Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders.

Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways

Evidence against global attention filters selective for absolute bar-orientation in human vision

The finding that an item of type A pops out from an array of distractors of type B typically is taken to support the inference that human vision contains a neural mechanism that is activated by items of type A but not by items of type B. Such a mechanism might be expected to yield a neural image in which items of type A produce high activation and items of type B low (or zero) activation. Access to such a neural image might further be expected to enable accurate estimation of the centroid of an ensemble of items of type A intermixed with to-be-ignored items of type B. Here, it is shown that as the number of items in stimulus displays is increased, performance in estimating the centroids of horizontal (vertical) items amid vertical (horizontal) distractors degrades much more quickly and dramatically than does performance in estimating the centroids of white (black) items among black (white) distractors. Together with previous findings, these results suggest that, although human vision does possess bottom-up neural mechanisms sensitive to abrupt local changes in bar-orientation, and although human vision does possess and utilize top-down global attention filters capable of selecting multiple items of one brightness or of one color from among others, it cannot use a top-down global attention filter capable of selecting multiple bars of a given absolute orientation and filtering bars of the opposite orientation in a centroid task

Utility of salt-marsh foraminifera, testate amoebae and bulk-sediment δ13C values as sea-level indicators in Newfoundland, Canada

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.We investigated the utility of foraminifera, testate amoebae and bulk-sediment δ 13 C measurements for reconstructing Holocene relative sea level from sequences of salt-marsh sediment in Newfoundland, Canada. Modern, surface sediment was collected along transects from low to supra-tidal elevations in eastern (at Placentia) and western (at Hynes Brook and Big River) Newfoundland. Consistent with previous work, low-diversity assemblages of foraminifera display an almost binary division into a higher salt-marsh assemblage dominated by Jadammina macrescens and Balticammina pseudomacrescens and a lower salt-marsh assemblage comprised of Miliammina fusca. This pattern and composition resembles those identified at other high latitude sites with cool climates and confirms that foraminifera are sea-level indicators. The lowest occurrence of testate amoebae was at approximately mean higher high water. The composition of high salt-marsh testate amoebae assemblages (Centropyxis cassis type, Trinema spp., Tracheleuglypha dentata type, and Euglypha spp.) in Newfoundland was similar to elsewhere in the North Atlantic, but preservation bias favors removal of species with idiosomic tests over those with xenosomic tests. The mixed high salt-marsh plant community in Newfoundland results in bulk surface-sediment δ 13 C values that are typical of C 3 plants, making them indistinguishable from freshwater sediment. Therefore we propose that the utility of this proxy for reconstructing RSL in eastern North America is restricted to the coastline between Chesapeake Bay and southern Nova Scotia. Using a simple, multi-proxy approach to establish that samples in three radiocarbon-dated sediment cores formed between the lowest occurrence of testate amoebae and the highest occurrence of foraminifera, we generated three example late Holocene sea-level index points at Hynes Brook.This work was supported by NSF awards OCE-1458921, OCE-1458904 and EAR-1402017 and the Robert L. Nichols student research fund of the Department of Earth and Ocean Sciences at Tufts University. Foraminiferal data from Hynes Brook and Big River were collected as part of a series of projects including “Ocean-climate variability and sea level in the North Atlantic region since AD 0” funded by the Dutch National Research Programme (NRP) on Global air pollution and Climate Change; “Coastal Records” funded by the Vrije Universiteit Amsterdam and “Simulations, Observations & Palaeoclimatic data: climate variability over the last 500 years” funded by the European Union

Solar-type dynamo behaviour in fully convective stars without a tachocline

In solar-type stars (with radiative cores and convective envelopes), the magnetic field powers star spots, flares and other solar phenomena, as well as chromospheric and coronal emission at ultraviolet to X-ray wavelengths. The dynamo responsible for generating the field depends on the shearing of internal magnetic fields by differential rotation. The shearing has long been thought to take place in a boundary layer known as the tachocline between the radiative core and the convective envelope. Fully convective stars do not have a tachocline and their dynamo mechanism is expected to be very different, although its exact form and physical dependencies are not known. Here we report observations of four fully convective stars whose X-ray emission correlates with their rotation periods in the same way as in Sun-like stars. As the X-ray activity - rotation relationship is a well-established proxy for the behaviour of the magnetic dynamo, these results imply that fully convective stars also operate a solar-type dynamo. The lack of a tachocline in fully convective stars therefore suggests that this is not a critical ingredient in the solar dynamo and supports models in which the dynamo originates throughout the convection zone.Comment: 6 pages, 1 figure. Accepted for publication in Nature (28 July 2016). Author's version, including Method

