Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation.

Genomic sequence interpretation can miss clinically relevant missense variants for several reasons. Rare missense variants are numerous in the exome and difficult to prioritise. Affected genes may also not have existing disease association. To improve variant prioritisation, we leverage population exome data to identify intragenic missense-depleted regions (MDRs) genome-wide that may be important in disease. We then use missense depletion analyses to help prioritise undiagnosed disease exome variants. We demonstrate application of this strategy to identify a novel gene association for human brain malformation. We identified de novo missense variants that affect the GDP/GTP-binding site of ARF1 in three unrelated patients. Corresponding functional analysis suggests ARF1 GDP/GTP-activation is affected by the specific missense mutations associated with heterotopia. These findings expand the genetic pathway underpinning neurologic disease that classically includes FLNA. ARF1 along with ARFGEF2 add further evidence implicating ARF/GEFs in the brain. Using functional ontology, top MDR-containing genes were highly enriched for nucleotide-binding function, suggesting these may be candidates for human disease. Routine consideration of MDR in the interpretation of exome data for rare diseases may help identify strong genetic factors for many severe conditions, infertility/reduction in reproductive capability, and embryonic conditions contributing to preterm loss

Collagen processing and cuticle formation is catalysed by the astacin metalloprotease DPY-31 in free-living and parasitic nematodes

The exoskeleton or cuticle performs many key roles in the development and survival of all nematodes. This structure is predominantly collagenous in nature and requires numerous enzymes to properly fold, modify, process and cross-link these essential structural proteins. The cuticle structure and its collagen components are conserved throughout the nematode phylum but differ from the collagenous matrices found in vertebrates. This structure, its formation and the enzymology of nematode cuticle collagen biogenesis have been elucidated in the free-living nematode Caenorhabditis elegans. The dpy-31 gene in C. elegans encodes a procollagen C-terminal processing enzyme of the astacin metalloprotease or bone morphogenetic protein class that, when mutated, results in a temperature-sensitive lethal phenotype associated with cuticle defects. In this study, orthologues of this essential gene have been identified in the phylogenetically diverse parasitic nematodes Haemonchus contortus and Brugia malayi. The DPY-31 protein is expressed in the gut and secretory system of C. elegans, a location also confirmed when a B. malayi transcriptional dpy-31 promoter-reporter gene fusion was expressed in C. elegans. Functional conservation between the nematode enzymes was supported by the fact that heterologous expression of the H. contortus dpy-31 orthologue in a C. elegans dpy-31 mutant resulted in the full rescue of the mutant body form. This interspecies conservation was further established when the recombinant nematode enzymes were found to have a similar range of inhibitable protease activities. In addition, the recombinant DPY-31 enzymes from both H. contortus and B. malayi were shown to efficiently process the C. elegans cuticle collagen SQT-3 at the correct C-terminal procollagen processing site

A Brownian particle in a microscopic periodic potential

We study a model for a massive test particle in a microscopic periodic potential and interacting with a reservoir of light particles. In the regime considered, the fluctuations in the test particle's momentum resulting from collisions typically outweigh the shifts in momentum generated by the periodic force, and so the force is effectively a perturbative contribution. The mathematical starting point is an idealized reduced dynamics for the test particle given by a linear Boltzmann equation. In the limit that the mass ratio of a single reservoir particle to the test particle tends to zero, we show that there is convergence to the Ornstein-Uhlenbeck process under the standard normalizations for the test particle variables. Our analysis is primarily directed towards bounding the perturbative effect of the periodic potential on the particle's momentum.Comment: 60 pages. We reorganized the article and made a few simplifications of the conten

The Architectural Design Rules of Solar Systems based on the New Perspective

On the basis of the Lunar Laser Ranging Data released by NASA on the Silver Jubilee Celebration of Man Landing on Moon on 21st July 1969-1994, theoretical formulation of Earth-Moon tidal interaction was carried out and Planetary Satellite Dynamics was established. It was found that this mathematical analysis could as well be applied to Star and Planets system and since every star could potentially contain an extra-solar system, hence we have a large ensemble of exoplanets to test our new perspective on the birth and evolution of solar systems. Till date 403 exoplanets have been discovered in 390 extra-solar systems. I have taken 12 single planet systems, 4 Brown Dwarf - Star systems and 2 Brown Dwarf pairs. Following architectural design rules are corroborated through this study of exoplanets. All planets are born at inner Clarke Orbit what we refer to as inner geo-synchronous orbit in case of Earth-Moon System. By any perturbative force such as cosmic particles or radiation pressure, the planet gets tipped long of aG1 or short of aG1. Here aG1 is inner Clarke Orbit. The exoplanet can either be launched on death spiral as CLOSE HOT JUPITERS or can be launched on an expanding spiral path as the planets in our Solar System are. It was also found that if the exo-planet are significant fraction of the host star then those exo-planets rapidly migrate from aG1 to aG2 and have very short Time Constant of Evolution as Brown Dwarfs have. This vindicates our basic premise that planets are always born at inner Clarke Orbit. This study vindicates the design rules which had been postulated at 35th COSPAR Scientific Assembly in 2004 at Paris, France, under the title ,New Perspective on the Birth & Evolution of Solar Systems.Comment: This paper has been reported to Earth,Moon and Planets Journal as MOON-S-09-0007

Deep forecasting of translational impact in medical research.

