Beyond homozygosity mapping: family-control analysis based on Hamming distance for prioritizing variants in exome sequencing

A major challenge in current exome sequencing in autosomal recessive (AR) families is the lack of an effective method to prioritize single-nucleotide variants (SNVs). AR families are generally too small for linkage analysis, and length of homozygous regions is unreliable for identification of causative variants. Various common filtering steps usually result in a list of candidate variants that cannot be narrowed down further or ranked. To prioritize shortlisted SNVs we consider each homozygous candidate variant together with a set of SNVs flanking it. We compare the resulting array of genotypes between an affected family member and a number of control individuals and argue that, in a family, differences between family member and controls should be larger for a pathogenic variant and SNVs flanking it than for a random variant. We assess differences between arrays in two individuals by the Hamming distance and develop a suitable test statistic, which is expected to be large for a causative variant and flanking SNVs. We prioritize candidate variants based on this statistic and applied our approach to six patients with known pathogenic variants and found these to be in the top 2 to 10 percentiles of ranks

Tunable anisotropy in inverse opals and emerging optical properties

Using self-assembly, nanoscale materials can be fabricated from the bottom up. Opals and inverse opals are examples of self-assembled nanomaterials made from crystallizing colloidal particles. As self-assembly requires a high level of control, it is challenging to use building blocks with anisotropic geometry to form complex opals, which limits the realizable structures. Typically, spherical colloids are employed as building blocks, leading to symmetric, isotropic superstructures. However, a significantly richer palette of directionally dependent properties are expected if less symmetric, anisotropic structures can be created, especially originating from the assembly of regular, spherical particles. Here we show a simple method to introduce anisotropy into inverse opals by subjecting them to a post-assembly thermal treatment that results in directional shrinkage of the silica matrix caused by condensation of partially hydrated sol-gel silica structures. In this way, we can tailor the shape of the pores, and the anisotropy of the final inverse opal preserves the order and uniformity of the self-assembled structure, while completely avoiding the need to synthesize complex oval-shaped particles and crystallize them into such target geometries. Detailed X-ray photoelectron spectroscopy (XPS) and infrared (IR) spectroscopy studies clearly identify increasing degrees of sol-gel condensation in confinement as a mechanism for the structure change. A computer simulation of structure changes resulting from the condensation-induced shrinkage further confirmed this mechanism. As an example of property changes induced by the introduction of anisotropy, we characterized the optical spectra of the anisotropic inverse opals and found that the optical properties can be controlled in a precise way using calcination temperature

Development, implementation, and evaluation of the Apollo model of pediatric rehabilitation service delivery

This article presents the experience of a rehabilitation program that un- dertook the challenge to reorganize its services to address accessibility issues and im- prove service quality. The context in which the reorganization process occurred, along with the relevant literature justifying the need for a new service delivery model, and an historical perspective on the planning; implementation; and evaluation phases of the process are described. In the planning phase, the constitution of the working committee, the data collected, and the information found in the literature are presented. Apollo, the new service delivery model, is then described along with each of its components (e.g., community, group, and individual interventions). Actions and lessons learnt during the implementation of each component are presented. We hope by sharing our experiences that we can help others make informed decisions about service reorganization to im- prove the quality of services provided to children with disabilities, their families, and their communities

Review Article : Atomic layer deposition of optoelectronic materials

Optoelectronic materials can source, detect, and control light wavelengths ranging from gamma and x rays to ultraviolet, visible, and infrared regions. Optoelectronic devices are usually systems that transduce electricity to optical signal or vice versa. Optoelectronic devices include many modern necessities such as lamps, displays, lasers, solar cells, and various photodetectors. Some important research topics in the field of optoelectronics materials are development of new materials, new technologies for fabricating materials, and design of device structures. Atomic layer deposition (ALD) is a technology that was developed in the early 1970s for manufacturing high-quality luminescent and dielectric films to be used in AC-driven thin film electroluminescent (TFEL) displays. Monochromic yellow-black displays based on a ZnS:Mn luminescent layer have been manufactured industrially using ALD since the mid-1980s. Multicolor displays (green-yellow-red) were successfully realized by filtering the broad emission band of ZnS:Mn or adding another luminescent material, e.g., green-emitting ZnS:Tb or SrS:Ce. However, applicable full-color AC TFEL devices could not be developed because of the lack of an efficient deep blue-emitting phosphor. Currently, the most promising application area in TFEL displays is transparent displays, which are commonly used in various vehicles. In the mid-1980s, epitaxial III-V semiconductors were studied using ALD. It was shown that manufacturing real epitaxial [atomic layer epitaxy (ALE)] films is possible for different III (Al, Ga, In) and V (N, P, As) materials. The advantages of ALE processing compared to more traditional metalorganic chemical vapor deposition or molecular beam epitaxy methods have remained low, however, and ALE is not used on a large scale. Research continues to be carried out using ALE, especially with nitride films. Thin film solar cells have continuously received attention in ALD research. ALD films may be used as both an absorber (CdTe, SnS) and a passivation [In2S3, Zn(O,S)] material. However, in the solar cell field, the real industrial-level use is in passivation of silicon cells. Thin ALD Al2O3 film effectively passivates all types of silicon cells and improves their efficiency. Transition metal dichalcogenides are emerging 2D materials that have potential uses as channel materials in field-effect transistors, as well as phototransistors and other optoelectronic devices. The problem with achieving large-scale use of these 2D materials is the lack of a scalable, low-temperature process for fabricating high-quality, large-area films. ALD is proposed as a solution for these limitations. This review covers all of these ALD applications in detail. (C) 2019 Author(s).Peer reviewe

Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity.

Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4 <sup>+</sup> T cell frequencies. These data suggest that the "Interferon paradox" previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity

XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia

XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair1,2. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP3,4,5 and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease