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Objective: Bcl-xL is an antiapoptotic member of the Bcl-2 family of proteins and a potent regulator of cell death. We investigated the importance of Bcl-xL for beta-cells by deleting the Bcl-x gene specifically in beta-cells and analyzing their survival in vivo and in culture.Research Design and Methods: Islets with beta-cells lacking the Bcl-x gene were assessed in vivo by histology and by treatment of mice with low-dose streptozotocin (STZ). Islets were isolated by collagenase digestion and treated in culture with the apoptosis inducers staurosporine, thapsigargin, gamma-irradiation, proinflammatory cytokines, or Fas ligand. Cell death was assessed by flow cytometric analysis of subgenomic DNA.Results: Bcl-xL-deficient beta-cells developed but were abnormally sensitive to apoptosis induced in vivo by low-dose STZ. Although a small proportion of beta-cells still expressed Bcl-xL, these did not have a survival advantage over their Bcl-xL-deficient neighbors. Islets appeared normal after collagenase isolation and whole-islet culture. They were, however, abnormally sensitive in culture to a number of different apoptotic stimuli including cytotoxic drugs, proinflammatory cytokines, and Fas ligand.Conclusions: Bcl-xL expression in beta-cells is dispensible during islet development in the mouse. Bcl-xL is, however, an important regulator of beta-cell death under conditions of synchronous stress. Bcl-xL expression at physiological levels may partially protect beta-cells from apoptotic stimuli, including apoptosis because of mediators implicated in type 1 diabetes and death or degeneration of transplanted islets. [ABSTRACT FROM AUTHOR]

The method of the stochastic Markov process used for the analysis of operation of a training aircraft-Cessna 150 was presented in the article. In this article, the time changing probability of readiness was determined on the basis of knowledge of the current aircraft operation. Markov stochastic processes have been used as a model to determine aircraft-Cessna 150 readiness for specific tasks. In order to determine the readiness, the probability of being in one of the investigated states is determined. The analysed states included: standby, pre-flight service, flight, interstate service, after-flight service and hangar service.

Apathy is a core negative symptom associated with an unfavorable functional outcome. Noninvasive brain stimulation has shown promise in the treatment of schizophrenia but has not been tested specifically for apathy. We conducted a randomized controlled trial of intermittent theta-burst (iTBS) transcranial magnetic stimulation and transcranial direct current stimulation (tDCS) targeted at the right dorsolateral prefrontal cortex (DLPFC) in patients diagnosed with a psychotic disorder suffering from apathy. The study was a multicenter, randomized, placebo-controlled, and rater-blinded trial. Patients (N = 88) were randomized into active iTBS, active tDCS, sham iTBS or sham tDCS treatment, daily for two weeks (excluding weekends). Effects were measured post-treatment and at four week and ten week follow-up. Primary outcome was apathy severity (Apathy Evaluation Scale, clinician-rated). Additional measures included assessment of negative symptoms, depression, anhedonia and quality of life. No significant difference in improvement of apathy or negative symptoms was observed for real versus sham treatment with either iTBS or tDCS, though all groups improved to a small extent. We conclude that two weeks of brain stimulation over the right DLPFC with either iTBS or tDCS is not effective for improving apathy or negative symptoms. Longer and more intensive protocols may yield different results., Competing Interests: Declaration of competing interest The authors declare no interests in relationship to the work reported in this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Tau protein is implicated in the pathogenesis of Alzheimer's disease (AD) and other tauopathies, but its physiological function is in debate. Mostly explored in the brain, tau is also expressed in the pancreas. We further explored the mechanism of tau's involvement in the regulation of glucose-stimulated insulin secretion (GSIS) in islet β-cells, and established a potential relationship between type 2 diabetes mellitus (T2DM) and AD. We demonstrate that pancreatic tau is crucial for insulin secretion regulation and glucose homeostasis. Tau levels were found to be elevated in β-islet cells of patients with T2DM, and loss of tau enhanced insulin secretion in cell lines, drosophila, and mice. Pharmacological or genetic suppression of tau in the db/db diabetic mouse model normalized glucose levels by promoting insulin secretion and was recapitulated by pharmacological inhibition of microtubule assembly. Clinical studies further showed that serum tau protein was positively correlated with blood glucose levels in healthy controls, which was lost in AD. These findings present tau as a common therapeutic target between AD and T2DM., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Abnormal function and connectivity of the fronto-parietal network (FPN) have been documented in patients with schizophrenia, but studies are correlational. We applied repetitive transcranial magnetic stimulation (rTMS) to the dorso-lateral prefrontal cortex (DLPFC) and observed causal connectivity to the inferior parietal lobe (IPL). We hypothesized that patients with schizophrenia would have lower activation and slower reaction in the IPL following DLPFC stimulation. Thirteen patients with schizophrenia (SZ) and fourteen healthy controls subjects (HC) underwent rTMS at 10 Hz to the right DLPFC. Simultaneously, we measured brain activation in the IPL, represented as oxygenized hemoglobin (HbO) levels, using functional near-infrared spectroscopy (fNIRS). rTMS consisted of 20 trains of impulses at 10 Hz for 3 seconds, and 60 seconds waiting time. Using NIRSLab software, GLM was applied to estimate both hemodynamic response function (HRF) and its derivative. Following TMS to the DLPFC, SZ showed a smaller decrease in HbO levels in the bilateral IPL than HC (p = 0.05). Timecourse analysis revealed an immediate decrease in parietal HbO levels in HC, but not in SZ. This difference was significant (at a threshold level of p ≤ 0.05, with Bonferroni correction) for several time segments and channels in both rights and left IPL. Our findings suggest abnormal fronto-temporal connectivity in patients with schizophrenia, beyond a mere decrease or slowing of information processing. This is in line with the hypothesis of reduced fronto-parietal inhibition in schizophrenia., (© 2022. The Author(s).)

