Human and mouse essentiality screens as a resource for disease gene discovery.

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery

Physiological, Sensory, and Functional Measures in a Model of Wrist Muscle Injury and Recovery

Purpose: To evaluate the effectiveness of muscle rehabilitation modalities, it is first necessary to develop a model to test measures that would assess physiological, sensory, and functional muscle recovery. This study attempted to develop such a model for wrist injury

Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment

Specific language impairment (SLI) is defined as an unexplained failure to acquire normal language skills despite adequate intelligence and opportunity. We have reported elsewhere a full-genome scan in 98 nuclear families affected by this disorder, with the use of three quantitative traits of language ability (the expressive and receptive tests of the Clinical Evaluation of Language Fundamentals and a test of nonsense word repetition). This screen implicated two quantitative trait loci, one on chromosome 16q (SLI1) and a second on chromosome 19q (SLI2). However, a second independent genome screen performed by another group, with the use of parametric linkage analyses in extended pedigrees, found little evidence for the involvement of either of these regions in SLI. To investigate these loci further, we have collected a second sample, consisting of 86 families (367 individuals, 174 independent sib pairs), all with probands whose language skills are greater-or-equal, slanted1.5 SD below the mean for their age. Haseman-Elston linkage analysis resulted in a maximum LOD score (MLS) of 2.84 on chromosome 16 and an MLS of 2.31 on chromosome 19, both of which represent significant linkage at the 2% level. Amalgamation of the wave 2 sample with the cohort used for the genome screen generated a total of 184 families (840 individuals, 393 independent sib pairs). Analysis of linkage within this pooled group strengthened the evidence for linkage at SLI1 and yielded a highly significant LOD score (MLS = 7.46, interval empirical P<.0004). Furthermore, linkage at the same locus was also demonstrated to three reading-related measures (basic reading [MLS = 1.49], spelling [MLS = 2.67], and reading comprehension [MLS = 1.99] subtests of the Wechsler Objectives Reading Dimensions)

Recovery and adaptation from repeated intermittent sprint exercise

PURPOSE: This investigation aimed to 1) ascertain a detailed physiological profile of recovery from intermittent sprint exercise on athletes familiar with the exercise, and 2) investigate if athletes receive a protective effect on markers of exercise-induced muscle damage (EIMD), inflammation and oxidative stress following a repeated exposure to an identical bout of intermittent sprint exercise. METHODS: Eight well trained male team sport athletes of National League or English University Premier Division standard (mean ± SD age 23 ± 3 years; VO2max 54.8 ± 4.6 ml·kg-1·min-1) completed the Loughborough Intermittent Shuttle Test (LIST) on two occasions, separated by 14 days. Maximal isometric voluntary contraction (MIVC), counter-movement jump (CMJ), creatine kinase (CK), C-reactive protein (CRP), interleukin-6 (IL-6), F2-isoprostanes and muscle soreness (DOMS) were measured before, and up to 72 h following the initial, and repeated LIST. RESULTS: MIVC, CMJ, CK, IL-6 and DOMS all showed main effects for time (P < 0.05) following the LIST indicating EIMD was present. DOMS peaked at 24 h following LIST 1 (110±53 mm) and was attenuated following LIST 2 (56±39 mm), and was the only dependent variable to demonstrate a reduction in the second bout (P = 0.008). All other markers indicated EIMD were not different between bouts. CONCLUSION: Well-trained games players experienced EIMD following exposure to both exercise tests, despite being accustomed to the exercise type. This suggests well-trained athletes receive a very limited protective effect from the first bou

Efeitos de um tratamento combinado (vitamina C pré-exercício e alongamento FNP, tratamento com ultrassom pós-exercício) sobre marcadores de dano muscular induzido por exercício

CONTEXTO: Várias estratégias de recuperação têm sido utilizadas na tentativa de minimizar os sintomas da dor muscular de início tardio (DMIT). Contudo, evidências científicas que apoiem este efeito profilático (pré-exercício) e terapêutico (pós-exercício) de um tratamento combinado (FNP e vitamina C, ultrassom) no dano muscular são inexistentes. OBJETIVO: Investigar os efeitos de um tratamento combinado (FNP e vitamina C, ultrassom) nos marcadores bioquímicos (níveis enzimáticos) e funcionais (ângulo do cotovelo, circunferência de braço, taxa de dor) de dano muscular induzido por exercício. MÉTODO: Amostra randomizada controlada. LOCAL: Laboratório da Universidade. PARTICIPANTES: Alunos universitários masculinos participaram voluntariamente do estudo, o qual não reportou nenhuma dor muscular de início tardio por no mínimo seis meses antes do estudo. Posteriormente, os sujeitos foram agrupados aleatoriamente em subgrupos com mão controle e mão experimental. INTERVENÇÃO(ÕES): Programa de exercício para indução de dano muscular induzido por exercício envolvendo o teste de bíceps Scott (contração excêntrica com duas mãos). PROCEDIMENTO(S) PRINCIPAL(IS): Circunferência de braço relaxado, circunferência de braço flexionado, ângulo de cotovelo em descanso, circunferência de antebraço, amplitude de movimento de cotovelo flexionado, amplitude de movimento de cotovelo estendido, dano muscular induzido por exercício, força máxima voluntária isométrica e isocinética foram registrados basal, imediatamente após exercício e 24, 48, 72 e 96 horas após exercício. RESULTADOS: O subgrupo experimental manifestou redução de sintomas de DMIT em menor amplitude de movimento de cotovelo flexionado e amplitude de movimento de cotovelo estendido, menor perda de força isométrica e isocinética voluntária máxima (P < 0,05) em comparação com o subgrupo controle. Contudo, nenhum efeito na circunferência de braço relaxado, circunferência de braço flexionado, ângulo de cotovelo em descanso ou circunferência de antebraço foi observado (P >0,05). CONCLUSÃO: Este tratamento combinado foi eficiente em contração máxima voluntária isométrica, dor muscular de início tardio e taxa de intensidade de dor ao longo do tempo. Finalmente, os resultados sugerem que os tratamentos combinados são eficientes na manutenção de força isométrica e diminuição de dor muscular de início tardio e taxa de intensidade de dor