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Here we report whole genome sequencing of four individuals (H3, H4, H5, and H6) from a family of Pakistani descent. Whole genome sequencing yielded 1084.92, 894.73, 1068.62, and 1005.77 million mapped reads corresponding to 162.73, 134.21, 160.29, and 150.86 Gb sequence data and 52.49x, 43.29x, 51.70x, and 48.66x average coverage for H3, H4, H5, and H6, respectively. We identified 3,529,659, 3,478,495, 3,407,895, and 3,426,862 variants in the genomes of H3, H4, H5, and H6, respectively, including 1,668,024 variants common in the four genomes. Further, we identified 42,422, 39,824, 28,599, and 35,206 novel variants in the genomes of H3, H4, H5, and H6, respectively. A major fraction of the variants identified in the four genomes reside within the intergenic regions of the genome. Single nucleotide polymorphism (SNP) genotype based comparative analysis with ethnic populations of 1000 Genomes database linked the ancestry of all four genomes with the South Asian populations, which was further supported by mitochondria based haplogroup analysis. In conclusion, we report whole genome sequencing of four individuals of Pakistani descent.

Hypoxia‐ischaemia (HI) can result in structural brain abnormalities, which in turn can lead to behavioural deficits in various cognitive and motor domains, in both adult and paediatric populations. Cardiorespiratory arrest (CA) is a major cause of hypoxia‐ischaemia in adults, but it is relatively rare in infants and children. While the effects of adult CA on brain and cognition have been widely studied, to date, there are no studies examining the neurodevelopmental outcome of children who suffered CA early in life. Here, we studied the long‐term outcome of 28 children who suffered early CA (i.e., before age 16). They were compared to a group of control participants (n = 28) matched for age, sex and socio‐economic status. The patient group had impairments in the domains of memory, language and academic attainment (measured using standardised tests). Individual scores within the impaired range were most commonly found within the memory domain (79%), followed by academic attainment (50%), and language (36%). The patient group also had reduced whole brain grey matter volume, and reduced volume and fractional anisotropy of the white matter. In addition, lower performance on memory tests was correlated with bilaterally reduced volume of the hippocampi, thalami, and striatum, while lower attainment scores were correlated with bilateral reduction of fractional anisotropy in the superior cerebellar peduncle, the main output tract of the cerebellum. We conclude that patients who suffered early CA are at risk of developing specific cognitive deficits associated with structural brain abnormalities. Research Highlights: Our data shed light on the long‐term outcome and associated neural mechanisms after paediatric hypoxia‐ischaemia as a result of cardiorespiratory arrest.Patients had impaired scores on memory, language and academic attainment.Memory impairments were associated with smaller hippocampi, thalami, and striatum.Lower academic attainment correlated with reduced fractional anisotropy of the superior cerebellar peduncle. [ABSTRACT FROM AUTHOR]

We previously investigated the transcriptome and proteome profiles of the murine ocular lens at six developmental time points including two embryonic (E15 and E18) and four postnatal time points (P0, P3, P6, and P9). Here, we extend our analyses to identify novel transcripts and peptides in developing  mouse lens. We identified a total of 9,707 novel transcripts and 325 novel fusion genes in developing mouse lens. Additionally, we identified 13,281 novel alternative splicing (AS) events in mouse lens including 6,990 exon skipping (ES), 2,447 alternative 3' splice site (A3SS), 1,900 alternative 5' splice site (A5SS), 1,771 mutually exclusive exons (MXE), and 173 intron retention (IR). Finally, we integrated our OMIC (Transcriptome and Proteome) datasets identifying 20 novel peptides in mouse lens. All 20 peptides were validated through matching MS/MS spectra of synthetic peptides. To the best of our knowledge, this is the first report integrating OMIC datasets to identify novel peptides in developing murine lens.

