Detection of an ultra-bright submillimeter galaxy in the Subaru/XMM-Newton Deep Field using AzTEC/ASTE

We report the detection of an extremely bright ($\sim$37 mJy at 1100 $\mu$m and $\sim$91 mJy at 880 $\mu$m) submillimeter galaxy (SMG), AzTEC-ASTE-SXDF1100.001 (hereafter referred to as SXDF1100.001 or Orochi), discovered in 1100 $\mu$m observations of the Subaru/XMM-Newton Deep Field using AzTEC on ASTE. Subsequent CARMA 1300 $\mu$m and SMA 880 $\mu$m observations successfully pinpoint the location of Orochi and suggest that it has two components, one extended (FWHM of $\sim$ 4$^{\prime\prime}$) and one compact (unresolved). Z-Spec on CSO has also been used to obtain a wide band spectrum from 190 to 308 GHz, although no significant emission/absorption lines are found. The derived upper limit to the line-to-continuum flux ratio is 0.1--0.3 (2 $\sigma$) across the Z-Spec band. Based on the analysis of the derived spectral energy distribution from optical to radio wavelengths of possible counterparts near the SMA/CARMA peak position, we suggest that Orochi is a lensed, optically dark SMG lying at $z \sim 3.4$ behind a foreground, optically visible (but red) galaxy at $z \sim 1.4$. The deduced apparent (i.e., no correction for magnification) infrared luminosity ($L_{\rm IR}$) and star formation rate (SFR) are $6 \times 10^{13}$ $L_{\odot}$ and 11000 $M_{\odot}$ yr$^{-1}$, respectively, assuming that the $L_{\rm IR}$ is dominated by star formation. These values suggest that Orochi will consume its gas reservoir within a short time scale ($3 \times 10^{7}$ yr), which is indeed comparable to those in extreme starbursts like the centres of local ULIRGs.Comment: 18 pages, 13 figure

Mechanisms of Allergen-Antibody Interaction of Cockroach Allergen Bla g 2 with Monoclonal Antibodies That Inhibit IgE Antibody Binding

BACKGROUND: Cockroach allergy is strongly associated with asthma, and involves the production of IgE antibodies against inhaled allergens. Reports of conformational epitopes on inhaled allergens are limited. The conformational epitopes for two specific monoclonal antibodies (mAb) that interfere with IgE antibody binding were identified by X-ray crystallography on opposite sites of the quasi-symmetrical cockroach allergen Bla g 2. METHODOLOGY/PRINCIPAL FINDINGS: Mutational analysis of selected residues in both epitopes was performed based on the X-ray crystal structures of the allergen with mAb Fab/Fab' fragments, to investigate the structural basis of allergen-antibody interactions. The epitopes of Bla g 2 for the mAb 7C11 or 4C3 were mutated, and the mutants were analyzed by SDS-PAGE, circular dichroism, and/or mass spectrometry. Mutants were tested for mAb and IgE antibody binding by ELISA and fluorescent multiplex array. Single or multiple mutations of five residues from both epitopes resulted in almost complete loss of mAb binding, without affecting the overall folding of the allergen. Preventing glycosylation by mutation N268Q reduced IgE binding, indicating a role of carbohydrates in the interaction. Cation-π interactions, as well as electrostatic and hydrophobic interactions, were important for mAb and IgE antibody binding. Quantitative differences in the effects of mutations on IgE antibody binding were observed, suggesting heterogeneity in epitope recognition among cockroach allergic patients. CONCLUSIONS/SIGNIFICANCE: Analysis by site-directed mutagenesis of epitopes identified by X-ray crystallography revealed an overlap between monoclonal and IgE antibody binding sites and provided insight into the B cell repertoire to Bla g 2 and the mechanisms of allergen-antibody recognition, including involvement of carbohydrates

Ethical issues in autologous stem cell transplantation (ASCT) in advanced breast cancer: A systematic literature review

BACKGROUND: An effectiveness assessment on ASCT in locally advanced and metastatic breast cancer identified serious ethical issues associated with this intervention. Our objective was to systematically review these aspects by means of a literature analysis. METHODS: We chose the reflexive Socratic approach as the review method using Hofmann's question list, conducted a comprehensive literature search in biomedical, psychological and ethics bibliographic databases and screened the resulting hits in a 2-step selection process. Relevant arguments were assembled from the included articles, and were assessed and assigned to the question list. Hofmann's questions were addressed by synthesizing these arguments. RESULTS: Of the identified 879 documents 102 included arguments related to one or more questions from Hofmann's question list. The most important ethical issues were the implementation of ASCT in clinical practice on the basis of phase-II trials in the 1990s and the publication of falsified data in the first randomized controlled trials (Bezwoda fraud), which caused significant negative effects on recruiting patients for further clinical trials and the doctor-patient relationship. Recent meta-analyses report a marginal effect in prolonging disease-free survival, accompanied by severe harms, including death. ASCT in breast cancer remains a stigmatized technology. Reported health-related-quality-of-life data are often at high risk of bias in favor of the survivors. Furthermore little attention has been paid to those patients who were dying. CONCLUSIONS: The questions were addressed in different degrees of completeness. All arguments were assignable to the questions. The central ethical dimensions of ASCT could be discussed by reviewing the published literature

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

The Mw 5.8 Mineral, Virginia, earthquake of August 2011 and aftershock sequence: Constraints on earthquake source parameters and fault geometry

The Mw 5.8 earthquake of 23 August 2011 (17:51:04 UTC) (moment, M0 5.7 × 1017 N·m) occurred near Mineral, Virginia, within the central Virginia seismic zone and was felt by more people than any other earthquake in United States history. The U.S. Geological Survey (USGS) received 148,638 felt reports from 31 states and 4 Canadian provinces. The USGS PAGER system estimates as many as 120,000 people were exposed to shaking intensity levels of IV and greater, with approximately 10,000 exposed to shaking as high as intensity VIII. Both regional and teleseismic moment tensor solutions characterize the earthquake as a northeaststriking reverse fault that nucleated at a depth of approximately 7 ± 2 km. The distribution of reported macroseismic intensities is roughly ten times the area of a similarly sized earthquake in the western United States (Horton and Williams, 2012). Nearsource and far-field damage reports, which extend as far away as Washington, D.C., (135 km away) and Baltimore, Maryland, (200 km away) are consistent with an earthquake of this size and depth in the eastern United States (EUS). Within the first few days following the earthquake, several government and academic institutions installed 36 portable seismograph stations in the epicentral region, making this among the best-recorded aftershock sequences in the EUS. Based on modeling of these data, we provide a detailed description of the source parameters of the mainshock and analysis of the subsequent aftershock sequence for defining the fault geometry, area of rupture, and observations of the aftershock sequence magnitude-frequency and temporal distribution. The observed slope of the magnitude-frequency curve or b-value for the aftershock sequence is consistent with previous EUS studies (b=0.75), suggesting that most of the accumulated strain was released by the mainshock. The aftershocks define a rupture that extends between approximately 2-8 km in depth and 8-10 km along the strike of the fault plane. Best-fit modeling of the geometry of the aftershock sequence defines a rupture plane that strikes N36°E and dips to the east-southeast at 49.5°. Moment tensor solutions of the mainshock and larger aftershocks are consistent with the distribution of aftershock locations, both indicating reverse slip along a northeast-southwest striking southeastdipping fault plane