To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal ...development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including
,
,
,
, and
) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.
The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ...ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.
We report mutations in a gene (
PRPF31) homologous to
Saccharomyces cerevisiae pre-mRNA splicing gene
PRP31 in families with autosomal dominant retinitis pigmentosa linked to chromosome 19q13.4 (
...RP11; MIM 600138). A positional cloning approach supported by bioinformatics identified
PRPF31 comprising 14 exons and encoding a protein of 499 amino acids. The level of sequence identity to the yeast
PRP31 gene indicates that
PRPF31 is also likely to be involved in pre-mRNA splicing. Mutations that include missense substitutions, deletions, and insertions have been identified in four
RP11-linked families and three sporadic RP cases. The identification of mutations in a pre-mRNA splicing gene implicates defects in the splicing process as a novel mechanism of photoreceptor degeneration.
Context: Opsoclonus, a rare neurological manifestation in scrub typhus, causes significant distress and disability. There is a paucity of clinical data and outcomes in these patients. Aim: This study ...aims to describe the clinical and laboratory profile and longitudinal outcomes in a scrub typhus patient cohort with opsoclonus. Settings and Design: This retrospective study was conducted in a 2700-bed teaching hospital in South India, in scrub typhus patients with opsoclonus over a 5-year period. Patients and Methods: Clinical, laboratory, and radiological data and outcomes at discharge and 6- and 12-weeks postdischarge were documented. Results: Of 1650 scrub typhus patients, 18 had opsoclonus. 17 had opsoclonus at presentation, while one patient developed opsoclonus on the 5th admission day, 1-day postdefervescence. Opsoclonus was first noted after a median interval of 11 (7-18) days from fever onset. It was associated with myoclonus in 94% (17/18), cerebellar dysfunction in 67% (12/18), extrapyramidal syndrome (EPS) in 33% (6/18), and aseptic meningitis in 17% (3/18) patients. Mean cerebrospinal fluid (CSF) white blood cell (WBC) count was 9 ± 2.7 cells/cumm, with mean CSF protein 118.5 ± 53.9 mg% and mean CSF glucose 97 ± 13 mg% in 1l/15 patients. Brain magnetic resonance imaging was unremarkable in 75% (9/12). Case-fatality rate was 5.5% (1/18). Complete resolution of the index neurological syndrome occurred at 12-week postdischarge. Conclusions: Opsoclonus is a rare neurological manifestation in scrub typhus, usually occurring in association with myoclonus, cerebellar dysfunction, or EPS. It appears to occur during the resolving febrile phase, with neurological deficits completely resolving at 12 weeks.
The majority of the Earth's terrestrial carbon is stored in the soil. If anthropogenic warming stimulates the loss of this carbon to the atmosphere, it could drive further planetary warming. Despite ...evidence that warming enhances carbon fluxes to and from the soil, the net global balance between these responses remains uncertain. Here we present a comprehensive analysis of warming-induced changes in soil carbon stocks by assembling data from 49 field experiments located across North America, Europe and Asia. We find that the effects of warming are contingent on the size of the initial soil carbon stock, with considerable losses occurring in high-latitude areas. By extrapolating this empirical relationship to the global scale, we provide estimates of soil carbon sensitivity to warming that may help to constrain Earth system model projections. Our empirical relationship suggests that global soil carbon stocks in the upper soil horizons will fall by 30 ± 30 petagrams of carbon to 203 ± 161 petagrams of carbon under one degree of warming, depending on the rate at which the effects of warming are realized. Under the conservative assumption that the response of soil carbon to warming occurs within a year, a business-as-usual climate scenario would drive the loss of 55 ± 50 petagrams of carbon from the upper soil horizons by 2050. This value is around 12-17 per cent of the expected anthropogenic emissions over this period. Despite the considerable uncertainty in our estimates, the direction of the global soil carbon response is consistent across all scenarios. This provides strong empirical support for the idea that rising temperatures will stimulate the net loss of soil carbon to the atmosphere, driving a positive land carbon-climate feedback that could accelerate climate change.
This paper presents the beam dynamics systematic corrections and their uncertainties for the Run-1 dataset of the Fermilab Muong−2Experiment. Two corrections to the measured muon precession ...frequencyωamare associated with well-known effects owing to the use of electrostatic quadrupole (ESQ) vertical focusing in the storage ring. An average vertically oriented motional magnetic field is felt by relativistic muons passing transversely through the radial electric field components created by the ESQ system. The correction depends on the stored momentum distribution and the tunes of the ring, which has relatively weak vertical focusing. Vertical betatron motions imply that the muons do not orbit the ring in a plane exactly orthogonal to the vertical magnetic field direction. A correction is necessary to account for an average pitch angle associated with their trajectories. A third small correction is necessary, because muons that escape the ring during the storage time are slightly biased in initial spin phase compared to the parent distribution. Finally, because two high-voltage resistors in the ESQ network had longer than designedRCtime constants, the vertical and horizontal centroids and envelopes of the stored muon beam drifted slightly, but coherently, during each storage ring fill. This led to the discovery of an important phase-acceptance relationship that requires a correction. The sum of the corrections toωamis0.50±0.09ppm; the uncertainty is small compared to the 0.43 ppm statistical precision ofωam.
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