Whole-genome sequencing in an autism multiplex family

BACKGROUND: Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental disorders that affect 1 in 88 children in the US. Previous exome sequencing studies on family trios have implicated a role for rare, de-novo mutations in the pathogenesis of autism. METHODS: To examine the utility of whole-genome sequencing to identify inherited disease candidate variants and genes, we sequenced two probands from a large pedigree, including two parents and eight children. We evaluated multiple analytical strategies to identify a prioritized list of candidate genes. RESULTS: By assuming a recessive model of inheritance, we identified seven candidate genes shared by the two probands. We also evaluated a different analytical strategy that does not require the assumption of disease model, and identified a list of 59 candidate variants that may increase susceptibility to autism. Manual examination of this list identified ANK3 as the most likely candidate gene. Finally, we identified 33 prioritized non-coding variants such as those near SMG6 and COQ5, based on evolutionary constraint and experimental evidence from ENCODE. Although we were unable to confirm rigorously whether any of these genes indeed contribute to the disease, our analysis provides a prioritized shortlist for further validation studies. CONCLUSIONS: Our study represents one of the first whole-genome sequencing studies in autism leveraging a large family-based pedigree. These results provide for a discussion on the relative merits of finding de-novo mutations in sporadic cases versus finding inherited mutations in large pedigrees, in the context of neuropsychiatric and neurodevelopmental diseases

Whole-genome DNA/RNA sequencing identifies truncating mutations in RBCK1 in a novel Mendelian disease with neuromuscular and cardiac involvement

Background: Whole-exome sequencing has identified the causes of several Mendelian diseases by analyzing multiple unrelated cases, but it is more challenging to resolve the cause of extremely rare and suspected Mendelian diseases from individual families. We identified a family quartet with two children, both affected with a previously unreported disease, characterized by progressive muscular weakness and cardiomyopathy, with normal intelligence. During the course of the study, we identified one additional unrelated patient with a comparable phenotype. Methods: We performed whole-genome sequencing (Complete Genomics platform), whole-exome sequencing (Agilent SureSelect exon capture and Illumina Genome Analyzer II platform), SNP genotyping (Illumina HumanHap550 SNP array) and Sanger sequencing on blood samples, as well as RNA-Seq (Illumina HiSeq platform) on transformed lymphoblastoid cell lines. Results: From whole-genome sequence data, we identified RBCK1, a gene encoding an E3 ubiquitin-protein ligase, as the most likely candidate gene, with two protein-truncating mutations in probands in the first family. However, exome data failed to nominate RBCK1 as a candidate gene, due to poor regional coverage. Sanger sequencing identified a private homozygous splice variant in RBCK1 in the proband in the second family, yet SNP genotyping revealed a 1.2Mb copy-neutral region of homozygosity covering RBCK1. RNA-Seq confirmed aberrant splicing of RBCK1 transcripts, resulting in truncated protein products. Conclusions: While the exact mechanism by which these mutations cause disease is unknown, our study represents an example of how the combined use of whole-genome DNA and RNA sequencing can identify a disease-predisposing gene for a novel and extremely rare Mendelian disease

Institutions, complementarity, human resource management and performance in a South-East Asian Petrostate: the case of Brunei

This is a study on the incidence and impact of specific sets of HR practices on organisational performance (OP) across different types of firm, within an emerging market setting, where institutional arrangements are fluid and developing. The literature on comparative capitalism suggests that, within advanced societies, formal and informal regulations are mutually supportive, and will be sustained by associated HR systems, optimising OP. In contrast, in settings where institutional arrangements are weaker, there will not be the same incentives for disseminating mutually supportive HR bundles, and when these do exist, they are unlikely to yield any better outcomes. We found that this was indeed the case in the petrostate of Brunei as the usage of integrated HR models did not work better than individual interventions. Whilst it is often assumed that, in petrostates, the primary focus of institution-building is to service the needs of the oil-and-gas industry, we found no evidence to suggest that integrated HR systems were any more effective there; this may reflect the extent to which the industry’s HR needs may be simply resolved through turning to overseas labour markets – both for skilled and unskilled labour. At the same time, we found that the efficacy of HR practices varied according to firm characteristics: even in challenging contexts, firms may devise their own solutions according to their capabilities and endowments

