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Abstract The microvasculature plays a key role in tissue perfusion and exchange of gases and metabolites. In this study we use human blood vessel organoids (BVOs) as a model of the microvasculature. BVOs fully recapitulate key features of the human microvasculature, including the reliance of mature endothelial cells on glycolytic metabolism, as concluded from metabolic flux assays and mass spectrometry-based metabolomics using stable tracing of 13C-glucose. Pharmacological targeting of PFKFB3, an activator of glycolysis, using two chemical inhibitors results in rapid BVO restructuring, vessel regression with reduced pericyte coverage. PFKFB3 mutant BVOs also display similar structural remodelling. Proteomic analysis of the BVO secretome reveal remodelling of the extracellular matrix and differential expression of paracrine mediators such as CTGF. Treatment with recombinant CTGF recovers microvessel structure. In this work we demonstrate that BVOs rapidly undergo restructuring in response to metabolic changes and identify CTGF as a critical paracrine regulator of microvascular integrity.

IntroductionThis study aimed to explore whether aerobic exercise (AE) can prevent fatal stress-induced myocardial injury.MethodsThirty C57BL/6J mice were divided into either a normal diet, high-fat diet, or high-fat diet plus AE (n=10 per group). The AE protocol consisted of eight weeks of swimming. At the end of the diet and AE interventions, the mice were stimulated with fatal stress caused by exhaustive exercise (forced weight-loaded swimming until exhaustion), after which cardiac function was evaluated using echocardiography, myocardial ultrastructure was examined using transmission electron microscopy, and myocardial apoptosis was assessed using western blotting and TUNEL. Mitophagy, mitochondrial biogenesis and dynamics, and activation of the macrophage migration inhibitor factor (MIF)/AMP-activated protein kinase (AMPK) pathway were evaluated using quantitative PCR and western blotting. Obesity phenotypes were assessed once per week.ResultsAE reversed high-fat diet-induced obesity as evidenced by reductions in body weight and visceral fat compared to obese mice without AE. Obesity exacerbated fatal stress-induced myocardial damage, as demonstrated by impaired left ventricular ejection fraction and myocardial structure. The apoptotic rate was also elevated upon fatal stress, and AE ameliorated this damage. Obesity suppressed mitophagy, mitochondrial fission and fusion, and mitochondrial biogenesis, and these effects were accompanied by suppression of the MIF/AMPK pathway in the myocardium of mice subjected to fatal stress. AE alleviated or reversed these effects.ConclusionThis study provides evidence that AE ameliorated fatal stress-induced myocardial injury in obese mice. The cardioprotective effect of AE in obese mice might be attributed to improved mitochondrial quality.

The locally adjusted cubic-spline capping (LACC) algorithm is well recognized for its effectiveness in the global time series reconstruction of vegetation biophysical and biochemical parameters. However, in its application, we often encounter issues, such as identifying positively biased outliers for vegetation biochemical parameters and reducing the influence of long consecutive gaps. In this study, we improved the LACC algorithm to address the above two issues by (1) incorporating a procedure to remove outliers and (2) integrating the spatial information of neighboring pixels for large data gap filling. To evaluate the performance of the new version of LACC (namely LACC2.0), leaf chlorophyll content (LCC) was taken as an example. A reference LCC curve was generated for each pixel of the global map as the true value for global evaluation, and a time series of LCC with real gaps in the original data for each pixel was created by adding Gaussian noises into observations for testing the effectiveness of time series reconstruction algorithms. Results showed that the percentage of pixels with an RMSE smaller than 5 μg/cm2 was improved from 81.2% in LACC to 96.4% in LACC2.0, demonstrating that LACC2.0 had the potential to provide a better reconstruction of global daily satellite-derived vegetation biochemical parameters. This finding highlights the significance of outlier removal and spatial-temporal fusion to enhance the accuracy and reliability of time series reconstruction.

Vascular endothelial cell (EC) dysfunction contributes to the occurrence of diabetic complications. Here the authors report that in diabetic conditions, upregulation of the RNA binding protein QKI-7 in ECs due to the imbalance of RNA splicing factors CUG-BP and hnRNPM contributes to EC dysfunction, and that in vivo QKI-7 silencing improves blood flow recovery in diabetic mice with limb ischemia.

Analysis of left ventricular systolic dysfunction remained at the centre of heart failure research for many years (also known as heart failure with reduced ejection fraction, HFrEF). Although more than 50% of all heart failure patients experience a form of heart failure characterised by preserved ejection fraction (HFpEF), the pathophysiological mechanisms leading to this form of heart failure remain not well-understood. Several evidence-based treatments for HFrEF are in routine use, but there are limited evidence-based therapies for HFpEF. The effects of these remain controversial, with current treatment options being limited to managing the associated symptoms and conditions. Accumulating evidence demonstrates that pro-inflammatory and oxidative stress pathways play key roles in the development and progression of HFpEF, such as the Unfolded Protein Response (UPR) and inducible nitric oxide synthase. Celastrol, derived from medicinal plants, is a bioactive compound with strong anti-inflammatory properties, which could deem it as fruitful in overcoming the effects of such dysregulated UPR. This literature review therefore focuses on Celastrol's anti-inflammatory and antioxidant activities, alongside its other potential therapeutic activities, and its ability to impede the pathways that are thought to be involved in the development of HFpEF, such as the JAK2/STAT pathway, to elucidate the potential therapeutic role of this bioactive compound, in the treatment of HFpEF.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

We are living in an era where environmental challenges are at their peak, and one of the reasons for such challenges is the use of plastic. Therefore, the key objective of the current study is to test the effect of waste plastic on environmental degradation. This study is empirical in nature, and we use data from the World Bank (World Development Indicators) to testify to the said nexus. This study is conducted particularly in the context of eight (8) Asian countries across ten (10) years. By using multivariate regression models, the statistical results testify that the use of waste plastic leads to environmental degradation. These outcomes are further robustly checked by using multiple proxies for both waste plastic usage and environmental degradation. These results indicate that the use of waste plastics has harmful impacts that are becoming obvious and greatly contribute to environmental deterioration. Moreover, the higher recycling rate helps minimize the consequences of waste plastic. This study significantly contributes to environmental policies and the safety level, particularly with respect to the use of waste plastic. [ABSTRACT FROM AUTHOR]