Neurology Case Reporting: a call for all

From antiquity to present day, the act of recording and publishing our observations with patients remains essential to the art of medicine and the care of patients. Neurology is rich with case reports over the centuries. They contribute to our understanding and knowledge of disease entities, and are a cornerstone of our professional development as physicians and the care of our patients. This editorial seeks to enthuse and invigorate house staff and practicing physicians everywhere to continue the long and time-honored tradition of neurology case reporting

Highly Absorbing Lead-Free Semiconductor Cu₂AgBiI₆ for Photovoltaic Applications from the Quaternary CuI-AgI-BiI₃ Phase Space

Since the emergence of lead halide perovskites for photovoltaic research, there has been mounting effort in the search for alternative compounds with improved or complementary physical, chemical, or optoelectronic properties. Here, we report the discovery of Cu_{2}AgBiI_{6}: a stable, inorganic, lead-free wide-band-gap semiconductor, well suited for use in lead-free tandem photovoltaics. We measure a very high absorption coefficient of 1.0 × 10^{5} cm^{–1} near the absorption onset, several times that of CH_{3}NH_{3}PbI_{3}. Solution-processed Cu2AgBiI6 thin films show a direct band gap of 2.06(1) eV, an exciton binding energy of 25 meV, a substantial charge-carrier mobility (1.7 cm^{2} V^{–1} s^{–1}), a long photoluminescence lifetime (33 ns), and a relatively small Stokes shift between absorption and emission. Crucially, we solve the structure of the first quaternary compound in the phase space among CuI, AgI and BiI_{3}. The structure includes both tetrahedral and octahedral species which are open to compositional tuning and chemical substitution to further enhance properties. Since the proposed double-perovskite Cs2AgBiI6 thin films have not been synthesized to date, Cu_{2}AgBiI_{6} is a valuable example of a stable Ag^{+}/Bi^{3+} octahedral motif in a close-packed iodide sublattice that is accessed via the enhanced chemical diversity of the quaternary phase space

Investigating the role of common cis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders

This is the final version. Available on open access from Nature Research via the DOI in this record. Data availability: The DDD data are available in the European Genome-Phenome Archive (EGA). These include the exome sequence data (EGAD00001004389), phenotypic and family descriptions (EGAD00001004388), CoreExome array data (EGAD00010001598, EGAD00010001600, EGAD00010001604) and Global Screening Array data (first batch raw data: EGAD00010002567, second batch raw data, EGAD00010002569 and QCed data: EGAD00010002568). The UKHLS genotype data are also available on EGA (EGAS00001001232).Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi-cis-expression quantitative trait loci (cis-eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6987 probands from the Deciphering Developmental Disorders (DDD) study and 9720 controls, and found one gene, RAB2A, that passed multiple testing correction (p = 6.7 × 10-7). We then investigated whether cis-eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7 × 10-3). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that common cis-eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.Health Innovation Challenge FundWellcome Sanger InstituteWellcome Trus

Fast interior point solution of quadratic programming problems arising from PDE-constrained optimization

Interior point methods provide an attractive class of approaches for solving linear, quadratic and nonlinear programming problems, due to their excellent efficiency and wide applicability. In this paper, we consider PDE-constrained optimization problems with bound constraints on the state and control variables, and their representation on the discrete level as quadratic programming problems. To tackle complex problems and achieve high accuracy in the solution, one is required to solve matrix systems of huge scale resulting from Newton iteration, and hence fast and robust methods for these systems are required. We present preconditioned iterative techniques for solving a number of these problems using Krylov subspace methods, considering in what circumstances one may predict rapid convergence of the solvers in theory, as well as the solutions observed from practical computations

Pathologic characteristics of resected squamous cell carcinoma of the trachea: prognostic factors based on an analysis of 59 cases

While squamous cell carcinoma (SCC) is the most common tracheal malignancy, few reports describe the pathologic considerations that may guide intraoperative decisions and prognostic assessment. We reviewed 59 tracheal SCC treated between 1985 and 2008 by segmental resection of the trachea, including resection of the carina in 24% and inferior larynx in 14%. We classified these tumors by grading histologic differentiation and microscopic features used in SCC of other sites. Of 59 tumors, 24% (14 of 59) were well differentiated, 49% (29 of 59) were moderately differentiated, and 27% (16 of 59) were poorly differentiated. Unfavorable prognostic factors were tumor extension into the thyroid gland (all of five so-afflicted patients died of tumor progression within 3 years) and lymphatic invasion (mean survival 4.6 versus 7.6 years). Keratinization, dyskeratosis, acantholysis, necrosis, and tumor thickness did not predict prognosis. As surgical resection is the only curative treatment; the surgeon should establish clean lines of resection using, as appropriate, intraoperative frozen section. The pathologist can provide additional important prognostic information, including tumor differentiation and extent, invasion of surgical margins, and extension into the thyroid