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Background: Although endothelial mesenchymal transition (EndMT) has been characterized as a basic process in embryogenesis, EndMT is the mechanism that accelerates the development of cardiovascular diseases, including heart failure, aging, and complications of diabetes or hypertension as well. Endothelial cells lose their distinct markers and take on a mesenchymal phenotype during EndMT, expressing distinct products. Methods: In this study, type 1 Diabetes mellitus (T1DM) was induced in rats with streptozotocin (STZ) by intraperitoneal injection at a 60 mg/kg dose. Diabetic rats were randomly divided into two groups, namely, control and diabetic rats, for 4 weeks. Heart, aorta, and plasma samples were collected at the end of 4 weeks. Sequentially, biochemical parameters, cytokines, reactive oxygen species (ROS), protein expression of EndMT markers (Chemokine C-X-C motif ligand-1 (CXCL-1), vimentin, citrullinated histone H3 (H3Cit), α-smooth muscle actin (α-SMA), and transforming growth factor beta (TGF-β) and versican), components of the extracellular matrix (matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinase-1(TIMP-1), and discoidin domain tyrosine kinase receptor 2 (DDR-2)) were detected by ELISA or Western blot, respectively. Results: Cytokines and ROS were increased in diabetic hearts, which induced partial EndMT. Among EndMT markers, histone citrullination, α-SMA, and CXCL-1 were increased; vimentin was decreased in DM. The endothelial marker endothelin-1 was significantly higher in the aortas of DM rats. Interestingly, TGF-β showed a significant decrease in the diabetic heart, plasma, and aorta. Additionally, MMP-2/TIMP-1 levels also decreased in DM. Conclusions: To sum up, the identification of molecules and regulatory pathways involved in EndMT provided novel therapeutic approaches for cardiac pathophysiological conditions.

The objective of this review is to examine the connection between osteoporosis and diabetes, compare the underlying causes of osteoporosis in various forms of diabetes, and suggest optimal methods for diagnosing and assessing fracture risk in diabetic patients. This narrative review discusses the key factors contributing to the heightened risk of fractures in individuals with diabetes, as well as the shared elements impacting the treatment of both diabetes mellitus and osteoporosis. Understanding the close link between diabetes and a heightened risk of fractures is crucial in effectively managing both conditions. There are several review articles of meta-analysis regarding diaporosis. Nevertheless, no review articles showed collected and well-organized medications of antidiabetics and made for inconvenient reading for those who were interested in details of drug mechanisms. In this article, we presented collected and comprehensive charts of every antidiabetic medication which was linked to fracture risk and indicated plausible descriptions according to research articles.

Peptidylarginine deiminase 4 (PAD4) catalyzes protein citrullination, a post-translational modification implicated in type 1 diabetes mellitus (T1DM). This study examined PAD4 expression and activity in the pancreas of streptozotocin (STZ)-induced diabetic Wistar rats. Animals were divided into three groups: (A) STZ-induced diabetic rats (60 mg/kg, i.p.), (B) non-diabetic controls, and (C) diabetic rats treated with Cl-amidine (5 mg/kg), a pan-PAD inhibitor, from week six post-induction. Analyses included PAD4 mRNA and protein expression, citrullinated histone H3 (CitH3), calcium concentration, and neutrophil elastase activity. Diabetic rats exhibited increased PAD4 expression, CitH3 levels, and NETosis markers, alongside reduced pancreatic calcium, suggesting calcium consumption during PAD4 activation. Cl-amidine treatment attenuated NETosis. These results implicate PAD4 in T1DM pathogenesis via NETosis and support the utility of STZ-induced diabetic rats as a model for PAD4-targeted studies. Cl-amidine may represent a promising therapeutic approach to reduce pancreatic inflammation in T1DM.

Early detection of acute ischemic stroke secondary to painless aortic dissection is a challenge for emergency physicians, especially when under the stress of the 3-hour golden time window for thrombolytic therapy. We reported a 57-year-old man with acute right hemisphere watershed ischemic stroke caused by painless type A aortic dissection was diagnosed in time with computed tomographic (CT) angiography. The possible detrimental impact which may have been incurred by thrombolytic therapy was avoided. We suggest that cerebral CT angiography, covering from the aortic arch to intracranial arteries, should be performed in acute ischemic stroke patients, particularly in those with watershed CT perfusion deficits, to exclude the possibility of aortic dissection before thrombolytic treatment.

