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

Exotic particles below the TeV from low scale flavour theories

A flavour gauge theory is observable only if the symmetry is broken at relatively low energies. The intrinsic parity-violation of the fermion representations in a flavour theory describing quark, lepton and higgsino masses and mixings generically requires anomaly cancellation by new fermions. Benchmark supersymmetric flavour models are built and studied to argue that: i) the flavour symmetry breaking should be about three orders of magnitude above the higgsino mass, enough also to efficiently suppress FCNC and CP violations coming from higher-dimensional operators; ii) new fermions with exotic decays into lighter particles are typically required at scales of the order of the higgsino mass.Comment: 19 pages, references added, one comment and one footnote added, results unchange

10 simple rules to create a serious game, illustrated with examples from structural biology

Serious scientific games are games whose purpose is not only fun. In the field of science, the serious goals include crucial activities for scientists: outreach, teaching and research. The number of serious games is increasing rapidly, in particular citizen science games, games that allow people to produce and/or analyze scientific data. Interestingly, it is possible to build a set of rules providing a guideline to create or improve serious games. We present arguments gathered from our own experience ( Phylo , DocMolecules , HiRE-RNA contest and Pangu) as well as examples from the growing literature on scientific serious games

Estrogen receptor transcription and transactivation: Structure-function relationship in DNA- and ligand-binding domains of estrogen receptors

Estrogen receptors are members of the nuclear receptor steroid family that exhibit specific structural features, ligand-binding domain sequence identity and dimeric interactions, that single them out. The crystal structures of their DNA-binding domains give some insight into how nuclear receptors discriminate between DNA response elements. The various ligand-binding domain crystal structures of the two known estrogen receptor isotypes (α and β) allow one to interpret ligand specificity and reveal the interactions responsible for stabilizing the activation helix H12 in the agonist and antagonist positions

The Glasgow Norms:Ratings of 5,500 words on nine scales

The Glasgow Norms are a set of normative ratings for 5,553 English words on nine psycholinguistic dimensions: arousal, valence, dominance, concreteness, imageability, familiarity, age of acquisition, semantic size, and gender association. The Glasgow Norms are unique in several respects. First, the corpus itself is relatively large, while simultaneously providing norms across a substantial number of lexical dimensions. Second, for any given subset of words, the same participants provided ratings across all nine dimensions (33 participants/word, on average). Third, two novel dimensions—semantic size and gender association—are included. Finally, the corpus contains a set of 379 ambiguous words that are presented either alone (e.g., toast) or with information that selects an alternative sense (e.g., toast (bread), toast (speech)). The relationships between the dimensions of the Glasgow Norms were initially investigated by assessing their correlations. In addition, a principal component analysis revealed four main factors, accounting for 82% of the variance (Visualization, Emotion, Salience, and Exposure). The validity of the Glasgow Norms was established via comparisons of our ratings to 18 different sets of current psycholinguistic norms. The dimension of size was tested with megastudy data, confirming findings from past studies that have explicitly examined this variable. Alternative senses of ambiguous words (i.e., disambiguated forms), when discordant on a given dimension, seemingly led to appropriately distinct ratings. Informal comparisons between the ratings of ambiguous words and of their alternative senses showed different patterns that likely depended on several factors (the number of senses, their relative strengths, and the rating scales themselves). Overall, the Glasgow Norms provide a valuable resource—in particular, for researchers investigating the role of word recognition in language comprehension

Standardized voluntary force measurement in a lower extremity rehabilitation robot

BACKGROUND: Isometric force measurements in the lower extremity are widely used in rehabilitation of subjects with neurological movement disorders (NMD) because walking ability has been shown to be related to muscle strength. Therefore muscle strength measurements can be used to monitor and control the effects of training programs. A new method to assess isometric muscle force was implemented in the driven gait orthosis (DGO) Lokomat. To evaluate the capabilities of this new measurement method, inter- and intra-rater reliability were assessed. METHODS: Reliability was assessed in subjects with and without NMD. Subjects were tested twice on the same day by two different therapists to test inter-rater reliability and on two separate days by the same therapist to test intra-rater reliability. RESULTS: Results showed fair to good reliability for the new measurement method to assess isometric muscle force of lower extremities. In subjects without NMD, intraclass correlation coefficients (ICC) for inter-rater reliability ranged from 0.72 to 0.97 and intra-rater reliability from 0.71 to 0.90. In subjects with NMD, ICC ranged from 0.66 to 0.97 for inter-rater and from 0.50 to 0.96 for intra-rater reliability. CONCLUSION: Inter- and intra- rater reliability of an assessment method for measuring maximal voluntary isometric muscle force of lower extremities was demonstrated. We suggest that this method is a valuable tool for documentation and controlling of the rehabilitation process in patients using a DGO

