limited when pH > PZC. Even when pH approximates PZC, NPs became stable at a HA concentration of 1 mg·L−1. The magnitude of interactions and dominant sites of interaction (basal planes versus edge sites) are significantly dependent on pH because both NPs and montmorillonite have pH-dependent (conditional) surface charges. Thus, solution pH, ionic strength, and the presence of natural colloids greatly modify the surface conditions of commercial γ-Al2O3 NPs, affecting aggregation and colloidal stability significantly in the aqueous environment.

Therapeutic inertia (TI) is defined as the inability of physicians to intensify or initiate a more aggressive treatment in patients who need it. This study aims to explore the evidence behind TI in the management of patients with moderate to severe psoriasis and to determine the factors that contribute to its occurrence. An extensive literature search was conducted systematically in Cochrane Library, Medline, Epistemonikos, Google Scholar, and HERDIN Plus from their inception up to June 2023. Cross‐sectional studies that looked into TI in patients with moderate to severe psoriasis and discussed the factors that lead to its occurrence were included in the study. The review was limited to peer‐reviewed journals in the English language. Outcomes were presented as counts and percentages, and notable findings from each study were highlighted. Three thousand two hundred and fifty six records were identified but only 4 studies met the inclusion criteria and were included in the analysis. Based on the available evidence, the prevalence of TI in psoriasis varies from 25.4% to 35.6%. Its occurence is largely caused by physician‐related factors (reluctance to escalate treatment due to lack of knowledge and experience) and patient‐related factors (satisfaction with current treatment or refusal to change treatment due to psychological barriers). Healthcare system‐related factors were not directly explored. The limited data on TI in the management of moderate to severe psoriasis presents opportunities to further explore its prevalence, the factors contributing to it, and its effect on treatment outcomes.

The presence of bilirubin in the sputum is uncommon but, when present, is most commonly associated with the presence of bronchobiliary fistula, which could be associated with a number of underlying conditions. However, the finding of bilioptysis without bronchobiliary fistula is uncommon, with one associated mechanism postulated to involve increased capillary membrane permeability. This case report describes a patient presenting with bilioptysis while being medically managed with prednisolone for severe alcoholic hepatitis. The patient developed hospital‐acquired pneumonia during her hospitalization associated with bilioptysis, resulting in progressive respiratory failure requiring ventilatory support. Alcohol‐related pulmonary dysfunction alters pulmonary immune processes, leading to increased susceptibility to pulmonary infection and disrupting the basal alveolar epithelial membrane, thus increasing permeability. This patient's findings were in the absence of a bronchobiliary or bronchopleural fistula, and we hypothesize that increased capillary membrane permeability was contributory to the bilioptysis in this case. This case report describes a patient presenting with bilioptysis while being medically managed with prednisolone for severe alcoholic hepatitis. The patient developed hospital‐acquired pneumonia during her hospitalization associated with bilioptysis, resulting in progressive respiratory failure requiring ventilatory support. Alcohol‐related pulmonary dysfunction alters pulmonary immune processes, leading to increased susceptibility to pulmonary infection and disrupting the basal alveolar epithelial membrane, thus increasing permeability. This patient's findings were in the absence of a bronchobiliary or bronchopleural fistula, and we hypothesize that increased capillary membrane permeability was contributory to the bilioptysis in this case.

BackgroundHospital morbidity and mortality reviews are common quality assurance activities, intended to uncover latent or unrecognised systemic issues that contribute to preventable adverse events and patient harm. Mortality reviews may be routinely mandated by hospital policy or for accreditation purposes. However, patients under the care of certain specialties, such as general internal medicine (GIM), are affected by a substantial burden of chronic disease, advanced age, frailty or limited life expectancy. Many of their deaths could be viewed as reasonably foreseeable, and unrelated to poor-quality care.MethodsWe sought to determine how frequently postmortem chart reviews for hospitalised GIM patients at our tertiary care centre in Canada would uncover patient safety or quality of care issues that directly led to these patients’ deaths. We reviewed the charts of all patients who died while admitted to the GIM admitting service over a 12-month time period between 1 July 2020 and 30 June 2021.ResultsWe found that in only 2% of cases was a clinical adverse event detected that directly contributed to a poor or unexpected outcome for the patient, and of those cases, more than half were related to unfortunate nosocomial transmission of COVID-19 infection.ConclusionDue to an overall low yield, we discourage routine mortality chart reviews for general medical patients, and instead suggest that organisations focus on strategies to recognise and capture safety incidents that may not necessarily result in death.