(1) Background: In cardiovascular applications, paclitaxel inhibits smooth muscle cell proliferation and migration and significantly reduces the occurrence of restenosis and target lesion revascularization. However, the cellular effects of paclitaxel in the myocardium are not well understood; (2) Methods: Wistar rats were divided into four groups: control (CTRL), isoproterenol (ISO) treated (1 mg/kg) and two groups treated with paclitaxel (PAC), which was administrated (10 mg/kg/day) for 5 days by gavage/per os alone or in combination (ISO + PAC) 3 weeks after ISO treatment. Ventricular tissue was harvested 24 h later for measurements of heme oxygenase (HO-1), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), NF-κB, TNF-α and myeloperoxidase (MPO); (3) Results: HO-1 protein concentration, HO-1 activity, SOD protein concentration and total glutathione significantly decreased in response to ISO treatment. When PAC was administered in conjunction with ISO, HO-1, SOD concentration and total glutathione were not different from control levels. MPO activity, NF-κB concentration and TNF-α protein concentration were significantly increased in the ISO-only group, while the levels of these molecules were restored when PAC was co-administered; (4) Conclusions: Oral administration of PAC can maintain the expression of important antioxidants, anti-inflammatory molecules, HO-1, SOD and GSH, and suppress the production of TNF-α, MPO and NF-κB, which are involved in myocardial damage. The principal component of this cellular defense seems to be the expression of HO-1.

Background Frail older adults are predisposed to multiple comorbidities and adverse events. Recent interventional studies have shown that frailty can be improved and managed. In this study, effective individualized home-based exercise and nutrition interventions were developed for reducing frailty in older adults. Methods This study was a four-arm, single-blind, randomized controlled trial conducted between October 2015 and June 2017 at Miaoli General Hospital in Taiwan. Overall, 319 pre-frail or frail older adults were randomly assigned into one of the four study groups (control, exercise, nutrition, and exercise plus nutrition [combination]) and followed up during a 3-month intervention period and 3-month self-maintenance period. Improvement in frailty scores was the primary outcome. Secondary outcomes included improvements in physical performance and mental health. The measurements were performed at baseline, 1 month, 3 months, and 6 months. Results At the 6-month measurement, the exercise (difference in frailty score change from baseline: − 0.23; 95% confidence interval [CI]: − 0.41, − 0.05; p  = 0.012), nutrition (− 0.28; 95% CI: − 0.46, − 0.11; p  = 0.002), and combination (− 0.34; 95% CI: − 0.52, − 0.16; p  <  0.001) groups exhibited significantly greater improvements in the frailty scores than the control group. Significant improvements were also observed in several physical performance parameters in the exercise, nutrition, and combination groups, as well as in the 12-Item Short Form Health Survey mental component summary score for the nutrition group. Conclusions The designated home-based exercise and nutrition interventions can help pre-frail or frail older adults to improve their frailty score and physical performance. Trial registration Retrospectively registered at ClinicalTrials.gov (identifier: NCT03477097); registration date: March 26, 2018.

Copper electrocatalysts have been shown to selectively reduce carbon dioxide to hydrocarbons. Nevertheless, the absence of a systematic study based on time-resolved spectroscopy renders the functional agent—either metallic or oxidative Copper—for the selectivity still undecidable. Herein, we develop an operando seconds-resolved X-ray absorption spectroscopy to uncover the chemical state evolution of working catalysts. An oxide-derived Copper electrocatalyst is employed as a model catalyst to offer scientific insights into the roles metal states serve in carbon dioxide reduction reaction (CO 2 RR). Using a potential switching approach, the model catalyst can achieve a steady chemical state of half-Cu(0)-and-half-Cu(I) and selectively produce asymmetric C 2 products - C 2 H 5 OH. Furthermore, a theoretical analysis reveals that a surface composed of Cu-Cu(I) ensembles can have dual carbon monoxide molecules coupled asymmetrically, which potentially enhances the catalyst’s CO 2 RR product selectivity toward C 2 products. Our results offer understandings of the fundamental chemical states and insights to the establishment of selective CO 2 RR. A systematic time-resolved study can provide key insights on selective carbon dioxide electro-reduction. Here, the authors report operando seconds-resolved X-ray absorption spectroscopy to uncover the chemical state evolution of working catalysts in a carbon dioxide electroreduction process.

