Citations

Background Remote limb ischemic postconditioning (RLIPoC) has been demonstrated to protect against ischemic stroke. However, the underlying mechanisms of RLIPoC mediating cross‐organ protection remain to be fully elucidated. Methods and Results Ischemic stroke was induced by middle cerebral artery occlusion for 60 minutes. RLIPoC was performed with 3 cycles of 10‐minute ischemia followed by 10‐minute reperfusion of the bilateral femoral arteries immediately after middle cerebral artery reperfusion. The percentage of regulatory T cells (Tregs) in the spleen, blood, and brain was detected using flow cytometry, and the number of Tregs in the ischemic hemisphere was counted using transgenic mice with an enhanced green fluorescent protein‐tagged Foxp3. Furthermore, the metabolic status was monitored dynamically using a multispectral optical imaging system. The Tregs were conditionally depleted in the depletion of Treg transgenic mice after the injection of the diphtheria toxin. The inflammatory response and neuronal apoptosis were investigated using immunofluorescent staining. Infarct volume and neurological deficits were evaluated using magnetic resonance imaging and the modified neurological severity score, respectively. The results showed that RLIPoC substantially reduced infarct volume, improved neurological function, and significantly increased Tregs in the spleen, blood, and ischemic hemisphere after middle cerebral artery occlusion. RLIPoC was followed by subsequent alteration in metabolites, such as flavin adenine dinucleotide and nicotinamide adenine dinucleotide hydrate, both in RLIPoC‐conducted local tissues and circulating blood. Furthermore, nicotinamide adenine dinucleotide hydrate can mimic RLIPoC in increasing Tregs. Conversely, the depletion of Tregs using depletion of Treg mice compromised the neuroprotective effects conferred by RLIPoC. Conclusions RLIPoC protects against ischemic brain injury, at least in part by activating and maintaining the Tregs through the nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrate pathway.

Small-molecule recruitment of an endogenous nuclease rescues pathologies associated with c9ALS/FTD in vivo by targeting an RNA repeat expansion.

Abstract The human RecQ helicase BLM is involved in the DNA damage response, DNA metabolism, and genetic stability. Loss of function mutations in BLM cause the genetic instability/cancer predisposition syndrome Bloom syndrome. However, the molecular mechanism underlying the regulation of BLM in cancers remains largely elusive. Here, we demonstrate that the deubiquitinating enzyme USP37 interacts with BLM and that USP37 deubiquitinates and stabilizes BLM, thereby sustaining the DNA damage response (DDR). Mechanistically, DNA double-strand breaks (DSB) promotes ATM phosphorylation of USP37 and enhances the binding between USP37 and BLM. Moreover, knockdown of USP37 increases BLM polyubiquitination, accelerates its proteolysis, and impairs its function in DNA damage response. This leads to enhanced DNA damage and sensitizes breast cancer cells to DNA-damaging agents in both cell culture and in vivo mouse models. Collectively, our results establish a novel molecular mechanism for the USP37–BLM axis in regulating DSB repair with an important role in chemotherapy and radiotherapy response in human cancers.

Abstract Background Non-invasive differentiation between schwannomas and neurofibromas is important for appropriate management, preoperative counseling, and surgical planning, but has proven difficult using conventional imaging. The objective of this study was to develop and evaluate machine learning approaches for differentiating peripheral schwannomas from neurofibromas. Methods We assembled a cohort of schwannomas and neurofibromas from 3 independent institutions and extracted high-dimensional radiomic features from gadolinium-enhanced, T1-weighted MRI using the PyRadiomics package on Quantitative Imaging Feature Pipeline. Age, sex, neurogenetic syndrome, spontaneous pain, and motor deficit were recorded. We evaluated the performance of 6 radiomics-based classifier models with and without clinical features and compared model performance against human expert evaluators. Results One hundred and seven schwannomas and 59 neurofibromas were included. The primary models included both clinical and imaging data. The accuracy of the human evaluators (0.765) did not significantly exceed the no-information rate (NIR), whereas the Support Vector Machine (0.929), Logistic Regression (0.929), and Random Forest (0.905) classifiers exceeded the NIR. Using the method of DeLong, the AUCs for the Logistic Regression (AUC = 0.923) and K Nearest Neighbor (AUC = 0.923) classifiers were significantly greater than the human evaluators (AUC = 0.766; p = 0.041). Conclusions The radiomics-based classifiers developed here proved to be more accurate and had a higher AUC on the ROC curve than expert human evaluators. This demonstrates that radiomics using routine MRI sequences and clinical features can aid in differentiation of peripheral schwannomas and neurofibromas.