FOXE3 is a lens-specific transcription factor that has been associated with anterior segment ocular dysgenesis. To determine the transcriptional target(s) of FOXE3 that are indispensable for the anterior segment development, we examined the transcriptome and the proteome of cells expressing truncated FOXE3 responsible for Peters anomaly identified through linkage-coupled next-generation whole-exome sequencing. We found that DNAJB1, an autophagy-associated protein, was the only candidate exhibiting differential expression in both screens. We confirmed the candidacy of DNAJB1 through chromatin immunoprecipitation and luciferase assays while knockdown of DNAJB1 in human lens epithelial cells resulted in a mitotic arrest. Subsequently, we targeted dnajb1a in zebrafish through injection of a splice-blocking morpholino. The dnajb1a morphants exhibited underdeveloped cataractous lenses with persistent apoptotic nuclei. In conclusion, here we report DNAJB1 is a transcriptional target of FOXE3 in a novel pathway that is crucial for the development of the anterior segment of the eye.

PurposeTranscriptome is the entire repertoire of transcripts present in a cell at any particular time. We undertook a next-generation whole transcriptome sequencing approach to gain insight into the transcriptional landscape of the developing mouse lens.MethodsWe ascertained mouse lenses at six developmental time points including two embryonic (E15 and E18) and four postnatal stages (P0, P3, P6, and P9). The ocular tissue at each time point was maintained as two distinct pools serving as biological replicates for each developmental stage. The mRNA and small RNA libraries were paired-end sequenced on Illumina HiSeq 2000 and subsequently analyzed using bioinformatics tools.ResultsMapping of mRNA and small RNA libraries generated 187.56 and 154.22 million paired-end reads, respectively. We detected a total of 14,465 genes in the mouse ocular lens at the above-mentioned six developmental stages. Of these, 46 genes exhibited a 40-fold differential (higher or lower) expression at one the five developmental stages (E18, P0, P3, P6, and P9) compared with their expression level at E15. Likewise, small RNA profiling identified 379 microRNAs (miRNAs) expressed in mouse lens at six developmental time points. Of these, 49 miRNAs manifested an 8-fold differential (higher or lower) expression at one the five developmental stages, as mentioned above compared with their expression level at E15.ConclusionsWe report a comprehensive profile of developing murine lens transcriptome including both mRNA and miRNA through next-generation RNA sequencing. A complete repository of the lens transcriptome of six developmental time points will be monumental in elucidating processes essential for the development of the ocular lens and maintenance of its transparency.

Air quality in subway systems is crucial as it affects the health of passengers and staff. Although most tests of PM2.5 concentrations in subway stations have taken place in public areas, PM2.5 is less understood in workplaces. Few studies have estimated the cumulative inhaled dose of passengers based on real-time changes in PM2.5 concentrations as they commute. To clarify the above issues, this study first measured PM2.5 concentrations in four subway stations in Changchun, China, where measuring points included five workrooms. Then, passengers' exposure to PM2.5 during the whole subway commute (20–30 min) was measured and segmented inhalation was calculated. The results showed that PM2.5 concentration in public places ranged from 50 to 180 μg/m3, and was strongly correlated with outdoors. While the PM2.5 average concentration in workplaces was 60 µg/m3, and it was less affected by outdoor PM2.5 concentration. Passenger's cumulative inhalations in single commuting were about 42 μg and 100 μg when the outdoor PM2.5 concentrations were 20–30 μg/m3 and 120–180 μg/m3, respectively. The PM2.5 inhalation in carriages accounted for the largest proportion of the entire commuting, about 25–40%, because of the longer exposure time and higher PM2.5 concentrations. It is recommended to improve the tightness of the carriage and filter the fresh air to improve the air quality inside. The average daily PM2.5 inhaled by staff was 513.53 μg, which was 5–12 times higher than that of passengers. Installing air purification devices in workplaces and reminding staff to take personal protection can positively protect their health. [ABSTRACT FROM AUTHOR]

