H0LiCOW III. Quantifying the effect of mass along the line of sight to the gravitational lens HE 0435-1223 through weighted galaxy counts

Based on spectroscopy and multiband wide-field observations of the gravitationally lensed quasar HE 0435-1223, we determine the probability distribution function of the external convergence $\kappa_\mathrm{ext}$ for this system. We measure the under/overdensity of the line of sight towards the lens system and compare it to the average line of sight throughout the universe, determined by using the CFHTLenS as a control field. Aiming to constrain $\kappa_\mathrm{ext}$ as tightly as possible, we determine under/overdensities using various combinations of relevant informative weighing schemes for the galaxy counts, such as projected distance to the lens, redshift, and stellar mass. We then convert the measured under/overdensities into a $\kappa_\mathrm{ext}$ distribution, using ray-tracing through the Millennium Simulation. We explore several limiting magnitudes and apertures, and account for systematic and statistical uncertainties relevant to the quality of the observational data, which we further test through simulations. Our most robust estimate of $\kappa_\mathrm{ext}$ has a median value $\kappa^\mathrm{med}_\mathrm{ext} = 0.004$ and a standard deviation of $\sigma_\kappa = 0.025$. The measured $\sigma_\kappa$ corresponds to $2.5\%$ uncertainty on the time delay distance, and hence the Hubble constant $H_0$ inference from this system. The median $\kappa^\mathrm{med}_\mathrm{ext}$ value is robust to $\sim0.005$ (i.e. $\sim0.5\%$ on $H_0$) regardless of the adopted aperture radius, limiting magnitude and weighting scheme, as long as the latter incorporates galaxy number counts, the projected distance to the main lens, and a prior on the external shear obtained from mass modeling. The availability of a well-constrained $\kappa_\mathrm{ext}$ makes \hequad\ a valuable system for measuring cosmological parameters using strong gravitational lens time delays.Comment: 24 pages, 17 figures, 6 tables. Submitted to MNRA

Notch ligand Delta-like 1 promotes in vivo vasculogenesis in human cord blood-derived endothelial colony forming cells

BACKGROUND AIMS: Human cord blood (CB) is enriched in circulating endothelial colony forming cells (ECFCs) that display high proliferative potential and in vivo vessel forming ability. Because Notch signaling is critical for embryonic blood vessel formation in utero, we hypothesized that Notch pathway activation may enhance cultured ECFC vasculogenic properties in vivo. METHODS: In vitro ECFC stimulation with an immobilized chimeric Notch ligand (Delta-like1(ext-IgG)) led to significant increases in the mRNA and protein levels of Notch regulated Hey2 and EphrinB2 that were blocked by treatment with γ-secretase inhibitor addition. However, Notch stimulated preconditioning in vitro failed to enhance ECFC vasculogenesis in vivo. In contrast, in vivo co-implantation of ECFCs with OP9-Delta-like 1 stromal cells that constitutively expressed the Notch ligand delta-like 1 resulted in enhanced Notch activated ECFC-derived increased vessel density and enlarged vessel area in vivo, an effect not induced by OP9 control stromal implantation. RESULTS: This Notch activation was associated with diminished apoptosis in the exposed ECFC. CONCLUSIONS: We conclude that Notch pathway activation in ECFC in vivo via co-implanted stromal cells expressing delta-like 1 promotes vasculogenesis and augments blood vessel formation via diminishing apoptosis of the implanted ECFC

The YH database: the first Asian diploid genome database

The YH database is a server that allows the user to easily browse and download data from the first Asian diploid genome. The aim of this platform is to facilitate the study of this Asian genome and to enable improved organization and presentation large-scale personal genome data. Powered by GBrowse, we illustrate here the genome sequences, SNPs, and sequencing reads in the MapView. The relationships between phenotype and genotype can be searched by location, dbSNP ID, HGMD ID, gene symbol and disease name. A BLAST web service is also provided for the purpose of aligning query sequence against YH genome consensus. The YH database is currently one of the three personal genome database, organizing the original data and analysis results in a user-friendly interface, which is an endeavor to achieve fundamental goals for establishing personal medicine. The database is available at http://yh.genomics.org.cn

Efficient pathway enrichment and network analysis of GWAS summary data using GSA-SNP2

