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Altitude, temperature, circadian rhythms and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Henning Wackerhage, Kenneth A. Dyar, Martin Schönfelder
In summary, Tibetans that live permanently at high altitude have experienced a natural selection of DNA variants of hypoxia-sensing genes such as EPAS1 which encodes HIF-2α, and EGLN1 which encodes PHD2. These mutations limit the increased haematocrit and haemoglobin concentrations at high altitude, allowing the carriers to avoid associated health problems. This is the opposite from the EPOR mutation carriers in Finland who have a higher haematocrit but live at sea level (23). In contrast, people that live in the Andean Altiplano have elevated haemoglobin concentrations, but perhaps selection of additional unidentified alleles that limit the negative consequences of high haemoglobin concentrations. Additionally, there is some evidence that high altitude mice and humans may favour carbohydrate oxidation which is associated with a greater production of ATP per oxygen atom (i.e. P/O ratio).
Genetics and genomics of exposure to high altitude
Published in Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson, Ward, Milledge and West's High Altitude Medicine and Physiology, 2021
Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson
The first three genomic studies to examine genotype-phenotype relationships between adaptive genomic variants and hemoglobin concentration in Tibetans applied these various techniques. Simonson et al. (2010) performed two tests of selection across nearly one million SNPs and identified top genes for adaptation as those that were both contained within a region exhibiting a selective sweep and likely involved in hypoxia sensing and response pathways (Simonson et al. 2010). Ten genes were identified in this overlap and six were related to the HIF system, including EPAS1 and EGLN1, which encode HIF-2α and the oxygen-sensing prolyl hydroxylase PHD2, respectively. EGLN1 and PPARA genes were further associated with relatively lower hemoglobin concentration in Tibetans, and subsequent studies identified associations with metabolic parameters suggesting reduced fatty acid oxidation (Ge et al. 2012) and decreased fatty acid oxidation, greater oxygen utilization, and protection from oxidative stress in skeletal muscle (Horscroft et al. 2017).
Ayurveda Renaissance – Quo Vadis?
Published in D. Suresh Kumar, Ayurveda in the New Millennium, 2020
EGLN1 was one of the 251 differentially expressed genes among the prakṛti types (Prasher et al. 2008). In a follow-up study Aggarwal et al. (2010) reported a link between high-altitude adaptation and common variations rs479200 (C/T) and rs480902 (T/C) in the EGLN1 gene. Additionally, the TT genotype of rs479200, which was more frequent in kapha types and correlated with higher expression of EGLN1, was associated with patients suffering from high-altitude pulmonary edema. However, it was present at a significantly lower frequency in pitta and almost absent in dwellers of high altitude. Analysis of the Human Genome Diversity Panel, Centre d’Étude du Polymorphisme Humain and Indian Genome Variation Consortium panels showed that dissimilar genetic lineages at high altitudes share the same ancestral allele (T) of rs480902 that is over-represented in pitta and positively correlated with altitude globally. Therefore, it can be inferred that EGLN1 polymorphisms are associated with high-altitude adaptation (also see Yi et al. 2010; Simonson et al. 2010; Storz 2010). A genotype rare in highlanders but over-represented in the kapha prakrti subgroup of normal lowlanders may render them more prone to high-altitude pulmonary edema. The authors concluded that genetic analysis of healthy individuals phenotyped using the principles of Ayurveda could uncover genetic variations associated with adaptation to external environment and susceptibility to diseases.
Effect of 3α-dihydroprogesterone and 5α-dihydroprogesterone on DCIS cells and possible impact for postmenopausal women
Published in Climacteric, 2023
M. Sourouni, M. Götte, L. Kiesel, M.-K. von Wahlde
The trend seen toward upregulation or downregulation of the examined markers in comparison to the control on day 5 and day 12 is depicted in Table 1. Interestingly, the trend toward upregulation or downregulation of the majority of markers appears to be dependent on the mere presence of 5αP and not its dose (+/+ or –/–). Only Ki67 and MYBL2 showed differential expression depending on the 5αP dose (± or –/+). In addition, treatment with 5αP triggered almost all markers in the same way over the 12 days (either +/+/+/+ or –/–/–/–). The proliferation markers STK15 and CCNB1, the invasion/metastasis markers MMP9 and GPR126, the anti-apoptotic marker EGLN1 as well as the markers ZEB2 and TWIST1 were overall upregulated (+/+/+/+), whereas the invasion/metastasis marker COL4A2 and the markers ZEB1 and SNAIL were overall downregulated (–/–/–/–). Time counteracted the effect of day 5 (–/–/+/+ or +/±/–) in the invasion/metastasis markers MMP11 and CTSV, the anti-apoptotic marker GSTM as well as the markers BAG1, TGFβ, CDH1, VIMENTIN, TWIST2, FOX C2 and SNAIL2 (Table 1).
A Kindred with a β-Globin Base Substitution [β89(F5)Ser→Arg (AGT>AGG); HBB: c.270T>G] Resulting in Hemoglobin Vanderbilt
Published in Hemoglobin, 2019
William Shomali, Rondeep Brar, Subramanyeswara R. Arekapudi, Jason R. Gotlib
Mutational testing of BPGM exons 1-4, EGLN1 (PHD2) exons 1-5, EPAS (HIF2A) exons 9 and 12, EPOR exon 8, and VHL genes was unrevealing (Mayo Medical Laboratories, Rochester MN, USA). The P50 measured using a Hemox-Analyzer (TCS Scientific Corp., New Hope, PA, USA) was abnormally low at 18.0 mmHg (normal 24-30), consistent with a high oxygen-affinity variant. Cation exchange high performance liquid chromatography (HPLC) and capillary electrophoresis (CE) (in an alkaline buffer using the CapillaryS instrument) (Sebia Inc., Norcross, GA USA) revealed a Hb variant measured at 42.8 and 39.9% by these two methods, respectively (Figure 1). This variant was identified as Hb Vanderbilt by mass spectrometry. Hb F and Hb A2 were within normal limits. No unstable Hb was detected by heat and isopropanol stability studies. β-Globin sequencing showed a heterozygous mutation at codon 89 (AGT>AGG) resulting in an amino acid change from serine to arginine [β89(F5)Ser→Arg, p.Ser90Arg] (Figure 2). β-Globin sequencing in his paternal great-uncle (PCV up to 0.53 L/L) revealed the same codon 89 (AGT>AGG) mutation.
Oxygen sensing; a stunningly elegant molecular machinery highjacked in cancer
Published in Upsala Journal of Medical Sciences, 2020
Very soon thereafter, the Ratcliffe and Kaelin groups published their papers back-to-back in Science, demonstrating that prolyl hydroxylation is the crucial oxygen- and iron-dependent posttranslational modification of HIF-1α, required for recognition by pVHL and HIF-1 stabilisation (30,31). Both the Kaelin and Ratcliffe groups contributed in different collaborative efforts to solve the structural aspects of pVHL recognition of HIF-1α prolyl hydroxylation (33,34); however, Ratcliffe was first to publish on the identification of a HIF prolyl hydroxylase (35). Kaelin followed suit and identified human EGLN1 (the homologue of C. elegans egl-9) as a prolyl hydroxylase binding to and hydroxylating HIF-1α peptides (46).