Observations with the High Altitude GAmma-Ray (HAGAR) telescope array in the Indian Himalayas

The High Altitude GAmma-Ray (HAGAR) array is a wavefront sampling array of 7 telescopes, set-up at Hanle, at 4270 m amsl, in the Ladakh region of the Himalayas (Northern India). It constitutes the first phase of the HImalayan Gamma-Ray Observatory (HIGRO) project. HAGAR is the first array of atmospheric Cherenkov telescopes established at a so high altitude, and was designed to reach a relatively low threshold (currently around 200 GeV) with quite a low mirror area (31 m2). Regular source observations are running since September 2008. Estimation of the sensitivity of the experiment is undergoing using several hours of data from the direction of Crab nebula, the standard candle source of TeV gamma-ray astronomy, and from dark regions. Data were acquired using the On-source/Off-source tracking mode, and by comparing these sky regions the strength of the gamma-ray signal could be estimated. Gamma-ray events arrive close to telescope axis direction while the cosmic-ray background events arrive from the whole field of view. We discuss our analysis procedures for the estimate of arrival direction, estimate of gamma ray flux from Crab nebula, and the sensitivity of the HAGAR system, in this paper

Risk of developing active tuberculosis following tuberculosis screening and preventive therapy for Tibetan refugee children and adolescents in India: An impact assessment.

BackgroundTuberculosis (TB) rates among Tibetan refugee children and adolescents attending boarding schools in India are extremely high. We undertook a comprehensive case finding and TB preventive treatment (TPT) program in 7 schools in the Zero TB Kids project. We aimed to measure the TB infection and disease burden and investigate the risk of TB disease in children and adults who did and did not receive TPT in the schools.Methods and findingsA mobile team annually screened children and staff for TB at the 7 boarding schools in Himachal Pradesh, India, using symptom criteria, radiography, molecular diagnostics, and tuberculin skin tests. TB infection (TBI) was treated with short-course regimens of isoniazid and rifampin or rifampin. TB disease was treated according to Tibetan and Indian guidelines. Between April 2017 and December 2019, 6,582 schoolchildren (median age 14 [IQR 11-16] years) and 807 staff (median age 40 [IQR 33-48] years) were enrolled. Fifty-one percent of the students and 58% of the staff were females. Over 13,161 person-years of follow-up in schoolchildren (median follow-up 2.3 years) and 1,800 person-years of follow-up in staff (median follow-up 2.5 years), 69 TB episodes occurred in schoolchildren and 4 TB episodes occurred in staff, yielding annual incidence rates of 524/100,000 (95% CI 414-663/100,000) person-years and 256/100,000 (95% CI 96-683/100,000) person-years, respectively. Of 1,412 schoolchildren diagnosed with TBI, 1,192 received TPT. Schoolchildren who received TPT had 79% lower risk of TB disease (adjusted hazard ratio [aHR] 0.21; 95% CI 0.07-0.69; p = 0.010) compared to non-recipients, the primary study outcome. Protection was greater in recent contacts (aHR 0.07; 95% CI 0.01-0.42; p = 0.004), the secondary study outcome. The prevalence of recent contacts was 28% (1,843/6,582). Two different TPT regimens were used (3HR and 4R), and both were apparently effective. No staff receiving TPT developed TB. Overall, between 2017 and 2019, TB disease incidence decreased by 87%, from 837/100,000 (95% CI 604-1,129/100,000) person-years to 110/100,000 (95% CI 36-255/100,000) person-years (p ConclusionsIn this study, following implementation of a school-wide TB screening and preventive treatment program, we observed a significant reduction in the burden of TB disease and TBI in children and adolescents. The benefit of TPT was particularly marked for recent TB contacts. This initiative may serve as a model for TB detection and prevention in children and adolescents in other communities affected by TB

Novel CARM1-Interacting Protein, DZIP3, Is a Transcriptional Coactivator of Estrogen Receptor-α