Aims: To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction., Methods and Results: Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs., Conclusions: Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

The aim of this study was to investigate whether apathy in schizophrenia is associated with rigidity in behavior and brain functioning. To this end, we studied associations between variability in dynamic functional connectivity (DFC) in relevant functional brain networks, apathy, and variability in physical activity in schizophrenia. Thirty-one patients with schizophrenia, scoring high on apathy, were included and wore an actigraph. Activity variability was calculated on the activity counts using the root of the Mean Squared Successive Difference (MSSD). Furthermore, we calculated DFC on resting-state data as phase interactions between blood oxygen-level dependent (BOLD) signals of 270 brain regions per volume. Variability (MSSD) in DFC was calculated for 3 networks, including the default-mode network (DMN), frontoparietal network, and salience-reward network (SRN). Finally, we calculated correlations between these DFC estimates and apathy and activity variability. First, lower activity variability was associated with higher levels of apathy. Second, higher levels of apathy were associated with lower variability in DFC in the DMN and SRN. Third, higher activity variability was associated with higher variability in DFC in the SRN. In conclusion, patients with schizophrenia and more severe levels of apathy showed less variability in their physical activity and more rigid functional brain network behavior in the DMN and SRN. These networks have been shown relevant for self-reflection, mental simulation, and reward processing, processes that are pivotal for self-initiated goal-directed behavior. Functional rigidity of these networks may therefore contribute to reduced goal-directed behavior, which is characteristic for these patients., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Human behaviour can be externally driven, e.g. catching a falling glass, or self-initiated and goal-directed, e.g. drinking a cup of coffee when one deems it is time for a break. Apathy refers to a reduction of self-initiated goal-directed or motivated behaviour, frequently present in neurological and psychiatric disorders. The amount of undertaken goal-directed behaviour varies considerably in clinical as well as healthy populations. In the present study, we investigated behavioural and neural correlates of self-initiated action in a student sample (N = 39) with minimal to high levels of apathy. We replicated activation of fronto-parieto-striatal regions during self-initiation. The neural correlates of self-initiated action did not explain varying levels of apathy in our sample, neither when mass-univariate analysis was used, nor when multivariate patterns of brain activation were considered. Other hypotheses, e.g. regarding a putative role of deficits in reward anticipation, effort expenditure or executive difficulties, deserve investigation in future studies.