Deep ugrizY imaging and DEEP2/3 spectroscopy: a photometric redshift testbed for LSST and public release of data from the DEEP3 Galaxy Redshift Survey

We present catalogues of calibrated photometry and spectroscopic redshifts in the Extended Groth Strip, intended for studies of photometric redshifts (photo-z’s). The data includes ugriz photometry from Canada–France–Hawaii Telescope Legacy Survey (CFHTLS) and Y-band photometry from the Subaru Suprime camera, as well as spectroscopic redshifts from the DEEP2, DEEP3, and 3D-HST surveys. These catalogues incorporate corrections to produce effectively matched-aperture photometry across all bands, based upon object size information available in the catalogue and Moffat profile point spread function fits. We test this catalogue with a simple machine learning-based photometric redshift algorithm based upon Random Forest regression, and find that the corrected aperture photometry leads to significant improvement in photo-z accuracy compared to the original SEXTRACTOR catalogues from CFHTLS and Subaru. The deep ugrizY photometry and spectroscopic redshifts are well suited for empirical tests of photometric redshift algorithms for LSST. The resulting catalogues are publicly available at http://d-scholarship.pitt.edu/36064/. We include a basic summary of the strategy of the DEEP3 Galaxy Redshift Survey to accompany the recent public release of DEEP3 data

Compound Evolutionary History of the Rhesus Macaque Mhc Class I B Region Revealed by Microsatellite Analysis and Localization of Retroviral Sequences

In humans, the single polymorphic B locus of the major histocompatibility complex is linked to the microsatellite MIB. In rhesus macaques, however, haplotypes are characterized by the presence of unique combinations of multiple B genes, which may display different levels of polymorphism. The aim of the study was to shed light on the evolutionary history of this highly complex region. First, the robustness of the microsatellite MIB-linked to almost half of the B genes in rhesus macaques (Mamu-B)–for accurate B haplotyping was studied. Based on the physical map of an established haplotype comprising 7 MIB loci, each located next to a certain Mamu-B gene, two MIB loci, MIB1 and MIB6, were investigated in a panel of MHC homozygous monkeys. MIB1 revealed a complex genotyping pattern, whereas MIB6 analysis resulted in the detection of one or no amplicon. Both patterns are specific for a given B haplotype, show Mendelian segregation, and even allow a more precise haplotype definition than do traditional typing methods. Second, a search was performed for retroelements that may have played a role in duplication processes as observed in the macaque B region. This resulted in the description of two types of duplicons. One basic unit comprises an expressed Mamu-B gene, adjacent to an HERV16 copy closely linked to MIB. The second type of duplicon comprises a Mamu-B (pseudo)gene, linked to a truncated HERV16 structure lacking its MIB segment. Such truncation seems to coincide with the loss of B gene transcription. Subsequent to the duplication processes, recombination between MIB and Mamu-B loci appears to have occurred, resulting in a hyperplastic B region. Thus, analysis of MIB in addition to B loci allows deciphering of the compound evolutionary history of the class I B region in Old World monkeys

Prostaglandins, masculinization and its disorders:effects of fetal exposure of the rat to the cyclooxygenase inhibitor- indomethacin

Recent studies have established that masculinization of the male reproductive tract is programmed by androgens in a critical fetal ‘masculinization programming window’ (MPW). What is peculiar to androgen action during this period is, however, unknown. Studies from 20 years ago in mice implicated prostaglandin (PG)-mediation of androgen-induced masculinization, but this has never been followed up. We therefore investigated if PGs might mediate androgen effects in the MPW by exposing pregnant rats to indomethacin (which blocks PG production by inhibiting cyclooxygenase activity) during this period and then examining if androgen production or action (masculinization) was affected. Pregnant rats were treated with indomethacin (0.8 mg/kg/day; e15.5–e18.5) to encompass the MPW. Indomethacin exposure decreased fetal bodyweight (e21.5), testis weight (e21.5) and testicular PGE2 (e17.5, e21.5), but had no effect on intratesticular testosterone (ITT; e17.5) or anogenital index (AGI; e21.5). Postnatally, AGI, testis weight and blood testosterone were unaffected by indomethacin exposure and no cryptorchidism or hypospadias occurred. Penis length was normal in indomethacin-exposed animals at Pnd25 but was reduced by 26% (p<0.001) in adulthood, an effect that is unexplained. Our results demonstrate that indomethacin can effectively decrease intra-testicular PGE2 level. However, the resulting male phenotype does not support a role for PGs in mediating androgen-induced masculinization during the MPW in rats. The contrast with previous mouse studies is unexplained but may reflect a species difference