Coactivator-associated arginine methyltransferase 1 (CARM1) is known to promote estrogen receptor (ER)α-mediated transcription in breast cancer cells. To further characterize the regulation of ERα-mediated transcription by CARM1, we screened CARM1-interacting proteins by yeast two-hybrid. Here, we have identified an E3 ubiquitin ligase, DAZ (deleted in azoospermia)-interacting protein 3 (DZIP3), as a novel CARM1-binding protein. DZIP3-dependent ubiquitination of histone H2A has been associated with repression of transcription. However, ERα reporter gene assays demonstrated that DZIP3 enhanced ERα-mediated transcription and cooperated synergistically with CARM1. Interaction with CARM1 was observed with the E3 ligase RING domain of DZIP3. The methyltransferase activity of CARM1 partially contributed to the synergy with DZIP3 for transcription activation, but the E3 ubiquitin ligase activity of DZIP3 was dispensable. DZIP3 also interacted with the C-terminal activation domain 2 of glucocorticoid receptor-interacting protein 1 (GRIP1) and enhanced the interaction between GRIP1 and CARM1. Depletion of DZIP3 by small interfering RNA in MCF7 cells reduced estradiol-induced gene expression of ERα target genes, GREB1 and pS2, and DZIP3 was recruited to the estrogen response elements of the same ERα target genes. These results indicate that DZIP3 is a novel coactivator of ERα target gene expression

Evolutionary history of Tibetans inferred from whole-genome sequencing

<div><p>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 <i>EPAS1</i> 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 <i>EPAS1</i> and <i>EGLN1</i> as the top two positive selection candidates, and in addition identified <i>PTGIS</i>, <i>VDR</i>, and <i>KCTD12</i> as new candidate genes. The advantageous Tibetan <i>EPAS1</i> 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 <i>EPAS1</i>, we observed no evidence of positive selection on Denisovan-like haplotypes.</p></div

Haplotype map and CMS score in four genomic regions.

<p>The upper bar plot demonstrates the CMS values at each SNV. The middle plot shows the haplotype structure of 27 Tibetan genomes in the region; each row represents one genome and each column is one SNV aligned with its CMS score in the upper figure. Both red and green color indicates uncommon variants (MAF<5%) in Yoruba, Europeans, Native Americans and Asians; variants in green in addition must be in the high-coverage reference Denisovan genome. When applicable, the lower plot represents the gene model for the protein-coding gene in the region, with each vertical line representing one exon. a) <i>VDR</i> gene region (Chr12:48257328–48357328); b) <i>EPAS1</i> gene region (Chr2: 46533376–46792633). The arrowed block above the bar plot indicates a previously identified 32.7kb region enriched for Denisovan variants; the dot above the bar plot indicates a previously identified deletion common in Tibetans (chr2: 46694276–46697683); c) <i>EGLN1</i> gene region (Chr1: 231457651–231657496); d) a 200-kb genomic region that presumably underwent no positive selection (showing Chr21: 32800690–33000356, the 200-kb region with the median CMS score).</p

Top 10 regions with the highest CMS scores (hg19 coordinates), with connecting 200-kb windows merged.

<p>Top 10 regions with the highest CMS scores (hg19 coordinates), with connecting 200-kb windows merged.</p

Timeline of important evolutionary events in the demographic history of Tibetans.

<p>The horizontal axis represents the estimated time of events (in years) in the past. The age of the <i>EGLN1</i> D4E mutation is based on previous estimates.</p

Illustration of the best-fitting ∂a∂i model.

<p>Illustration of the best-fitting ∂a∂i model.</p

Manhattan plot of the CMS score across the autosome.

<p>The x-axis represents the chromosome number and each dot represents one SNV. A) All autosomal SNVs; B) SNVs that are present in the high-coverage reference Denisovan genome and Tibetans but uncommon (MAF<5%) in Yoruba, Europeans, Native Americans and Asians. CMS scores all have negative values, with higher scores corresponding to stronger positive selection signals.</p