The value of biomedical research-a $1.7 trillion annual investment-is ultimately determined by its downstream, real-world impact, whose predictability from simple citation metrics remains unquantified. Here we sought to determine the comparative predictability of future real-world translation-as indexed by inclusion in patents, guidelines, or policy documents-from complex models of title/abstract-level content versus citations and metadata alone. We quantify predictive performance out of sample, ahead of time, across major domains, using the entire corpus of biomedical research captured by Microsoft Academic Graph from 1990-2019, encompassing 43.3 million papers. We show that citations are only moderately predictive of translational impact. In contrast, high-dimensional models of titles, abstracts, and metadata exhibit high fidelity (area under the receiver operating curve [AUROC] > 0.9), generalize across time and domain, and transfer to recognizing papers of Nobel laureates. We argue that content-based impact models are superior to conventional, citation-based measures and sustain a stronger evidence-based claim to the objective measurement of translational potential

μChIP—a rapid micro chromatin immunoprecipitation assay for small cell samples and biopsies

Chromatin immunoprecipitation (ChIP) is a powerful technique for studying protein–DNA interactions. Drawbacks of current ChIP assays however are a requirement for large cell numbers, which limits applicability of ChIP to rare cell samples, and/or lengthy procedures with limited applications. There are to date no protocols for fast and parallel ChIPs of post-translationally modified histones from small cell numbers or biopsies, and importantly, no protocol allowing for investigations of transcription factor binding in small cell numbers. We report here the development of a micro (μ) ChIP assay suitable for up to nine parallel quantitative ChIPs of modified histones or RNA polymerase II from a single batch of 1000 cells. μChIP can also be downscaled to monitor the association of one protein with multiple genomic sites in as few as 100 cells. μChIP is applicable to small fresh tissue biopsies, and a cross-link-while-thawing procedure makes the assay suitable for frozen biopsies. Using μChIP, we characterize transcriptionally permissive and repressive histone H3 modifications on developmentally regulated promoters in human embryonal carcinoma cells and in osteosarcoma biopsies. μChIP creates possibilities for multiple parallel and rapid transcription factor binding and epigenetic analyses of rare cell and tissue samples

A Keck HIRES Doppler Search for Planets Orbiting Metal-Poor Dwarfs. II. On the Frequency of Giant Planets in the Metal-Poor Regime

We present an analysis of three years of precision radial velocity measurements of 160 metal-poor stars observed with HIRES on the Keck 1 telescope. We report on variability and long-term velocity trends for each star in our sample. We identify several long-term, low-amplitude radial-velocity variables worthy of follow-up with direct imaging techniques. We place lower limits on the detectable companion mass as a function of orbital period. Our survey would have detected, with a 99.5% confidence level, over 95% of all companions on low-eccentricity orbits with velocity semi-amplitude K > 100 m/s, or M_p*sin(i) > 3.0 M_JUP*(P/yr)^(1/3), for orbital periods P< 3 yr. None of the stars in our sample exhibits radial-velocity variations compatible with the presence of Jovian planets with periods shorter than the survey duration. The resulting average frequency of gas giants orbiting metal-poor dwarfs with -2.0 < [Fe/H] < -0.6 is f_p<0.67% (at the 1-sigma confidence level). We examine the implications of this null result in the context of the observed correlation between the rate of occurrence of giant planets and the metallicity of their main-sequence solar-type stellar hosts. By combining our dataset with the Fischer & Valenti (2005) uniform sample, we confirm that the likelihood of a star to harbor a planet more massive than Jupiter within 2 AU is a steeply rising function of the host's metallicity. However, the data for stars with -1.0 < [Fe/H] < 0.0 are compatible, in a statistical sense, with a constant occurrence rate f_p~1%. Our results can usefully inform theoretical studies of the process of giant planet formation across two orders of magnitude in metallicity.Comment: 59 pages, 7 tables, 8 figures. Accepted for publication in the Astrophysical Journa

Could Public Restrooms Be an Environment for Bacterial Resistomes?

PMCID: PMC3547874This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited