Optical spectrum of the post-AGB star HD56126 in the region 4010-8790 AA

We studied in detail the optical spectrum of the post-AGB star HD56126 (IRAS07134+1005). We use high resolution spectra (R=25000 and 60000) obtained with the echelle spectrographs of the 6-m telescope. About one and a half thousand absorptions of neutral atoms and ions, absorption bands of C_2, CN, and CH molecules, and interstellar bands (DIBs) are identified in the 4010 to 8790 AA wavelength region, and the depths and radial velocities of these spectral features are measured. Differences are revealed between the variations of the radial velocities measured from spectral features of different excitation. In addition to the well-known variability of the Halpha profile, we found variations in the profiles of a number of FeII, YII, and BaII lines. We also produce an atlas of the spectrum of HD56126 and its comparison staralpha Per. The full version of the atlas is available in electronic form from Web-address: http://www.sao.ru/hq/ssl/Atlas/Atlas.htmlComment: 42 pages, 6 figure

Integrating GWAS with bulk and single-cell RNA-sequencing reveals a role for LY86 in the anti-Candida host response

Contains fulltext : 220669.pdf (publisher's version ) (Open Access)Candida bloodstream infection, i.e. candidemia, is the most frequently encountered life-threatening fungal infection worldwide, with mortality rates up to almost 50%. In the majority of candidemia cases, Candida albicans is responsible. Worryingly, a global increase in the number of patients who are susceptible to infection (e.g. immunocompromised patients), has led to a rise in the incidence of candidemia in the last few decades. Therefore, a better understanding of the anti-Candida host response is essential to overcome this poor prognosis and to lower disease incidence. Here, we integrated genome-wide association studies with bulk and single-cell transcriptomic analyses of immune cells stimulated with Candida albicans to further our understanding of the anti-Candida host response. We show that differential expression analysis upon Candida stimulation in single-cell expression data can reveal the important cell types involved in the host response against Candida. This confirmed the known major role of monocytes, but more interestingly, also uncovered an important role for NK cells. Moreover, combining the power of bulk RNA-seq with the high resolution of single-cell RNA-seq data led to the identification of 27 Candida-response QTLs and revealed the cell types potentially involved herein. Integration of these response QTLs with a GWAS on candidemia susceptibility uncovered a potential new role for LY86 in candidemia susceptibility. Finally, experimental follow-up confirmed that LY86 knockdown results in reduced monocyte migration towards the chemokine MCP-1, thereby implying that this reduced migration may underlie the increased susceptibility to candidemia. Altogether, our integrative systems genetics approach identifies previously unknown mechanisms underlying the immune response to Candida infection

Evolution of cytokine production in Europeans

As our ancestors migrated throughout the different continents, natural selection increased the presence of alleles advantageous in the new environments. Heritable variations that alter the susceptibility to diseases vary with the historical period, the virulence of the infections, and their geographical spread. In this study we built polygenic scores for heritable traits influencing the genetic adaptation in the production of cytokines and immune-mediated disorders, including infectious, inflammatory, and autoimmune diseases, and applied them to the genomes of several ancient European populations. We observed that the advent of the Neolithic was a turning point for immune-mediated traits in Europeans, favoring those alleles linked with the development of tolerance against intracellular pathogens and promoting inflammatory responses against extracellular microbes. These evolutionary patterns are also associated with an increased presence of traits related to inflammatory and auto-immune diseases.N

Pretransplant endotrophin predicts delayed graft function after kidney transplantation

Delayed graft function after kidney transplantation is common and increases morbidity and health care costs. There is evidence that endotrophin, a specific fragment of pro-collagen type VI, promotes the inflammatory response in kidney diseases. We tested the hypothesis that pretransplant endotrophin in kidney transplant recipients may be associated with the risk of delayed graft function. Pretransplant plasma endotrophin was assessed using an enzyme-linked immunosorbent assay in three independent cohorts with 806 kidney transplant recipients. The primary outcome was delayed graft function, i.e., the necessity of at least one dialysis session within one-week posttransplant. In the discovery cohort median pretransplant plasma endotrophin was higher in 32 recipients (12%) who showed delayed graft function when compared to 225 recipients without delayed graft function (58.4 ng/mL [IQR 33.4–69.0]; N = 32; vs. 39.5 ng/mL [IQR 30.6–54.5]; N = 225; P = 0.009). Multivariable logistic regression, fully adjusted for confounders showed, that pretransplant plasma endotrophin as a continuous variable was independently associated with delayed graft function in both validation cohorts, odds ratio 2.09 [95% CI 1.30–3.36] and 2.06 [95% CI 1.43–2.97]. Pretransplant plasma endotrophin, a potentially modifiable factor, was independently associated with increased risk of delayed graft function and may be a new avenue for therapeutic interventions

