Constraints on the Assembly and Dynamics of Galaxies: I. Detailed Rest-frame Optical Morphologies on Kiloparsec-scale of z ~ 2 Star-forming Galaxies

We present deep and high-resolution HST/NIC2 F160W imaging at 1.6micron of six z~2 star-forming galaxies with existing near-IR integral field spectroscopy from SINFONI at the VLT. The unique combination of rest-frame optical imaging and nebular emission-line maps provides simultaneous insight into morphologies and dynamical properties. The overall rest-frame optical emission of the galaxies is characterized by shallow profiles in general (Sersic index n<1), with median effective radii of ~5kpc. The morphologies are significantly clumpy and irregular, which we quantify through a non-parametric morphological approach, estimating the Gini (G), Multiplicity (Psi), and M_20 coefficients. The strength of the rest-frame optical emission lines in the F160W bandpass indicates that the observed structure is not dominated by the morphology of line-emitting gas, and must reflect the underlying stellar mass distribution of the galaxies. The sizes and structural parameters in the rest-frame optical continuum and Halpha emission reveal no significant differences, suggesting similar global distributions of the on-going star formation and more evolved stellar population. While no strong correlations are observed between stellar population parameters and morphology within the NIC2/SINFONI sample itself, a consideration of the sample in the context of a broader range of z~2 galaxy types indicates that these galaxies probe the high specific star formation rate and low stellar mass surface density part of the massive z~2 galaxy population, with correspondingly large effective radii, low Sersic indices, low G, and high Psi and M_20. The combined NIC2 and SINFONI dataset yields insights of unprecedented detail into the nature of mass accretion at high redshift. [Abridged]Comment: 44 pages, 19 figures. Revised version accepted for publication in the Astrophysical Journa

A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.

We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation

Newborn spheroids at high redshift: when and how did the dominant, old stars in today's massive galaxies form?

We study ~330 massive (M* > 10^9.5 MSun), newborn spheroidal galaxies (SGs) around the epoch of peak star formation (1<z<3), to explore the high-redshift origin of SGs and gain insight into when and how the old stellar populations that dominate today's Universe formed. The sample is drawn from the HST/WFC3 Early-Release Science programme, which provides deep 10-filter (0.2 - 1.7 micron) HST imaging over a third of the GOODS-South field. We find that the star formation episodes that built the SGs likely peaked in the redshift range 2<z<5 (with a median of z~3) and have decay timescales shorter than ~1.5 Gyr. Starburst timescales and ages show no trend with stellar mass in the range 10^9.5 < M* < 10^10.5 MSun. However, the timescales show increased scatter towards lower values ( 10^10.5 MSun, and an age trend becomes evident in this mass regime: SGs with M* > 10^11.5 MSun are ~2 Gyrs older than their counterparts with M* < 10^10.5 MSun. Nevertheless, a smooth downsizing trend with galaxy mass is not observed, and the large scatter in starburst ages indicate that SGs are not a particularly coeval population. Around half of the blue SGs appear not to drive their star formation via major mergers, and those that have experienced a recent major merger, show only modest enhancements (~40%) in their specific star formation rates. Our empirical study indicates that processes other than major mergers (e.g. violent disk instability driven by cold streams and/or minor mergers) likely play a dominant role in building SGs, and creating a significant fraction of the old stellar populations that dominate today's Universe.Comment: MNRAS in pres

‘Everyone has an agenda’: Professionals’ understanding and negotiation of risk within the Guardianship system of Victoria, Australia

It is frequently asserted that pressures to assess and manage risk have eroded the therapeutic, rights‐based foundation of the human services profession. Some argue that human service workers operate in a culture of fear in which self‐protection and blame avoidance, rather than clients’ needs, primarily drive decision‐making. In the field of Adult Guardianship, it has been suggested that organisational risk avoidance may be motivating applications for substitute decision‐makers, unnecessarily curtailing clients’ rights and freedoms. However, the absence of research examining the operation of risk within Guardianship decision‐making inhibits verifying and responding to this very serious suggestion. This article draws on semi‐structured interviews conducted with 10 professionals involved in the Victorian Guardianship system, which explored how issues of risk are perceived and negotiated in everyday practice. Risk was found to be a complex and subjective construct which can present both dangers and opportunities for Guardianship practitioners and their clients. While a number of participants reported that Guardianship might sometimes operate as an avenue for mitigating the fear and uncertainty of risk, most participants also valued positive risk‐taking and were willing, in their clients’ interests, to challenge conservative logics of risk. These findings highlight the need for further research which examines how service providers and policy makers can create spaces that support open discussions around issues of risk and address practitioners’ sense of fear and vulnerability

A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation

We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation.This work was supported by grants from the Congress Directed Medical Research Program (BC995364 and DAMD17-01-1-0241), Cure Cancer Australia Foundation, NHMRC Australia (projects 1047149, Fellowships 1058356, 481310, 1043400), the Australian Research Council Discovery Project (DP110102288), Princeton University, NIH grant 1R01GM110161-01 (AK), Sidney Kimmel Foundation for Cancer Research (AK), Burroughs Wellcome Foundation (AK), Banque Nationale de Paris-Paribas Australia and New Zealand, Mostyn Family Foundation, Cue Clothing Co., Estee Lauder Australia, RT Hall Trust and Fellowships (ECF-13-08 and ECF-16-022) from the National Breast Cancer Foundatio

