Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform.

Colon length in pediatric health and constipation measured using magnetic resonance imaging and three dimensional skeletonization.

Recent magnetic resonance imaging (MRI) studies showed that colonic volumes in children are different between health and functional constipation. The length of the colon has however been rarely measured and principally using unphysiological colon preparations or cadaver studies. The main objective of this study was to measure the length of the undisturbed colon in children with functional constipation (FC) and healthy controls.

Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and with new innovative methods can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the GREGoR consortium.

Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria.

Importance: Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases.

Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements.

Accurate somatic mutation detection from single-cell DNA sequencing is challenging due to amplification-related artifacts. To reduce this artifact burden, an improved amplification technique, primary template-directed amplification (PTA), was recently introduced. We analyzed whole-genome sequencing data from 52 PTA-amplified single neurons using SCAN2, a new genotyper we developed to leverage mutation signatures and allele balance in identifying somatic single-nucleotide variants (SNVs) and small insertions and deletions (indels) in PTA data.

Somatic genomic changes in single Alzheimer's disease neurons.

Dementia in Alzheimer's disease progresses alongside neurodegeneration, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations at rates similar to those of dividing cells which suggests that genetic factors, environmental exposures or disease states might influence this accumulation. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer's disease and neurotypical control individuals.

A review of acute pancreatitis in the era of COVID-19.

Acute pancreatitis is uncommon in childhood with an estimated incidence of approximately 1 in 10,000 children per year. It is an important condition, which may escape prompt diagnosis and is associated with significant morbidity and mortality. Most often, it will result in an acute hospital admission.

Colonic Volume Changes in Paediatric Constipation Compared to Normal Values Measured Using MRI.

Background: Functional constipation in children is common. Management of this condition can be challenging and is often based on symptom reports. Increased, objective knowledge of colonic volume changes in constipation compared to health could provide additional information.

4-Methylcyclohexane methanol (MCHM) affects viability, development, and movement of embryos.

Following chemical spill disasters, it is important to estimate the effects of spilled chemicals on humans and the environment. Here we analyzed the toxicological effects of the coal cleaning chemical, 4-methylcyclohexane methanol (MCHM), which was spilled into the Elk River water supply in 2014. The viability of HEK293 T human cell line cultures and embryos was negatively affected, and the addition of the antioxidants alleviated toxicity with MCHM exposure.

Intonational Variation in the North-West of England: The Origins of a Rising Contour in Liverpool.

This paper investigates intonation in the urban dialect of Liverpool, Scouse. Scouse is reported to be part of a group of dialects in the north of the UK where rising contours in declaratives are a traditional aspect of the dialect. This intonation is typologically unusual and has not been the subject of detailed previous research.

Feasibility Study of a New Magnetic Resonance Imaging Mini-capsule Device to Measure Whole Gut Transit Time in Paediatric Constipation.

Objective: In England, 27,500 children are referred annually to hospital with constipation. An objective measure of whole gut transit time (WGTT) could aid management. The current standard WGTT assessment, the x-ray radiopaque marker (ROM) test, gives poor definition of colonic anatomy and the radiation dose required is undesirable in children.

Dynamic acoustic-articulatory relations in back vowel fronting: Examining the effects of coda consonants in two dialects of British English.

This study examines dynamic acoustic-articulatory relations in back vowels, focusing on the effect of different coda consonants on acoustic-articulatory dynamics in the production of vowel contrast. This paper specifically investigates the contribution of the tongue and the lips in modifying F2 in the foot-goose contrast in English, using synchronized acoustic and electromagnetic articulography data collected from 16 speakers. The vowels foot and goose were elicited in pre-coronal and pre-lateral contexts from two dialects that are reported to be at different stages of back vowel fronting: Southern Standard British English and West Yorkshire English.

A typology of laterals in twelve English dialects.

Allophonic patterns of variation in English laterals have been well studied in phonetics and phonology for decades, but establishing broad generalizations across varieties has proven challenging. In this study, a typology of onset/coda lateral distinctions in English is advanced using crowdsourced recordings from 95 speakers across twelve dialects of Anglo (UK) English. Results confirm the existence of dialects with and without onset/coda distinctions, and conditional inference trees are used to identify three main patterns in the data: (1) clear onsets and dark codas; (2) intermediate/dark onsets and dark codas, but with a positional distinction intact; and (3) dark onsets and dark codas, with minimal or no distinctions between positions.

The acoustics of three-way lateral and nasal palatalisation contrasts in Scottish Gaelic.

This paper presents an acoustic description of laterals and nasals in an endangered minority language, Scottish Gaelic (known as "Gaelic"). Gaelic sonorants are reported to take part in a typologically unusual three-way palatalisation contrast. Here, the acoustic evidence for this contrast is considered, comparing lateral and nasal consonants in both word-initial and word-final position.

