Busana et al. (doi.org/10.1152/japplphysiol.00871.2020) published 5 patients with COVID-19 in whom the fraction of non-aerated lung tissue had been quantified by computed tomography. They assumed ...that shunt flow fraction was proportional to the non-aerated lung fraction, and, by randomly generating 10.sup.6 different bimodal distributions for the ventilation-perfusion (V/Q) ratios in the lung, specified as sets of paired values {Vi,Qi}, sought to identify as solutions those that generated the observed arterial partial pressures of CO.sub.2 and O.sub.2 (Pa.sub.CO2 and Pa.sub.O2). Our study sought to develop a direct method of calculation to replace the approach of randomly generating different distributions, and so provide more accurate solutions that were within the measurement error of the blood-gas data. For the one patient in whom Busana et al. did not find solutions, we demonstrated that the assumed shunt flow fraction led to a non-shunt blood flow that was too low to support the required gas exchange. For the other four patients, we found precise solutions (prediction error < 1x10.sup.-3 mmHg for both Pa.sub.CO2 and Pa.sub.O2 ), with distributions qualitatively similar to those of Busana et al. These distributions were extremely wide and unlikely to be physically realisable, because they predict the maintenance of very large concentration gradients in regions of the lung where convection is slow. We consider that these wide distributions arise because the assumed value for shunt flow is too low in these patients, and we discuss possible reasons why the assumption relating to shunt flow fraction may break down in COVID-19 pneumonia.
The indigenous people of the Tibetan Plateau have been the subject of much recent interest because of their unique genetic adaptations to high altitude. Recent studies have demonstrated that the ...Tibetan EPAS1 haplotype is involved in high altitude-adaptation and originated in an archaic Denisovan-related population. We sequenced the whole-genomes of 27 Tibetans and conducted analyses to infer a detailed history of demography and natural selection of this population. We detected evidence of population structure between the ancestral Han and Tibetan subpopulations as early as 44 to 58 thousand years ago, but with high rates of gene flow until approximately 9 thousand years ago. The CMS test ranked EPAS1 and EGLN1 as the top two positive selection candidates, and in addition identified PTGIS, VDR, and KCTD12 as new candidate genes. The advantageous Tibetan EPAS1 haplotype shared many variants with the Denisovan genome, with an ancient gene tree divergence between the Tibetan and Denisovan haplotypes of about 1 million years ago. With the exception of EPAS1, we observed no evidence of positive selection on Denisovan-like haplotypes.
The Tibetan Plateau is one of the highest regions on Earth. Tibetan highlanders are adapted to life and reproduction in a hypoxic environment and possess a suite of distinctive physiological traits. ...Recent studies have identified genomic loci that have undergone natural selection in Tibetans. Two of these loci, EGLN1 and EPAS1, encode major components of the hypoxia-inducible factor transcriptional system, which has a central role in oxygen sensing and coordinating an organism's response to hypoxia, as evidenced by studies in humans and mice. An association between genetic variants within these genes and hemoglobin concentration in Tibetans at high altitude was demonstrated in some of the studies (8, 80, 96). Nevertheless, the functional variants within these genes and the underlying mechanisms of action are still not known. Furthermore, there are a number of other possible phenotypic traits, besides hemoglobin concentration, upon which natural selection may have acted. Integration of studies at the genomic level with functional molecular studies and studies in systems physiology has the potential to provide further understanding of human evolution in response to high-altitude hypoxia. The Tibetan paradigm provides further insight on the role of the hypoxia-inducible factor system in humans in relation to oxygen homeostasis.
The hepcidin/ferroportin axis controls systemic iron homeostasis by regulating iron acquisition from the duodenum and reticuloendothelial system, respective sites of iron absorption and recycling. ...Ferroportin is also abundant in the kidney, where it has been implicated in tubular iron reabsorption. However, it remains unknown whether endogenous hepcidin regulates ferroportin-mediated iron reabsorption under physiological conditions, and whether such regulation is important for kidney and/or systemic iron homeostasis. To address these questions, we generated a novel mouse model with an inducible kidney-tubule specific knock-in of fpnC326Y, which encodes a hepcidin-resistant ferroportin termed FPNC326Y. Under conditions of normal iron availability, female mice harboring this allele had consistently decreased kidney iron but only transiently increased systemic iron indices. Under conditions of excess iron availability, male and female mice harboring this allele had milder kidney iron overload, but greater systemic iron overload relative to controls. Additionally, despite comparable systemic iron overload, kidney iron overload occurred in wild type mice fed an iron-loaded diet but not in hemochromatosis mice harboring a ubiquitous knock-in of fpnC326Y. Thus, our study demonstrates that endogenous hepcidin controls ferroportin-mediated tubular iron reabsorption under physiological conditions. It also shows that such control is important for both kidney and systemic iron homeostasis in the context of iron overload.
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Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting ...activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells.
The human side of hypoxia‐inducible factor Smith, Thomas G.; Robbins, Peter A.; Ratcliffe, Peter J.
British journal of haematology,
20/May , Letnik:
141, Številka:
3
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Summary
When humans are exposed to hypoxia, systemic and intracellular changes operate together to minimise hypoxic injury and restore adequate oxygenation. Emerging evidence indicates that the ...hypoxia‐inducible factor (HIF) family of transcription factors plays a central regulatory role in these homeostatic changes at both the systemic and cellular levels. HIF was discovered through its action as the transcriptional activator of erythropoietin, and has subsequently been found to control intracellular hypoxic responses throughout the body. HIF is primarily regulated by specific prolyl hydroxylase‐domain enzymes (PHDs) that initiate its degradation via the von Hippel‐Lindau tumour suppressor protein (VHL). The oxygen and iron dependency of PHD activity accounts for regulation of the pathway by both cellular oxygen and iron status. Recent studies conducted in patients with rare genetic diseases have begun to uncover the wider importance of the PHD‐VHL‐HIF axis in systems‐level human biology. These studies indicate that, in addition to regulating erythropoiesis, the system plays an important role in cardiopulmonary regulation. This article reviews our current understanding of the importance of HIF in human systems‐level physiology, and is modelled around the classic physiological response to high‐altitude hypoxia.
Iron is essential to the cell. Both iron deficiency and overload impinge negatively on cardiac health. Thus, effective iron homeostasis is important for cardiac function. Ferroportin (FPN), the only ...known mammalian iron-exporting protein, plays an essential role in iron homeostasis at the systemic level. It increases systemic iron availability by releasing iron from the cells of the duodenum, spleen, and liver, the sites of iron absorption, recycling, and storage respectively. However, FPN is also found in tissues with no known role in systemic iron handling, such as the heart, where its function remains unknown. To explore this function, we generated mice with a cardiomyocyte-specific deletion ofFpn. We show that these animals have severely impaired cardiac function, with a median survival of 22 wk, despite otherwise unaltered systemic iron status. We then compared their phenotype with that of ubiquitous hepcidin knockouts, a recognized model of the iron-loading disease hemochromatosis. The phenotype of the hepcidin knockouts was far milder, with normal survival up to 12 mo, despite far greater iron loading in the hearts. Histological examination demonstrated that, although cardiac iron accumulates within the cardiomyocytes ofFpnknockouts, it accumulates predominantly in other cell types in the hepcidin knockouts. We conclude, first, that cardiomyocyte FPN is essential for intracellular iron homeostasis and, second, that the site of deposition of iron within the heart determines the severity with which it affects cardiac function. Both findings have significant implications for the assessment and treatment of cardiac complications of iron dysregulation.
In the adult, the liver-derived hormone hepcidin (HAMP) controls systemic iron levels by blocking the iron-exporting protein ferroportin (FPN) in the gut and spleen, the sites of iron absorption and ...recycling, respectively. Impaired HAMP expression or FPN responsiveness to HAMP result in iron overload. HAMP is also expressed in the fetal liver but its role in controlling fetal iron stores is not understood. To address this question in a manner that safeguards against the confounding effects of altered maternal iron homeostasis, we generated fetuses harboring a paternally-inherited ubiquitous knock-in of the HAMP-resistant fpnC326Y. Additionally, to safeguard against any confounding effects of altered placental iron homeostasis, we generated fetuses with a liver-specific knock-in of fpnC326Y or knockout of the hamp gene. These fetuses had reduced liver iron stores and hemoglobin, and markedly increased FPN in the liver, but not in the placenta. Thus, fetal liver HAMP operates cell-autonomously to increase fetal liver iron stores. Our findings also suggest that FPN in the placenta is not actively regulated by fetal liver HAMP under normal physiological conditions.
•Fetal liver hepcidin operates cell-autonomously to enable rapid buildup of fetal liver iron stores in the third trimester of gestation.•Placental ferroportin is not regulated by fetal hepcidin under normal physiological conditions.
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