A mutation in the viral sensor 2’-5’-oligoadenylate synthetase 2 causes failure of lactation

We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation.Samantha R. Oakes, David Gallego-Ortega, Prudence M. Stanford, Simon Junankar, Wendy Wing Yee Au ... Moira K. O’Bryan ... et al

Guidelines for Disclosing Genetic Information to Family Members: from Development to Use

[À l'origine dans / Was originally part of : CRDP - Droit, biotechnologie et rapport au milieu

Requirements for Receptor Engagement during Infection by Adenovirus Complexed with Blood Coagulation Factor X

Human adenoviruses from multiple species bind to coagulation factor X (FX), yet the importance of this interaction in adenovirus dissemination is unknown. Upon contact with blood, vectors based on adenovirus serotype 5 (Ad5) binds to FX via the hexon protein with nanomolar affinity, leading to selective uptake of the complex into the liver and spleen. The Ad5:FX complex putatively targets heparan sulfate proteoglycans (HSPGs). The aim of this study was to elucidate the specific requirements for Ad5:FX-mediated cellular uptake in this high-affinity pathway, specifically the HSPG receptor requirements as well as the role of penton base-mediated integrin engagement in subsequent internalisation. Removal of HS sidechains by enzymatic digestion or competition with highly-sulfated heparins/heparan sulfates significantly decreased FX-mediated Ad5 cell binding in vitro and ex vivo. Removal of N-linked and, in particular, O-linked sulfate groups significantly attenuated the inhibitory capabilities of heparin, while the chemical inhibition of endogenous HSPG sulfation dose-dependently reduced FX-mediated Ad5 cellular uptake. Unlike native heparin, modified heparins lacking O- or N-linked sulfate groups were unable to inhibit Ad5 accumulation in the liver 1h after intravascular administration of adenovirus. Similar results were observed in vitro using Ad5 vectors possessing mutations ablating CAR- and/or αv integrin binding, demonstrating that attachment of the Ad5:FX complex to the cell surface involves HSPG sulfation. Interestingly, Ad5 vectors ablated for αv integrin binding showed markedly delayed cell entry, highlighting the need for an efficient post-attachment internalisation signal for optimal Ad5 uptake and transport following surface binding mediated through FX. This study therefore integrates the established model of αv integrin-dependent adenoviral infection with the high-affinity FX-mediated pathway. This has important implications for mechanisms that define organ targeting following contact of human adenoviruses with blood

Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia.

Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology

Health Care Utilization During the COVID-19 Pandemic Among Individuals Born Preterm

Importance: Limited data exist on pediatric health care utilization during the COVID-19 pandemic among children and young adults born preterm. Objective: To investigate differences in health care use related to COVID-19 concerns during the pandemic among children and young adults born preterm vs those born at term. Design, Setting, and Participants: In this cohort study, questionnaires regarding COVID-19 and health care utilization were completed by 1691 mother-offspring pairs from 42 pediatric cohorts in the National Institutes of Health Environmental Influences on Child Health Outcomes Program. Children and young adults (ages 1-18 years) in these analyses were born between 2003 and 2021. Data were recorded by the August 31, 2021, data-lock date and were analyzed between October 2021 and October 2022. Exposures: Premature birth (<37 weeks' gestation). Main Outcomes and Measures: The main outcome was health care utilization related to COVID-19 concerns (hospitalization, in-person clinic or emergency department visit, phone or telehealth evaluations). Individuals born preterm vs term (≥37 weeks' gestation) and differences among preterm subgroups of individuals (<28 weeks', 28-36 weeks' vs ≥37 weeks' gestation) were assessed. Generalized estimating equations assessed population odds for health care used and related symptoms, controlling for maternal age, education, and psychiatric disorder; offspring history of bronchopulmonary dysplasia (BPD) or asthma; and timing and age at COVID-19 questionnaire completion. Results: Data from 1691 children and young adults were analyzed; among 270 individuals born preterm, the mean (SD) age at survey completion was 8.8 (4.4) years, 151 (55.9%) were male, and 193 (71.5%) had a history of BPD or asthma diagnosis. Among 1421 comparison individuals with term birth, the mean (SD) age at survey completion was 8.4 (2.4) years, 749 (52.7%) were male, and 233 (16.4%) had a history of BPD or asthma. Preterm subgroups included 159 individuals (58.5%) born at less than 28 weeks' gestation. In adjusted analyses, individuals born preterm had a significantly higher odds of health care utilization related to COVID-19 concerns (adjusted odds ratio [aOR], 1.70; 95% CI, 1.21-2.38) compared with term-born individuals; similar differences were also seen for the subgroup of individuals born at less than 28 weeks' gestation (aOR, 2.15; 95% CI, 1.40-3.29). Maternal history of a psychiatric disorder was a significant covariate associated with health care utilization for all individuals (aOR, 1.44; 95% CI, 1.17-1.78). Conclusions and Relevance: These findings suggest that during the COVID-19 pandemic, children and young adults born preterm were more likely to have used health care related to COVID-19 concerns compared with their term-born peers, independent of a history of BPD or asthma. Further exploration of factors associated with COVID-19-related health care use may facilitate refinement of care models