Evolving patterns in the presentation of coeliac disease over the last 25 years.

Objective: To document changes in the clinical features of coeliac disease (CD) at presentation over the last 25 years.

Design: Observational study.

Patients: 802 subjects diagnosed between 1993 and 2017 at a single general hospital.

Reduced skeletal muscle protein balance in paediatric Crohn's disease.

Background & Aims: An inability to respond to nutrition could be implicated in low muscle mass in Crohn's disease. We aim to determine skeletal muscle metabolic response to feeding in Crohn's disease and healthy volunteers.

Methods: Twenty asymptomatic Crohn's disease participants (15.

Dialect variation in formant dynamics: The acoustics of lateral and vowel sequences in Manchester and Liverpool English.

This study analyses the time-varying acoustics of laterals and their adjacent vowels in Manchester and Liverpool English. Generalized additive mixed-models (GAMMs) are used for quantifying time-varying formant data, which allows the modelling of non-linearities in acoustic time series while simultaneously modelling speaker and word level variability in the data. These models are compared to single time-point analyses of lateral and vowel targets in order to determine what analysing formant dynamics can tell about dialect variation in speech acoustics.

Amphiphilic Peptide-Based Supramolecular, Noncytotoxic, Stimuli-Responsive Hydrogels with Antibacterial Activity.

A series of peptides with a long fatty acyl chain covalently attached to the C-terminal part and a free amine (-NH) group at the N-terminus have been designed so that these molecules can be assembled in aqueous medium by using various noncovalent interactions. Five different peptide amphiphiles with a general chemical formula [HN-(CH)CONH-Phe-CONHC (n = 1-5, C = dodecylamine)] have been synthesized, characterized, and examined for self-assembly and hydrogelation. All of these molecules [P1 (n = 1), P2 (n = 2), P3 (n = 3), P4 (n = 4), P5 (n = 5)] form thermoresponsive hydrogels in water (pH 6.

Needle-free devices: keeping the system closed.

Health professionals are under increasing pressure to reduce costs while ensuring patient safety. As the number of vascular access devices (VADs) used in health care continues to increase, there is a need to reduce the complications of infection and occlusion associated with them. Needle-free devices (NFDs), also known as needleless connectors, have been available since the early 1990s and the type and variety of these devices has continued to develop.

Two-Component Fluorescent-Semiconducting Hydrogel from Naphthalene Diimide-Appended Peptide with Long-Chain Amines: Variation in Thermal and Mechanical Strengths of Gels.

Two-component fluorescent hydrogels have been discovered, containing the mixtures of naphthalene diimide (NDI)-conjugated peptide-functionalized bola-amphiphile and primary amines with long alkyl chains at physiological pH 7.46. The aggregation-induced enhanced emission associated with an NDI-appended peptide in aqueous medium is rare, as water is known to be a good quencher of fluorescence.

Nanosheet Formation by an Anionic Surfactant-like Peptide and Modulation of Self-Assembly through Ionic Complexation.

The surfactant-like peptide (Ala)-(Asp) (AD) is shown to self-assemble into ultrathin (3 nm thick) nanosheets in aqueous solution above a critical aggregation concentration. A combination of circular dichroism and FTIR spectroscopy and X-ray diffraction shows that the nanosheets comprise interdigitated bilayers of the peptide with β-sheet conformation. The self-assembly can be modulated by addition of hexamethylenediamine which is expected to interact with the anionic C terminus (and C-terminal D residue) of the peptide.

TOR complex 2 localises to the cytokinetic actomyosin ring and controls the fidelity of cytokinesis.

The timing of cell division is controlled by the coupled regulation of growth and division. The target of rapamycin (TOR) signalling network synchronises these processes with the environmental setting. Here, we describe a novel interaction of the fission yeast TOR complex 2 (TORC2) with the cytokinetic actomyosin ring (CAR), and a novel role for TORC2 in regulating the timing and fidelity of cytokinesis.

The effect of topical anti blister products on the risk of friction blister formation on the foot.

Introduction: Foot blisters are a common injury, which can impact on activity and lead to infection. Increased skin surface hydration has been identified as a risk factor for blister formation, indicating that a reduction in hydration could reduce the risk of blister.

Method: Thirty healthy adults were randomised into 3 groups, each receiving a preventative foot blister treatment (2Toms(®) Blister Shield(®); Flexitol(®) Blistop and Boots Anti-Perspirant Foot Spray).

Self-Assembly of the Cyclic Lipopeptide Daptomycin: Spherical Micelle Formation Does Not Depend on the Presence of Calcium Chloride.

The cyclic lipopeptide Daptomycin, used as a treatment for infections where antimicrobial resistance is observed, is shown to self-assemble into spherical micelles above a critical aggregation concentration. Micelles are observed either in the absence or presence of CaCl2 , in contrast to claims in the literature that CaCl2 is required for micellization.