Biological Functions and Regulatory Mechanisms of Hypoxia-Inducible Factor-1α in Ischemic Stroke

Ischemic stroke is caused by insufficient cerebrovascular blood and oxygen supply. It is a major contributor to death or disability worldwide and has become a heavy societal and clinical burden. To date, effective treatments for ischemic stroke are limited, and innovative therapeutic methods are urgently needed. Hypoxia inducible factor-1α (HIF-1α) is a sensitive regulator of oxygen homeostasis, and its expression is rapidly induced after hypoxia/ischemia. It plays an extensive role in the pathophysiology of stroke, including neuronal survival, neuroinflammation, angiogenesis, glucose metabolism, and blood brain barrier regulation. In addition, the spatiotemporal expression profile of HIF-1α in the brain shifts with the progression of ischemic stroke; this has led to contradictory findings regarding its function in previous studies. Therefore, unveiling the Janus face of HIF-1α and its target genes in different type of cells and exploring the role of HIF-1α in inflammatory responses after ischemia is of great importance for revealing the pathogenesis and identifying new therapeutic targets for ischemic stroke. Herein, we provide a succinct overview of the current approaches targeting HIF-1α and summarize novel findings concerning HIF-1α regulation in different types of cells within neurovascular units, including neurons, endothelial cells, astrocytes, and microglia, during the different stages of ischemic stroke. The current representative translational approaches focused on neuroprotection by targeting HIF-1α are also discussed.

Regulation of suberin biosynthesis and Casparian strip development in the root endodermis by two plant auxins

The biological function of the auxin phenylacetic acid (PAA) is not well characterized in plants. Although some aspects of its biology; transport, signaling and metabolism have recently been described. Previous work on this phytohormone has suggested that PAA behaves in an identical manner to IAA (indole-3-acetic acid) in promoting plant growth, yet plants require greater concentrations of PAA to elicit the same physiological responses. Here we show that normalized PAA treatment results in the differential expression of a unique list of genes, suggesting that plants can respond differently to the two auxins. This is further explored in endodermal barrier regulation where the two auxins invoke striking differences in the deposition patterns of suberin. We further show that auxin acts antagonistically on Casparian strip (CS) formation as it can circumvent the CS transcriptional machinery to repress CS related genes. Additionally, altered suberin biosynthesis reduces endogenous levels of PAA and CS deficiency represses the biosynthesis of IAA and the levels of both auxins. These findings implicate auxin as a regulator of endodermal barrier formation and highlight a novel role for PAA in root development and differentiation.

Impact of Tariffs and Nontariff Barriers on the International Trade

In the modern world economy, tariff and non-tariff barrier regulation actsas an effective regulator, promoting greater openness of the market, oras the most widespread foreign trade instrument of protectionism. Over the past decades there has been a steady decline in the rates of import customs duties. On the other hand, non-tariff measures to regulate foreign trade are being applied more and more effectively. But at the same time customs and tariff policy continues to be a key factor determining the national trade regime and the conditions for access of foreign products to the domestic market.The main purpose of this research is to assess the influence of tariffs and non-tariff barriers on international trade, asthese factors play an essential role in the international trade.The theoretical and methodological basis of the study was the work of scientists in the field of finance, state regulation of foreign economic activity and international relations. In the methodology part gravity model regression is assessed for tariff and non-tariff measures (NTMs)regulatingforeign trade flows. As result, non-tariff barriers (NTMs) such as Sanitary and Phytosanitary Standards (SPS) and Technical Barriers to trade (TBT) have had the largest negative impact.

Estrogen-mediated upregulation of the Mas receptor contributes to sex differences in acute lung injury and lung vascular barrier regulation

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; yet sex-dependent incidences of acute respiratory distress syndrome (ARDS) remain controversial and sex-dependent mechanisms of endothelial barrier regulation is unknown. In premenopausal women increased signalling of angiotensin (Ang)-(1–7) via the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang-(1–7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang-(1–7)/Mas signalling may protect females over males in ALI/ARDS.Clinical data were collected from Charité inpatients. Sex differences in ALI were assessed in wild-type (WT) and Mas-deficient (Mas−/−) mice. Endothelial permeability was assessed as weight change in isolated lungs and as trans-endothelial electrical resistance in vitro.In 734 090 Charité inpatients (2005–2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung edema, protein leak, and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and female Mas−/− mice than female WT, whereas Mas receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas receptor expression. In vitro, estrogen increased Mas receptor expression and attenuated endothelial leak in response to thrombin; this effect was alleviated by Mas receptor blockade.Improved lung endothelial barrier function protects female mice from ALI-induced lung edema. This effect is partially mediated via enhanced Ang-(1–7)/Mas signalling as a result of estrogen-dependent Mas expression.

ACE2-expressing endothelial cells in aging mouse brain

Angiotensin-converting enzyme 2 (ACE2) is a key receptor mediating the entry of SARS-CoV-2 into the host cell. Through a systematic analysis of publicly available mouse brain sc/snRNA-seq data, we found that ACE2 is specifically expressed in small sub-populations of endothelial cells and mural cells, namely pericytes and vascular smooth muscle cells. Further, functional changes in viral mRNA transcription and replication, and impaired blood-brain barrier regulation were most prominently implicated in the aged, ACE2-expressing endothelial cells, when compared to the young adult mouse brains. Concordant EC transcriptomic changes were further found in normal aged human brains. Overall, this work reveals an outline of ACE2 distribution in the mouse brain and identify putative brain host cells that may underlie the selective susceptibility of the aging brain to viral infection.