PEX19 is a predominantly cytosolic chaperone and import receptor for class 1 peroxisomal membrane proteins

Integral peroxisomal membrane proteins (PMPs) are synthesized in the cytoplasm and imported posttranslationally. Here, we demonstrate that PEX19 binds and stabilizes newly synthesized PMPs in the cytosol, binds to multiple PMP targeting signals (mPTSs), interacts with the hydrophobic domains of PMP targeting signals, and is essential for PMP targeting and import. These results show that PEX19 functions as both a chaperone and an import receptor for newly synthesized PMPs. We also demonstrate the existence of two PMP import mechanisms and two classes of mPTSs: class 1 mPTSs, which are bound by PEX19 and imported in a PEX19-dependent manner, and class 2 mPTSs, which are not bound by PEX19 and mediate protein import independently of PEX19

PEX3 functions as a PEX19 docking factor in the import of class I peroxisomal membrane proteins

PEX19 is a chaperone and import receptor for newly synthesized, class I peroxisomal membrane proteins (PMPs). PEX19 binds these PMPs in the cytoplasm and delivers them to the peroxisome for subsequent insertion into the peroxisome membrane, indicating that there may be a PEX19 docking factor in the peroxisome membrane. Here we show that PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes. PEX3 is also sufficient to dock PEX19 at heterologous organelles and binds PEX19 via a conserved motif that is essential for this docking activity and for PEX3 function in general. Not surprisingly, transient inhibition of PEX3 abrogates class I PMP import but has no effect on class II PMP import or peroxisomal matrix protein import. Taken together, these results suggest that PEX3 plays a selective, essential, and direct role in PMP import as a docking factor for PEX19

A Comprehensive Archival Search for Counterparts to Ultra-Compact High Velocity Clouds: Five Local Volume Dwarf Galaxies

We report five Local Volume dwarf galaxies (two of which are presented here for the first time) uncovered during a comprehensive archival search for optical counterparts to ultra-compact high velocity clouds (UCHVCs). The UCHVC population of HI clouds are thought to be candidate gas-rich, low mass halos at the edge of the Local Group and beyond, but no comprehensive search for stellar counterparts to these systems has been presented. Careful visual inspection of all publicly available optical and ultraviolet imaging at the position of the UCHVCs revealed six blue, diffuse counterparts with a morphology consistent with a faint dwarf galaxy beyond the Local Group. Optical spectroscopy of all six candidate dwarf counterparts show that five have an H$\alpha$-derived velocity consistent with the coincident HI cloud, confirming their association, the sixth diffuse counterpart is likely a background object. The size and luminosity of the UCHVC dwarfs is consistent with other known Local Volume dwarf irregular galaxies. The gas fraction ($M_{HI}/M_{star}$) of the five dwarfs are generally consistent with that of dwarf irregular galaxies in the Local Volume, although ALFALFA-Dw1 (associated with ALFALFA UCHVC HVC274.68+74.70$-$123) has a very high $M_{HI}/M_{star}$$\sim$40. Despite the heterogenous nature of our search, we demonstrate that the current dwarf companions to UCHVCs are at the edge of detectability due to their low surface brightness, and that deeper searches are likely to find more stellar systems. If more sensitive searches do not reveal further stellar counterparts to UCHVCs, then the dearth of such systems around the Local Group may be in conflict with $\Lambda$CDM simulations.Comment: 18 pages, 4 tables, 4 figures, ApJ Accepte

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension

Visual Pigment Gene Changes in Adrenoleukodystrophy

Purpose. The gene for X-linked adrenoleukodystrophy, a neurodegenerative disorder, is closely linked to the red/green color pigment genes on the distal X-chromosome Xq28 and one kindred is known to have a genetic change affecting both loci. The purpose of this article is to perform a systematic assessment of the frequency of this situation in many affected kindreds. Methods. Recombinant DNA probes were used in blot hybridization studies to determine the structure of the color pigment genes in affected males from 59 different adrenoleukodystrophy kindreds. Whenever possible, color vision was measured using the Farnsworth 100-Hue test. Results. Eleven of the 59 kindreds had abnormal color pigment gene clusters; these included fusion genes and changes in gene number. Only one kindred had a deletion of sequences immediately 5' to the color pigment genes. Conclusions. The incidence of color pigment gene changes in our 59 adrenoleukodystrophy kindreds is approximately twice the frequency of defective color vision reported in historic studies but is about the same as that found in studies of the actual genes in large populations. However, the range of changes in the color pigment genes in adrenoleukodystrophy is broader than encountered in most populations. Changes in the highly conserved color pigment genes reflect reorganizations in the Xq28 chromosomal region, some of which involve the contiguous gene for adrenoleukodystrophy. Invest Ophthalmol Vis Sci. 1993;34:2634-2637 -?k-linked Adrenoleukodystrophy (ALD) is a devastating neurodegenerative disease affecting boys 6 to 12 years old. Although the underlying metabolic abnormality is unknown, ALD is associated with diagnostic accumulations of very long chain fatty acids. 1 To localize the ALD gene on the human X-chromosome we showed that ALD and the anonymous Xq28 DNA fragment DXS52 cosegregate with a lod score >13 at d = 0.0 in seven kindreds

Measuring psychological health in the perinatal period: workshop consensus statement, 19 March 2013

This consensus statement is the result of an invited workshop funded by the society for Reproductive and Infant Psychology on Measuring Psychological Health in the Perinatal Period which was held in Oxford on the 19th March 2013. The details of those who participated in the workshop can be found at the end of the consensus statement. The workshop evolved out of recognition that a major limitation to research and practice in the perinatal period is identifying valid, reliable and clinically relevant measures of psychological health

Genetics and genomics of pulmonary arterial hypertension.

Since 2000 there have been major advances in our understanding of the genetic and genomics of pulmonary arterial hypertension (PAH), although there remains much to discover. Based on existing knowledge, around 25-30% of patients diagnosed with idiopathic PAH have an underlying Mendelian genetic cause for their condition and should be classified as heritable PAH (HPAH). Here, we summarise the known genetic and genomic drivers of PAH, the insights these provide into pathobiology, and the opportunities afforded for development of novel therapeutic approaches. In addition, factors determining the incomplete penetrance observed in HPAH are discussed. The currently available approaches to genetic testing and counselling, and the impact of a genetic diagnosis on clinical management of the patient with PAH, are presented. Advances in DNA sequencing technology are rapidly expanding our ability to undertake genomic studies at scale in large cohorts. In the future, such studies will provide a more complete picture of the genetic contribution to PAH and, potentially, a molecular classification of this disease

Cognitive behaviour therapy versus counselling intervention for anxiety in young people with high-functioning autism spectrum disorders: a pilot randomised controlled trial

The use of cognitive-behavioural therapy (CBT) as a treatment for children and adolescents with autism spectrum disorder (ASD) has been explored in a number of trials. Whilst CBT appears superior to no treatment or treatment as usual, few studies have assessed CBT against a control group receiving an alternative therapy. Our randomised controlled trial compared use of CBT against person-centred counselling for anxiety in 36 young people with ASD, ages 12–18. Outcome measures included parent- teacher- and self-reports of anxiety and social disability. Whilst each therapy produced improvements inparticipants, neither therapy was superior to the other to a significant degree on any measure. This is consistent with findings for adults