A common polymorphism in the oxygen-dependent degradation (ODD) domain of hypoxia inducible factor-1α (HIF-1α) does not impair Pro-564 hydroxylation

BACKGROUND: The hypoxia-inducible factor (HIF) transcription complex, which is activated by low oxygen tension, controls a diverse range of cellular processes including angiogenesis and erythropoiesis. Under normoxic conditions, the α subunit of HIF is rapidly degraded in a manner dependent on hydroxylation of two conserved proline residues at positions 402 and 564 in HIF-1α in the oxygen-dependent degradation (ODD) domain. This allows subsequent recognition by the von Hippel-Lindau (VHL) tumor suppressor protein, which targets HIF for degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, prolyl hydroxylation of HIF is inhibited, allowing it to escape VHL-mediated degradation. The transcriptional regulation of the erythropoietin gene by HIF raises the possibility that HIF may play a role in disorders of erythropoiesis, such as idiopathic erythrocytosis (IE). RESULTS: Patients with IE were screened for changes in the HIF-1α coding sequence, and a change in the ODD domain that converts Pro-582 to Ser was identified in several patients. This same change, however, was also detected at a significant frequency, 0.073, in unaffected controls compared to 0.109 in the IE patient group. In vitro hydroxylation assays examining this amino acid change failed to reveal a discernible effect on HIF hydroxylation at Pro-564. CONCLUSION: The Pro582Ser change represents a common polymorphism of HIF-1α that does not impair HIF-1α prolyl hydroxylation. Although the Pro582Ser polymorphism is located in the ODD domain of HIF-1α it does not diminish the association of HIF-1α with VHL. Thus, it is unlikely that this polymorphism accounts for the erythrocytosis in the group of IE patients studied

The Association of Persistent Symptoms of Depression and Anxiety with Recurrent Acute Coronary Syndrome Events: A Prospective Observational Study

The purpose of this study was to examine the role of persistent symptoms of depression and anxiety in a second acute coronary syndrome (ACS) event. Data presented in this study were from an RCT study. A follow-up for 24 months after baseline to detect a second ACS event among 1162 patients from five hospitals. Hierarchal Cox regression analyses were used. The results showed that persistent depression only (HR 2.27; 95% CI: 1.35–3.81; p = 0.002), and comorbid persistent depression and anxiety (HR 2.03; 95% CI: 1.03–3.98; p = 0.040) were the significant predictors of a second ACS event. Secondary education level compared to primary educational level (HR 0.63; 95% CI: 0.43–0.93; p = 0.020) and college or more education level compared to primary educational level (HR 0.47; 95% CI: 0.27–0.84; p = 0.011) were the only demographic variables that were significant predictors of a second event. The study reveals that attention must be paid by healthcare providers to assess and manage persistent depression; particularly when it is co-morbid with anxiety

Exposures among Pregnant Women near the World Trade Center Site on 11 September 2001

We have characterized environmental exposures among 187 women who were pregnant, were at or near the World Trade Center (WTC) on or soon after 11 September 2001, and are enrolled in a prospective cohort study of health effects. Exposures were assessed by estimating time spent in five zones around the WTC and by developing an exposure index (EI) based on plume reconstruction modeling. The daily reconstructed dust levels were correlated with levels of particulate matter ≤ 2.5 μm in aerodynamic diameter (PM(2.5); r = 0.68) or PM(10) (r = 0.73–0.93) reported from 26 September through 8 October 2001 at four of six sites near the WTC whose data we examined. Biomarkers were measured in a subset. Most (71%) of these women were located within eight blocks of the WTC at 0900 hr on 11 September, and 12 women were in one of the two WTC towers. Daily EIs were determined to be highest immediately after 11 September and became much lower but remained highly variable over the next 4 weeks. The weekly summary EI was associated strongly with women’s perception of air quality from week 2 to week 4 after the collapse (p < 0.0001). The highest levels of polycyclic aromatic hydrocarbon–deoxyribonucleic acid (PAH-DNA) adducts were seen among women whose blood was collected sooner after 11 September, but levels showed no significant associations with EI or other potential WTC exposure sources. Lead and cobalt in urine were weakly correlated with ∑EI, but not among samples collected closest to 11 September. Plasma OC levels were low. The median polychlorinated biphenyl level (sum of congeners 118, 138, 153, 180) was 84 ng/g lipid and had a nonsignificant positive association with ∑EI (p > 0.05). 1,2,3,4,6,7,8-Heptachlorodibenzodioxin levels (median, 30 pg/g lipid) were similar to levels reported in WTC-exposed firefighters but were not associated with EI. This report indicates intense bystander exposure after the WTC collapse and provides information about nonoccupational exposures among a vulnerable population of pregnant women