Purpose: To review the current options in the management of Warthin tumors (WTs) and to propose a working management protocol. Methods: A systematic literature search was conducted using PubMed and ScienceDirect database. A total of 141 publications were selected and have been included in this review. Publications were selected based on relevance, scientific evidence, and actuality. Results: The importance of parotid WTs is increasing due to its rising incidence in many countries, becoming the most frequently encountered benign parotid tumor in certain parts of the world. In the past, all WTs were treated with surgery, but because of their slow growth rate, often minimal clinical symptoms, and the advanced age of many patients, active observation has gradually become more widely used. In order to decide on active surveillance, the diagnosis of WT must be reliable, and clinical, imaging, and cytological data should be concordant. There are four clear indications for upfront surgery: uncertain diagnosis; cosmetic problems; clinical complaints, such as pain, ulceration, or recurrent infection; and the patient’s wish to have the tumor removed. In the remaining cases, surgery can be elective. Active surveillance is often suggested as the first approach, with surgery being considered if the tumor progresses and/or causes clinical complaints. The extent of surgery is another controversial topic, and the current trend is to minimize the resection using partial parotidectomies and extracapsular dissections when possible. Recently, non-surgical options such as microwave ablation, radiofrequency ablation, and ultrasound-guided ethanol sclerotherapy have been proposed for selected cases. Conclusions: The management of WT is gradually shifting from superficial or total parotidectomy to more conservative approaches, with more limited resections, and to active surveillance in an increasing number of patients. Additionally, non-surgical treatments are emerging, but their role needs to be defined in future studies.

Abstract Background: The current pandemic of COVID-19 impacted the psychological wellbeing of populations globally. Objectives: We aimed to examine the extent and identify associated factors of psychological distress, fear of COVID-19, and coping.Methods: We conducted a cross-sectional study across 17 countries during Jun-2020 to Jan-2021. Levels of psychological distress (Kessler Psychological Distress Scale), fear of COVID-19 (Fear of COVID-19 Scale), and coping (Brief Resilient Coping Scale) were assessed. Results: A total of 8,559 people participated; mean age (±SD) was 33(±13) years, 64% were females and 40% self-identified as frontline workers. More than two-thirds (69%) experienced moderate-to-very high levels of psychological distress, which was 46% in Thailand and 91% in Egypt. A quarter (24%) had high levels of fear of COVID-19, which was as low as 9% in Libya and as high as 38% in Bangladesh. More than half (57%) exhibited medium to high resilient coping; the lowest prevalence (3%) was reported in Australia and the highest (72%) in Syria. Being female (AOR 1.31 [95% CIs 1.09-1.57]), perceived distress due to change of employment status (1.56 [1.29-1.90]), comorbidity with mental health conditions (3.02 [1.20-7.60]) were associated with higher levels of psychological distress and fear. Doctors had higher psychological distress (1.43 [1.04-1.97]), but low levels of fear of COVID-19 (0.55 [0.41-0.76]); nurses had medium to high resilient coping (1.30 [1.03-1.65]). Conclusions: The extent of psychological distress, fear of COVID and coping varied by country; however, some groups were more vulnerable than others. There is an urgent need to prioritise health and well-being of these people through well-designed intervention that may need to be tailored to meet country specific requirements.