The gait pattern of exoskeleton control conflicting with the human operator’s (the pilot) intention may cause awkward maneuvering or even injury. Therefore, it has been the focus of many studies to help decide the proper gait operation. However, the timing for the recognization plays a crucial role in the operation. The delayed detection of the pilot’s intent can be equally undesirable to the exoskeleton operation. Instead of recognizing the motion, this study examines the possibility of identifying the transition between gaits to achieve in-time detection. This study used the data from IMU sensors for future mobile applications. Furthermore, we tested using two machine learning networks: a linearfFeedforward neural network and a long short-term memory network. The gait data are from five subjects for training and testing. The study results show that: 1. The network can successfully separate the transition period from the motion periods. 2. The detection of gait change from walking to sitting can be as fast as 0.17 s, which is adequate for future control applications. However, detecting the transition from standing to walking can take as long as 1.2 s. 3. This study also find that the network trained for one person can also detect movement changes for different persons without deteriorating the performance.

Background The c.G6055A (p.G2019S) mutation in leucine-rich repeat kinase 2 ( LRRK2 ) is the most prevalent genetic cause of Parkinson’s disease (PD). CRISPR/Cas9-mediated genome editing by homology-directed repair (HDR) has been applied to correct the mutation but may create small insertions and deletions (indels) due to double-strand DNA breaks. Adenine base editors (ABEs) could convert targeted A·T to G·C in genomic DNA without double-strand breaks. However, the correction efficiency of ABE in LRRK2 c.G6055A (p.G2019S) mutation remains unknown yet. This study aimed to compare the mutation correction efficiencies and off-target effects between HDR and ABEs in induced pluripotent stem cells (iPSCs) carrying LRRK2 c.G6055A (p.G2019S) mutation. Methods A set of mutation-corrected isogenic lines by editing the LRRK2 c.G6055A (p.G2019S) mutation in a PD patient-derived iPSC line using HDR or ABE were established. The mutation correction efficacies, off-target effects, and indels between HDR and ABE were compared. Comparative transcriptomic and proteomic analyses between the LRRK2 p.G2019S iPSCs and isogenic control cells were performed to identify novel molecular targets involved in LRRK2-parkinsonism pathways. Results ABE had a higher correction rate (13/53 clones, 24.5%) than HDR (3/47 clones, 6.4%). Twenty-seven HDR clones (57.4%), but no ABE clones, had deletions, though 14 ABE clones (26.4%) had off-target mutations. The corrected isogenic iPSC-derived dopaminergic neurons exhibited reduced LRRK2 kinase activity, decreased phospho-α-synuclein expression, and mitigated neurite shrinkage and apoptosis. Comparative transcriptomic and proteomic analysis identified different gene expression patterns in energy metabolism, protein degradation, and peroxisome proliferator-activated receptor pathways between the mutant and isogenic control cells. Conclusions The results of this study envision that ABE could directly correct the pathogenic mutation in iPSCs for reversing disease-related phenotypes in neuropathology and exploring novel pathophysiological targets in PD.

The B.1.1.7 variant of SARS-CoV-2 first detected in the UK harbors amino-acid substitutions and deletions in the spike protein that potentially enhance host angiotensin conversion enzyme 2 (ACE2) receptor binding and viral immune evasion. Here we report cryo-EM structures of the spike protein of B.1.1.7 in the apo and ACE2-bound forms. The apo form showed one or two receptor-binding domains (RBDs) in the open conformation, without populating the fully closed state. All three RBDs were engaged in ACE2 binding. The B.1.1.7-specific A570D mutation introduces a molecular switch that could modulate the opening and closing of the RBD. The N501Y mutation introduces a π – π interaction that enhances RBD binding to ACE2 and abolishes binding of a potent neutralizing antibody (nAb). Cryo-EM also revealed how a cocktail of two nAbs simultaneously bind to all three RBDs, and demonstrated the potency of the nAb cocktail to neutralize different SARS-CoV-2 pseudovirus strains, including B.1.1.7. Cryo-EM structures and functional analyses of the SARS-CoV-2 B.1.1.7 variant spike protein reveal that the A570D mutation creates a molecular switch to regulate up-down conformations of the ACE2 receptor-binding domain through a pedal-bin-like mechanism.