Explore the vast range of titles available.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor ( BMPR2 ), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17 , and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2 , encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention. Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2 , ATP13A3 , AQP1 and SOX17 .

Background Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 ( BMPR2 ) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes ( BMPR2 , GDF2 , and TBX4 ), two recently identified candidate genes ( SOX17 , KDR ), and two new candidate genes (fibulin 2, FBLN2 ; platelet-derived growth factor D, PDGFD ). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions Rare variant analysis of a large international consortium identified two new candidate genes— FBLN2 and PDGFD . The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.

Although the invention of right heart catheterisation in the 1950s enabled accurate clinical diagnosis of pulmonary arterial hypertension (PAH), it was not until 2000 when the landmark discovery of the causative role of bone morphogenetic protein receptor type II (BMPR2) mutations shed new light on the pathogenesis of PAH. Since then several genes have been discovered, which now account for around 25% of cases with the clinical diagnosis of idiopathic PAH. Despite the ongoing efforts, in the majority of patients the cause of the disease remains elusive, a phenomenon often referred to as “missing heritability”. In this review, we discuss research approaches to uncover the genetic architecture of PAH starting with forward phenotyping, which in a research setting should focus on stable intermediate phenotypes, forward and reverse genetics, and finally reverse phenotyping. We then discuss potential sources of “missing heritability” and how functional genomics and multi-omics methods are employed to tackle this problem.

Using grounded theory methods, we examined coparenting relationships for 25 divorced mothers who experienced violence during their marriages. How well former husbands were able to differentiate, or keep separate, their parental and spousal roles emerged as central to coparenting dynamics and was partly related to type of marital violence. Linking differentiation to types of martial violence advances our theoretical understanding of variations in coparenting relationships after divorce. Results can be used to more effectively match divorcing parents with appropriate interventions.

Bay anchovyAnchoa mitchilliand naked gobyGobiosoma bosclarvae have been reported to move up-estuary. In the present study, we examined depth preferences and periodic vertical movements that might promote such along-estuary transport in these 2 species. We conducted 2 cruises of 3 d each in the Hudson River estuary, USA. The cruises were 1 wk apart, coinciding with spring and neap tides. We sampled every 2 h with an ichthyoplankton trawl to permit tests of time, depth, and lateral position on larval concentration. We also collected data on water-column structure with a CTD, and current velocity with an acoustic Doppler current profiler (ADCP). We briefly sampled at several sites over a distance of 25 km along the river, and found that larvae of both species were uniformly abundant along this section although salinity decreased sharply with increasing distance upriver. Bay anchovy larvae were more abundant than goby larvae (median concentration 234 vs 6.6 ind. 100 m–3). Most sampling was conducted at an oligohaline location (mean salinity = 3 to 5 psu). Larvae were typically more concentrated at greater depths; among anchovy larvae during neap tide conditions, and goby larvae during neap and spring tide conditions, larvae were more concentrated at 6 and 8 m than at the surface by a factor of 2 to 9. Large larvae showed a stronger depth preference than small larvae. During spring tide, the water column was less stratified, and anchovy larvae under these conditions were uniformly distributed vertically. There were slight lateral differences in larval concentration, with fewer larvae in shallow water over the shoals than in similar depths in the main channel. We evaluated periodic cycles in flow and larval distributions via harmonic regression. Tidal constituents of the depth-averaged current flow included the K1 (period = 23.9 h), M2 (period = 12.4 h), and the M4 (period = 6.2 h) tides. Harmonic regression explained >95% of the observed variability in mean flow. Diel periodicity in depth-averaged larvae concentration was evident, particularly among large anchovy and goby larvae during neap tide conditions. Larvae were more abundant in the sampled depths at night than during the day by a factor of 3 to 10. There was also diel periodicity in the mean depth of goby larvae, such that larvae were about 2 m shallower at night than during the day. There was no periodic variability in the mean depth of anchovy larvae. We suggest that diel periodicity in larval concentration and mean depth reflects diel migration to shallower water at night, noting that temporal variability in net avoidance may also contribute to the periodicity. We conclude that anchovy and goby larvae exhibit a depth distribution and vertical migration behavior that promotes upriver transport. Transport should be most rapid during neap tide periods.

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG , and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH. Idiopathic pulmonary arterial hypertension is a rare and fatal disease with a heterogeneous treatment response. Here the authors show that unsupervised machine learning of whole blood transcriptomes from 359 patients with idiopathic pulmonary arterial hypertension identifies 3 subgroups (endophenotypes) that improve risk stratification and provide new molecular insights.

Little is known about the health care received by women with disabilities, who comprise a substantial subset of the population. This article describes the health care of a national sample of low-income female Medicaid recipients. Despite having similar potential for care (health insurance, usual source of care, and having a physician as a usual source of care) as compared to nondisabled women, women with disabilities had substantially worse rates of receiving medical care and medication when they were needed and of cervical cancer screenings. Women with disabilities were also much less likely to be satisfied with their care than were nondisabled women. These results support calls to mandate quality-based reimbursement incentives within Medicaid, specifically for women with disabilities.