Reports of adverse events and near-misses provide the opportunity to learn about latent (systems) errors. However, voluntary incident reporting systems are underused by physicians. While reports submitted by nursing staff relate to common hazards such as medication administration or falls, physicians have broader exposure to patients’ entire hospital journey. Reports by physicians have the potential to uncover more serious errors that could span multiple departments and layers of personnel. Organisational safety culture thrives when all staff are represented and feel empowered to share safety concerns.At the South Health Campus (SHC) Hospital in Calgary, Alberta, Canada, the baseline proportion of physician-submitted reports within our site’s Reporting and Learning System (RLS) from July 2013 to December 2016 was 1.12%. We implemented an intervention to double the proportion of physician-submitted RLS reports, using quality improvement methods.Focus groups identified lack of experience with the RLS system, lack of feedback or closure after an RLS submission, and apprehensions about disclosing the incident to the affected patient as barriers to physician submission. Accordingly, the intervention involved direct responses from physician leadership to each physician-submitted RLS report, multimedia demonstrations of efficient RLS submission to physician groups and medical learners, and linkage to materials on safe disclosures. Effectiveness was assessed using a controlled before-and-after design, comparing SHC with the rest of Calgary and with the rest of Alberta.Following the intervention, the proportion of RLS reports that were physician submitted increased to 2.65% (OR 2.42 [95% CI 1.96 to 3.02], p<0.001), sustained over the following 4 years. While an increase was observed for the rest of Calgary, it was smaller (OR 1.27 [1.15 to 1.40], p<0.001). A decrease in the odds of physician submission was observed for the rest of Alberta. Differences between sites were significant (p<0.001).Overall, we found that physician-submitted incident reports can be increased and sustained over time if submitters receive personalised feedback by a physician safety leader. At our site, reports submitted by physicians have been valuable in uncovering complex systems issues that may not have been readily apparent.

Investigation of the potential adverse effects of chemicals and drugs is essential during the drug development process. In vitro cell model systems have been developed over the past years towards such toxicity investigation. 96-well plate is the common platform for screening drug toxicity due to its simplicity. However, this platform only offers 2D cell culture environment and lacks the flow of solutions, which fails to provide the suitable environment for the cells to adequately metabolize the drugs, for the media to replenish, and for the metabolites and wastes to be removed. Microfluidic chips populated with human or animal cells, known as organ-on-a-chip (OOC), can reconcile many issues of in vitro cell models, such as the lack of extracellular matrix and flow as well as the species difference. However, OOC can be complicated to fabricate and operate. To bridge this gap, we utilized paper as a primary substrate for OOC, considering its fibrous structure that can mimic natural extracellular matrix, as well as a syringe pump and filter that are commonly available in most laboratories. Paper microfluidic model was designed and fabricated by wax printing on nitrocellulose paper, seeded and proliferated with liver cells (primary rat hepatocytes and HepG2 cells), and two paper substrates were stacked together to complete the paper model. To this paper-based liver cell model, the following drugs were added: Phenacetin (pain reliever and fever reducer), Bupropion (antidepressant), Dextromethorphan (antidepressant), and phosphate-buffered saline (PBS) as a control, all under a physiologically relevant flow rate. The combination of these drugs with Fluconazole (antifungal drug) was also investigated. Cell count, cell morphology, protein production, and urea secretion after drug treatment confirmed that the model successfully predicted toxicity within 40 minutes. This simple, paper-based liver cell model provided enhanced and faster cell response to drug toxicity and showed comparable or better behavior than the cells cultured in conventional 2D in vitro models.