Telehealth is a broad term used to describe the use of electronic or digital information and communications technologies to support clinical healthcare, patient and professional health related education, and public health and health administration. Telerehabilitation refers to the delivery of rehabilitation and habilitation services via information and communication technologies (ICT), also commonly referred to as” telehealth” technologies. Telerehabilitation services can include evaluation, assessment, monitoring, prevention, intervention, supervision, education, consultation, and coaching. Telerehabilitation services can be deployed across all patient populations and multiple healthcare settings including clinics, homes, schools, or community-based worksites. This document was adapted from the American Telemedicine Association’s (ATA) “A Blueprint for Telerehabilitation Guidelines” (2010) and reflects the current utilization of telerehabilitation services. It was developed collaboratively by members of the ATA Telerehabilitation Special Interest Group, with input and guidance from other practitioners in the field, strategic stakeholders, and ATA staff. Its purpose is to inform and assist practitioners in providing effective and secure services that are based on client needs, current empirical evidence, and available technologies. Rehabilitation professionals, in conjunction with professional associations and other organizations are encouraged to use this document as a resource for developing discipline-specific standards, guidelines, and practice requirements. Keywords: American Telemedicine Association, Habilitation, Rehabilitation, Telehealth, Telepractice

Peter's Anomaly is a developmental disorder of the eye and has been linked to mutations in a range of genes, including the transcription factor FOXE3. Here the authors use next-generation RNA sequencing and mass spectrometry to identify an autophagy-associated protein, DNAJB1 as the transcriptional target of FOXE3.

The neuropsychological and clinical histories of three male siblings affected by pyridoxine-dependent seizures with known homozygous antiquitin mutations are presented. Neuropsychological evaluation is reported from when the siblings were 11, 9, and 7 years of age. Two of the siblings had received early pyridoxine treatment (antenatal, 2-4 wks into pregnancy) and one had received late treatment (2 mo postnatal). However, there was no differential effect on cognitive outcome, with all three siblings having moderate to severe learning disability. Unlike previously reported cases that received early postnatal treatment, none of the siblings had relatively preserved non-verbal cognitive skills. Equally, their intellectual performance over time did not increase above the 1st centile despite high maintenance doses of vitamin B6 (range 16-26 mg/kg/d), and mild sensory neuropathy was reported on nerve conduction studies. The findings in these siblings challenge assumptions that early and high dose pyridoxine treatment can benefit cognition in this population and suggest routine electromyography monitoring may be beneficial. (Contains 2 tables and 2 figures.)

Synaptotagmin-1 (SYT1) is a calcium-binding synaptic vesicle protein that is required for both exocytosis and endocytosis. Here, we describe a human condition associated with a rare variant in SYT1. The individual harboring this variant presented with an early onset dyskinetic movement disorder, severe motor delay, and profound cognitive impairment. Structural MRI was normal, but EEG showed extensive neurophysiological disturbances that included the unusual features of low-frequency oscillatory bursts and enhanced paired-pulse depression of visual evoked potentials. Trio analysis of whole- exome sequence identified a de novo SYT1 missense variant (I368T). Expression of rat SYT1 containing the equivalent human variant in WT mouse primary hippocampal cultures revealed that the mutant form of SYT1 correctly localizes to nerve terminals and is expressed at levels that are approximately equal to levels of endogenous WT protein. The presence of the mutant SYT1 slowed synaptic vesicle fusion kinetics, a finding that agrees with the previously demonstrated role for I368 in calcium-dependent membrane penetration. Expression of the I368T variant also altered the kinetics of synaptic vesicle endocytosis. Together, the clinical features, electrophysiological phenotype, and in vitro neuronal phenotype associated with this dominant negative SYT1 mutation highlight presynaptic mechanisms that mediate human motor control and cognitive development., Introduction Many postsynaptic genes and processes have been linked to neurodevelopmental disorders (1), and it is increasingly apparent that presynaptic dysfunction is another major contributory pathway. Rare variants have been [...]

Author(s): Nicholas Ware [sup.1] , Neil J. Sebire [sup.1] , W. K. Chong [sup.1] , Rajesh Krishnan [sup.2] , Stephen D. Marks [sup.1] Author Affiliations: (1) 0000 0004 0426 7394grid.424537.3Department [...]