BK channels, abundantly expressed in vascular smooth muscle cells (VSMCs), are the key determinant of vascular physiology. BK channel activity is tightly regulated by its accessory β 1 (BK-β 1 ) subunits. BK-β 1 protein expression is down-regulated in diabetic vessels, contributing to diabetic vascular complications including hypertension, stroke and coronary heart disease. However, BK-β 1 mRNA is not reduced in diabetic vessels suggesting increased BK-β 1 turnover. Since ubiquitin-proteasome system (UPS) accounts for 80~90% of intracellular protein degradations in mammalian cells, we hypothesize that muscle ring finger-1 (MuRF-1) protein, the muscle specific E3 ligase, accelerates vascular BK-β 1 degradation in diabetes mellitus. In this study, we found that BK-β 1 protein level was decreased by 1.95±0.14 fold, accompanied by a 2.83±0.16 fold increase of MuRF-1 expression in streptozotocin-induced diabetic mouse vessels (n=3, p<0.05 vs. control). Moreover, response of vascular BK channel activation by DHS-1 (a specific BK-β 1 activator) was absent in diabetic mouse vascular smooth muscle cells (VSMCs). Similar results were observed in human VSMCs cultured with 22 mM glucose (HG) compared to those cultured with 5 mM glucose. Knockdown of MuRF-1 by siRNA (100 nM) produced a 4.2-fold decrease of MuRF-1 protein level and a 1.8-fold increase in BK-β 1 expression in HG-cultured VSMCs. In addition, the total BK-β 1 expression was 2.58±0.04 fold lower but the ubiquitinated BK-β 1 protein was 5.18±0.04 fold higher in HEK293 cells 48-h after transfection with MuRF-1, compared to those with MuRF-1ΔR (an inactive mutant with the Ring structure deletion) transfection (n=3, p<0.05). Immunoprecipitation experiments confirmed that the N-terminus of BK-β 1 was physically associated with MuRF-1. Inhibition of UPS activity by 10 μM MG-132 (a proteasome inhibitor) enhanced BK-β 1 expression by 1.70±0.01 fold (n=3, p<0.05 vs. control). Our results indicate that MuRF-1 participated in ubiquitin-mediated vascular BK-β 1 protein proteasomal degradation and delineated a fundamental mechanism underlying vasculopathy in diabetes.

We tested the hypothesis that endothelial PPARδ plays an important role in the protection of neurovascular unit. Cerebral microvessels were isolated from mice with endothelium-specific deficiency of PPARδ (ePPARδ-/-) and littermate wild type (WT) mice. After ex vivo incubation of cerebral microvessels for 24 h, supernatant was collected and levels of soluble amyloid precursor protein α [sAPPα, a product of non-amyloidogenic processing of amyloid precursor protein (APP)] were measured using an ELISA kit. The production of sAPPα in cerebral microvessels of ePPARδ-/- mice was reduced by 54%, as compared to WT mice (n=6-7, P<0.05). Western blot analysis demonstrated that microvascular expression of ADAM10 was reduced in ePPARδ-/- mice (80%) (n=18, P<0.05), while ADAM17 protein level was increased in by 132% (n=4, P<0.05), as compared to WT mice. Protein expressions of APP, ADAM9, and BACE1 were not significantly different between cerebral microvessels derived from ePPARδ-/- mice and WT mice. Real-time RT-PCR demonstrated that in brain microvessels of ePPARδ-/- mice mRNA levels of ADAM10 were also decreased by 56% (n=5, P<0.05). Furthermore, Western blot analysis of the brain regions showed that sAPPα content was selectively reduced in hippocampus of ePPARδ-/- mice by 80% (n=11, P<0.05). This was associated with significantly reduced expression of ADAM10 in the hippocampus (n=11, P<0.05). In contrast, protein levels of ADAM10, and sAPPα were not altered in cortex and cerebellum of ePPARδ-/- mice. In addition, we did not detect any changes in Aβ40 and Aβ42 levels (measured using ELISA assay) in all three examined brain regions. Since sAPPα is a potent neurotrophic and neuro-protective molecule, our results suggest that loss of endothelial PPARδ may selectively increase vulnerability of hippocampus. This mechanism may contribute to susceptibility of hippocampus to injury during initiation and progression of neuro-degenerative diseases.