Formulation of Mathematical Modeling to Characterize The Aluminium Metals Using Ultrasonic Non-Destructive Techniques

Predicting the type of aluminium metals and composition of elements present in the aluminium samples through Nondestructive testing (NDT) is a matter of very importance for aluminium Industry. The unique method to determine grade of the aluminium sample is required to characterize the aluminium metals. The Nondestructive Technique (NDT) and determination of characteristics and mechanical properties of aluminium metals are used to identify the grade of aluminium metals so that accordingly it can be used for the specific applications. Therefore a technique is required to predict the percentage of aluminium, Iron, Copper, Manganese of aluminium metals so as to categorize into different grades and applications. In Aluminium samples percentage of Aluminium plays very important role which may help to decide the grade of the aluminium metals hence its applications. The present work is focused on how the percentage of aluminium in aluminium samples can be calculated by adopting the mathematical modeling technique. There are various parameters which generally affect the percentage of aluminium in aluminium samples, and play a very major role. Therefore through this investigation an attempt is being made to formulate an approximate mathematical model which will certainly predict the percentage of aluminium in aluminium samples. In advent of this a dimensionless pie terms of various prominent parameters or variables have been taken to form a mathematical model. Some of these variables used to formulate this model are given as follows (i) physical properties of the aluminium samples like hardness, density, modulus of elasticity etc (ii) Signal analysis properties like Peak amplitude of Time signal, FFT, PSD and (iii) both the properties. The data of such types of variables have been recorded and calculated and thus the formulation of model is being done by multiple regression analysis. The model is then optimized and the reliability of the model has also been estimated. In fact this type of model will be helpful to estimate the aluminium percentage

The unresolved urban dilemma of self-medication practices and its association with various socio demographic factors among adults in urban slum

Background: Self-medication has grown increasingly in developing countries, such as India, perhaps causing drug addiction and microbial resistance. Without proper medical supervision, self-medication can cause ineffective or excessive treatment, a delay in treatment, misdiagnosis, resistance to antibiotics, medicine abuse, and an increase in morbidity. Methodology: The population-based cross-sectional analytical research done in urban slum. We questioned 400 individuals over the age of 18 at their homes. Data were acquired from individuals using a predesigned, pretested questionnaire as an interview tool. Objective: To determine self medication prevalence and its connection to various demographic risk factors. Results: Self-medication was prevalent, with 51% in selected urban slums. The most commonly self-administered drugs were analgesics (59.8%) and antacids (46.07%). Body discomfort (60.29%), Headaches (55.78%), feverish (53.43%), cough (41.01%), were among the most common conditions when participants used medication on their own. There was a significant relationship with self-prescribed medication use and healthcare professionals in the household (p = 0.00001) and among working participants (p = 0.009). Conclusion: Lower socioeconomic groups often use medications without consulting doctors, and chronic illnesses require continuous follow-up. Education on the dangers of self-medication is crucial

Economic manufacturing quantity in a just-in-time delivery system

A just-in-time (JIT) buyer demands frequent deliveries of small lots of certain products. However, there is a perception among the suppliers that participation in a JIT delivery system is economically disadvantageous for them. To test this conjecture, a generalized inventory model is developed for a supplier who has to meet a deterministic demand at fixed intervals. The generalized total cost model developed here is found to be a piecewise convex function. A simple algorithm is developed to compute the optimal batch size. When production uptime and cycle time are each equal to an integer multiple of the shipment interval, a perfect matching of shipment size occurs, and for such a situation, the generalized model specializes to more traditional inventory models. The solution approach for such models becomes much easier. It is found that, under certain conditions, the total cost decreases linearly with reduced shipment size and the suppliers benefit from this. Economic impact of ordering and setup costs reduction are also investigated. © 1992 Taylor & Francis Group, LLC

Vascular micro-thrombotic disease in pregnancy.

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