Pathway-based analysis in genome-wide association study (GWAS) is being widely used to uncover novel multi-genic functional associations. Many of these pathway-based methods have been used to test the enrichment of the associated genes in the pathways, but exhibited low powers and were highly affected by free parameters. We present the novel method and software GSA-SNP2 for pathway enrichment analysis of GWAS P-value data. GSA-SNP2 provides high power, decent type I error control and fast computation by incorporating the random set model and SNP-count adjusted gene score. In a comparative study using simulated and real GWAS data, GSA-SNP2 exhibited high power and best prioritized gold standard positive pathways compared with six existing enrichment-based methods and two self-contained methods (alternative pathway analysis approach). Based on these results, the difference between pathway analysis approaches was investigated and the effects of the gene correlation structures on the pathway enrichment analysis were also discussed. In addition, GSA-SNP2 is able to visualize protein interaction networks within and across the significant pathways so that the user can prioritize the core subnetworks for further studies. GSA-SNP2 is freely available at https://sourceforge.net/projects/gsasnp2

Crystallography of a Lewis-Binding Norovirus, Elucidation of Strain-Specificity to the Polymorphic Human Histo-Blood Group Antigens

Noroviruses, an important cause of acute gastroenteritis in humans, recognize the histo-blood group antigens (HBGAs) as host susceptible factors in a strain-specific manner. The crystal structures of the HBGA-binding interfaces of two A/B/H-binding noroviruses, the prototype Norwalk virus (GI.1) and a predominant GII.4 strain (VA387), have been elucidated. In this study we determined the crystal structures of the P domain protein of the first Lewis-binding norovirus (VA207, GII.9) that has a distinct binding property from those of Norwalk virus and VA387. Co-crystallization of the VA207 P dimer with Ley or sialyl Lex tetrasaccharides showed that VA207 interacts with these antigens through a common site found on the VA387 P protein which is highly conserved among most GII noroviruses. However, the HBGA-binding site of VA207 targeted at the Lewis antigens through the α-1, 3 fucose (the Lewis epitope) as major and the β-N-acetyl glucosamine of the precursor as minor interacting sites. This completely differs from the binding mode of VA387 and Norwalk virus that target at the secretor epitopes. Binding pocket of VA207 is formed by seven amino acids, of which five residues build up the core structure that is essential for the basic binding function, while the other two are involved in strain-specificity. Our results elucidate for the first time the genetic and structural basis of strain-specificity by a direct comparison of two genetically related noroviruses in their interaction with different HBGAs. The results provide insight into the complex interaction between the diverse noroviruses and the polymorphic HBGAs and highlight the role of human HBGA as a critical factor in norovirus evolution

Bibliometric analysis of academic journal recommendations and requirements for surgical and anesthesiologic adverse events reporting.

BACKGROUND Standards for reporting surgical adverse events vary widely within the scientific literature. Failure to adequately capture adverse events hinders efforts to measure the safety of healthcare delivery and improve the quality of care. The aim of the present study is to assess the prevalence and typology of perioperative adverse event reporting guidelines among surgery and anesthesiology journals. MATERIALS AND METHODS In November 2021, three independent reviewers queried journal lists from the SCImago Journal & Country Rank (SJR) portal (www.scimagojr.com), a bibliometric indicator database for surgery and anesthesiology academic journals. Journal characteristics were summarized using SCImago, a bibliometric indicator database extracted from Scopus journal data. Quartile 1 (Q1) was considered the top quartile and Q4 bottom quartile based on the journal impact factor. Journal author guidelines were collected to determine whether adverse event reporting recommendations were included and, if so, the preferred reporting procedures. RESULTS Of 1,409 journals queried, 655 (46.5%) recommended surgical adverse event reporting. Journals most likely to recommend adverse event reporting were: 1) by category surgery (59.1%), urology (53.3%), and anesthesia (52.3%); 2) in top SJR quartiles (i.e. more influential); 3) by region, based in Western Europe (49.8%), North America (49.3%), and the Middle East (48.3%). CONCLUSIONS Surgery and anesthesiology journals do not consistently require or provide recommendations on perioperative adverse event reporting. Journal guidelines regarding adverse event reporting should be standardized and are needed to improve the quality of surgical adverse event reporting with the ultimate goal of improving patient morbidity and mortality

