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Emily Olfson Catherine E. Cottrell Nicholas O. Davidson Christina A. Gurnett Jonathan W. Heusel Nathan O. Stitziel Li-Shiun Chen Sarah Hartz Rakesh Nagarajan Nancy L. Saccone Laura J. Bierut 《PloS one》2015,10(9)
The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations. 相似文献
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James A. Simmons Andrea Megela Simmons 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2011,197(5):585-594
Widely divergent vertebrates share a common central temporal mechanism for representing periodicities of acoustic waveform
events. In the auditory nerve, periodicities corresponding to frequencies or rates from about 10 Hz to over 1,000 Hz are extracted
from pure tones, from low-frequency complex sounds (e.g., 1st harmonic in bullfrog calls), from mid-frequency sounds with
low-frequency modulations (e.g., amplitude modulation rates in cat vocalizations), and from time intervals between high-frequency
transients (e.g., pulse-echo delay in bat sonar). Time locking of neuronal responses to periodicities from about 50 ms down
to 4 ms or less (about 20–300 Hz) is preserved in the auditory midbrain, where responses are dispersed across many neurons
with different onset latencies from 4–5 to 20–50 ms. Midbrain latency distributions are wide enough to encompass two or more
repetitions of successive acoustic events, so that responses to multiple, successive periods are ongoing simultaneously in
different midbrain neurons. These latencies have a previously unnoticed periodic temporal pattern that determines the specific
times for the dispersed on-responses. 相似文献
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Ernest I. Onyishi Piotr Sorokowski Agnieszka Sorokowska R. Nathan Pipitone 《Evolution and human behavior》2012,33(6):771-774
Previous research has demonstrated that having more children decreases marital satisfaction among parents. However, the universality of these findings is limited since the vast majority of the studies have been conducted in Western countries. In the present study, 374 people from the Igbo ethnic group (Nigeria) were assessed for levels of marital satisfaction and the number of children. In contrast to almost all previous findings, we found a positive relationship between the number of children and marital satisfaction among parents. Number of children was the strongest predictor of marital satisfaction even when compared to other variables like wealth and education. Our results suggest that the negative relationship between the number of children and marital satisfaction is not culturally universal and probably only characterizes developed, individualistic Western countries. We discuss our findings from a sociocultural and evolutionary perspective. 相似文献
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Vertical ionization energies (VIEs) of medazepam, nordazepam and their molecular subunits have been calculated using the electron
propagator method in the P3/CEP-31G* approximation. Vertical electron affinities (VEAs) have been obtained with a ∆SCF procedure
at the DFT-B3LYP/6-31+G* level of theory. Excellent correlations have been achieved between IEcalc and IEexp, allowing reliable assignment of the ionization processes. Our proposed assignment differs in many instances from that previously
reported in the literature. The electronic structure of the frontier Dyson orbitals shows that the IE and EA values of the
benzodiazepines can be modulated by substitution at the benzene rings. Hardness values, evaluated as (IE − EA)/2, follow the
trend of the experimental singlet transition energies. Medazepam is a less hard (i.e., less stable) compound than nordazepam. 相似文献
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Luca Racca Andrea Villa Lukardis C. M. Wencker Marco Camaiti Hugues-Alexandre Blain Massimo Delfino 《Journal of morphology》2020,281(7):808-833
The skull osteology of Hierophis viridiflavus is here described and figured in detail on the basis of 18 specimens. The sample includes specimens from the ranges of both H. viridiflavus viridiflavus and H. viridiflavus carbonarius as well as specimens not identified at sub-specific level. The main characters that define H. viridiflavus in comparison to the parapatric congeneric species Hierophis gemonensis are wide maxillary diastema, basioccipital crest well distinct in three lobes and basioccipital process well marked. The foramina of the otoccipital and prootic, and the basioccipital process of the basioccipital are among the most ontogenetically variable characters, as indicated by two juvenile specimens included in the sample. A specimen-level phylogenetic analysis including H. gemonensis and other outgroups (overall 6 species, 26 specimens, 64 skull characters) recovered all H. viridiflavus specimens in one clade, indicating the presence of a clear phylogenetic signal in the applied characters. However, the resolution within the H. viridiflavus clade is poor the monophyly of H. viridiflavus carbonarius was retrieved, but not that of Hierophis v. viridiflavus. Probably due to the relatively high variability, the skull morphology does not support the recently proposed specific status of the two subspecies. 相似文献
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Silvia Pastorekova Daniela Vullo Angela Casini Andrea Scozzafava Jaromir Pastorek Isao Nishimori 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):211-217
The tumor-associated transmembrane carbonic anhydrase (CA, EC 4.2.1.1) isozymes IX (CA IX) and XII (CA XII) are involved in acidification of hypoxic tumors, a process correlated with poor prognosis and clinical outcome of patients harboring such tumors. This process may be reversed by inhibiting these enzymes with potent sulfonamide/sulfamate inhibitors. A series of such aromatic/heterocyclic sulfonamides incorporating 2,3,5,6-tetrafluorobenzoyl-, 2,3,5,6-tetrafluoro- phenylsulfonyl- and pentafluorophenylureido moieties has been investigated for its interaction with the catalytic domain of the human isozymes hCA IX and hCA XII. Some of these compounds showed excellent inhibitory properties against both isozymes IX and XII, with several subnanomolar inhibitors detected for the first time. These sulfonamides may constitute valuable candidates for the development of novel antitumor therapies based on the inhibition of such tumor-associated CA isozymes. 相似文献
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W. Maartin Strauss Robyn S. Hetem Duncan Mitchell Shane K. Maloney Leith C. R. Meyer Andrea Fuller 《PloS one》2015,10(2)
In artiodactyls, arterial blood destined for the brain can be cooled through counter-current heat exchange within the cavernous sinus via a process called selective brain cooling. We test the hypothesis that selective brain cooling, which results in lowered hypothalamic temperature, contributes to water conservation in sheep. Nine Dorper sheep, instrumented to provide measurements of carotid blood and brain temperature, were dosed with deuterium oxide (D2O), exposed to heat for 8 days (40◦C for 6-h per day) and deprived of water for the last five days (days 3 to 8). Plasma osmolality increased and the body water fraction decreased over the five days of water deprivation, with the sheep losing 16.7% of their body mass. Following water deprivation, both the mean 24h carotid blood temperature and the mean 24h brain temperature increased, but carotid blood temperature increased more than did brain temperature resulting in increased selective brain cooling. There was considerable inter-individual variation in the degree to which individual sheep used selective brain cooling. In general, sheep spent more time using selective brain cooling, and it was of greater magnitude, when dehydrated compared to when they were euhydrated. We found a significant positive correlation between selective brain cooling magnitude and osmolality (an index of hydration state). Both the magnitude of selective brain cooling and the proportion of time that sheep spent selective brain cooling were negatively correlated with water turnover. Sheep that used selective brain cooling more frequently, and with greater magnitude, lost less water than did conspecifics using selective brain cooling less efficiently. Our results show that a 50kg sheep can save 2.6L of water per day (~60% of daily water intake) when it employs selective brain cooling for 50% of the day during heat exposure. We conclude that selective brain cooling has a water conservation function in artiodactyls. 相似文献