Ex Vivo Expansion of Human CD8+ T Cells Using Autologous CD4+ T Cell Help

Background: Using in vivo mouse models, the mechanisms of CD4+ T cell help have been intensively investigated. However, a mechanistic analysis of human CD4+ T cell help is largely lacking. Our goal was to elucidate the mechanisms of human CD4+ T cell help of CD8+ T cell proliferation using a novel in vitro model. Methods/Principal Findings: We developed a genetically engineered novel human cell-based artificial APC, aAPC/mOKT3, which expresses a membranous form of the anti-CD3 monoclonal antibody OKT3 as well as other immune accessory molecules. Without requiring the addition of allogeneic feeder cells, aAPC/mOKT3 enabled the expansion of both peripheral and tumor-infiltrating T cells, regardless of HLA-restriction. Stimulation with aAPC/mOKT3 did not expand Foxp3+ regulatory T cells, and expanded tumor infiltrating lymphocytes predominantly secreted Th1-type cytokines, interferon-γ and IL-2. In this aAPC-based system, the presence of autologous CD4+ T cells was associated with significantly improved CD8+ T cell expansion in vitro. The CD4+ T cell derived cytokines IL-2 and IL-21 were necessary but not sufficient for this effect. However, CD4+ T cell help of CD8+ T cell proliferation was partially recapitulated by both adding IL-2/IL-21 and by upregulation of IL-21 receptor on CD8+ T cells. Conclusions: We have developed an in vitro model that advances our understanding of the immunobiology of human CD4+ T cell help of CD8+ T cells. Our data suggests that human CD4+ T cell help can be leveraged to expand CD8+ T cells in vitro

A VERITAS/Breakthrough Listen Search for Optical Technosignatures

The Breakthrough Listen Initiative is conducting a program using multiple telescopes around the world to search for "technosignatures": artificial transmitters of extraterrestrial origin from beyond our solar system. The VERITAS Collaboration joined this program in 2018, and provides the capability to search for one particular technosignature: optical pulses of a few nanoseconds duration detectable over interstellar distances. We report here on the analysis and results of dedicated VERITAS observations of Breakthrough Listen targets conducted in 2019 and 2020 and of archival VERITAS data collected since 2012. Thirty hours of dedicated observations of 136 targets and 249 archival observations of 140 targets were analyzed and did not reveal any signals consistent with a technosignature. The results are used to place limits on the fraction of stars hosting transmitting civilizations. We also discuss the minimum-pulse sensitivity of our observations and present VERITAS observations of CALIOP: a space-based pulsed laser onboard the CALIPSO satellite. The detection of these pulses with VERITAS, using the analysis techniques developed for our technosignature search, allows a test of our analysis efficiency and serves as an important proof-of-principle.Comment: 15 pages, 7 figure

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Global variability in leaf respiration in relation to climate, plant functional types and leaf traits

• Leaf dark respiration (Rdark) is an important yet poorly quantified component of the global carbon cycle. Given this, we analyzed a new global database of Rdark and associated leaf traits. • Data for 899 species were compiled from 100 sites (from the Arctic to the tropics). Several woody and nonwoody plant functional types (PFTs) were represented. Mixed-effects models were used to disentangle sources of variation in Rdark. • Area-based Rdark at the prevailing average daily growth temperature (T) of each site increased only twofold from the Arctic to the tropics, despite a 20°C increase in growing T (8–28°C). By contrast, Rdark at a standard T (25°C, Rdark25) was threefold higher in the Arctic than in the tropics, and twofold higher at arid than at mesic sites. Species and PFTs at cold sites exhibited higher Rdark25 at a given photosynthetic capacity (Vcmax25) or leaf nitrogen concentration ([N]) than species at warmer sites. Rdark25 values at any given Vcmax25 or [N] were higher in herbs than in woody plants. • The results highlight variation in Rdark among species and across global gradients in T and aridity. In addition to their ecological significance, the results provide a framework for improving representation of Rdark in terrestrial biosphere models (TBMs) and associated land-surface components of Earth system models (ESMs)