Genome wide SNP discovery, analysis and evaluation in mallard (Anas platyrhynchos)

<p>Abstract</p> <p>Background</p> <p>Next generation sequencing technologies allow to obtain at low cost the genomic sequence information that currently lacks for most economically and ecologically important organisms. For the mallard duck genomic data is limited. The mallard is, besides a species of large agricultural and societal importance, also the focal species when it comes to long distance dispersal of Avian Influenza. For large scale identification of SNPs we performed Illumina sequencing of wild mallard DNA and compared our data with ongoing genome and EST sequencing of domesticated conspecifics. This is the first study of its kind for waterfowl.</p> <p>Results</p> <p>More than one billion base pairs of sequence information were generated resulting in a 16× coverage of a reduced representation library of the mallard genome. Sequence reads were aligned to a draft domesticated duck reference genome and allowed for the detection of over 122,000 SNPs within our mallard sequence dataset. In addition, almost 62,000 nucleotide positions on the domesticated duck reference showed a different nucleotide compared to wild mallard. Approximately 20,000 SNPs identified within our data were shared with SNPs identified in the sequenced domestic duck or in EST sequencing projects. The shared SNPs were considered to be highly reliable and were used to benchmark non-shared SNPs for quality. Genotyping of a representative sample of 364 SNPs resulted in a SNP conversion rate of 99.7%. The correlation of the minor allele count and observed minor allele frequency in the SNP discovery pool was 0.72.</p> <p>Conclusion</p> <p>We identified almost 150,000 SNPs in wild mallards that will likely yield good results in genotyping. Of these, ~101,000 SNPs were detected within our wild mallard sequences and ~49,000 were detected between wild and domesticated duck data. In the ~101,000 SNPs we found a subset of ~20,000 SNPs shared between wild mallards and the sequenced domesticated duck suggesting a low genetic divergence. Comparison of quality metrics between the total SNP set (122,000 + 62,000 = 184,000 SNPs) and the validated subset shows similar characteristics for both sets. This indicates that we have detected a large amount (~150,000) of accurately inferred mallard SNPs, which will benefit bird evolutionary studies, ecological studies (e.g. disentangling migratory connectivity) and industrial breeding programs.</p

Mutation Rates of TGFBR2 and ACVR2 Coding Microsatellites in Human Cells with Defective DNA Mismatch Repair

Microsatellite instability promotes colonic tumorigenesis through generating frameshift mutations at coding microsatellites of tumor suppressor genes, such as TGFBR2 and ACVR2. As a consequence, signaling through these TGFβ family receptors is abrogated in DNA Mismatch repair (MMR)-deficient tumors. How these mutations occur in real time and mutational rates of these human coding sequences have not previously been studied. We utilized cell lines with different MMR deficiencies (hMLH1−/−, hMSH6−/−, hMSH3−/−, and MMR-proficient) to determine mutation rates. Plasmids were constructed in which exon 3 of TGFBR2 and exon 10 of ACVR2 were cloned +1 bp out of frame, immediately after the translation initiation codon of an enhanced GFP (EGFP) gene, allowing a −1 bp frameshift mutation to drive EGFP expression. Mutation-resistant plasmids were constructed by interrupting the coding microsatellite sequences, preventing frameshift mutation. Stable cell lines were established containing portions of TGFBR2 and ACVR2, and nonfluorescent cells were sorted, cultured for 7–35 days, and harvested for flow cytometric mutation detection and DNA sequencing at specific time points. DNA sequencing revealed a −1 bp frameshift mutation (A9 in TGFBR2 and A7 in ACVR2) in the fluorescent cells. Two distinct fluorescent populations, M1 (dim, representing heteroduplexes) and M2 (bright, representing full mutants) were identified, with the M2 fraction accumulating over time. hMLH1 deficiency revealed 11 (5.91×10−4) and 15 (2.18×10−4) times higher mutation rates for the TGFBR2 and ACVR2 microsatellites compared to hMSH6 deficiency, respectively. The mutation rate of the TGFBR2 microsatellite was ∼3 times higher in both hMLH1 and hMSH6 deficiencies than the ACVR2 microsatellite. The −1 bp frameshift mutation rates of TGFBR2 and ACVR2 microsatellite sequences are dependent upon the human MMR background