Potential impact of celiac disease genetic risk factors on T cell receptor signaling in gluten-specific CD4+ T cells

Celiac disease is an auto-immune disease in which an immune response to dietary gluten leads to inflammation and subsequent atrophy of small intestinal villi, causing severe bowel discomfort and malabsorption of nutrients. The major instigating factor for the immune response in celiac disease is the activation of gluten-specific CD4+ T cells expressing T cell receptors that recognize gluten peptides presented in the context of HLA-DQ2 and DQ8. Here we provide an in-depth characterization of 28 gluten-specific T cell clones. We assess their transcriptional and epigenetic response to T cell receptor stimulation and link this to genetic factors associated with celiac disease. Gluten-specific T cells have a distinct transcriptional profile that mostly resembles that of Th1 cells but also express cytokines characteristic of other types of T-helper cells. This transcriptional response appears not to be regulated by changes in chromatin state, but rather by early upregulation of transcription factors and non-coding RNAs that likely orchestrate the subsequent activation of genes that play a role in immune pathways. Finally, integration of chromatin and transcription factor binding profiles suggest that genes activated by T cell receptor stimulation of gluten‑specific T cells may be impacted by genetic variation at several genetic loci associated with celiac disease.</p

An integrative genomics approach identifies KDM4 as a modulator of trained immunity

Innate immune cells are able to build memory characteristics via a process termed trained immunity. Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro-induced trained immunity responses were assessed in two independent population-based cohorts of healthy individuals, the 300 Bacillus Calmette-Guérin (300BCG; n = 267) and 200 Functional Genomics (200FG; n = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta-analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K-Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec-5 and Siglec-14). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions.</p

Steroid hormone-related polymorphisms associate with the development of bone erosions in rheumatoid arthritis and help to predict disease progression: Results from the REPAIR consortium

Here, we assessed whether 41 SNPs within steroid hormone genes associated with erosive disease. The most relevant finding was the rheumatoid factor (RF)-specific effect of the CYP1B1, CYP2C9, ESR2, FcγR3A, and SHBG SNPs to modulate the risk of bone erosions (P = 0.004, 0.0007, 0.0002, 0.013 and 0.015) that was confirmed through meta-analysis of our data with those from the DREAM registry (P = 0.000081, 0.0022, 0.00074, 0.0067 and 0.0087, respectively). Mechanistically, we also found a gender-specific correlation of the CYP2C9rs1799853T/T genotype with serum vitamin D3 levels (P = 0.00085) and a modest effect on IL1β levels after stimulation of PBMCs or blood with LPS and PHA (P = 0.0057 and P = 0.0058). An overall haplotype analysis also showed an association of 3 ESR1 haplotypes with a reduced risk of erosive arthritis (P = 0.009, P = 0.002, and P = 0.002). Furthermore, we observed that the ESR2, ESR1 and FcγR3A SNPs influenced the immune response after stimulation of PBMCs or macrophages with LPS or Pam3Cys (P = 0.002, 0.0008, 0.0011 and 1.97•10−7). Finally, we found that a model built with steroid hormone-related SNPs significantly improved the prediction of erosive disease in seropositive patients (PRF+ = 2.46•10−8) whereas no prediction was detected in seronegative patients (PRF− = 0.36). Although the predictive ability of the model was substantially lower in the replication population (PRF+ = 0.014), we could confirm that CYP1B1 and CYP2C9 SNPs help to predict erosive disease in seropositive patients. These results are the first to suggest a RF-specific association of steroid hormone-related polymorphisms with erosive disease

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

Association Study of Common Genetic Variants and HIV- 1 Acquisition in 6,300 Infected Cases and 7,200 Controls

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception ofCCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: A European register-based study

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors