There is an increasing need to use genome and transcriptome sequencing to genetically diagnose patients suffering from suspected monogenic rare diseases. The proper detection of compound heterozygous ...variant combinations as disease-causing candidates is a challenge in diagnostic workflows as haplotype information is lost by currently used next-generation sequencing technologies. Consequently, computational tools are required to phase, or resolve the haplotype of, the high number of heterozygous variants in the exome or genome of each patient. Here we present SmartPhase, a phasing tool designed to efficiently reduce the set of potential compound heterozygous variant pairs in genetic diagnoses pipelines. The phasing algorithm of SmartPhase creates haplotypes using both parental genotype information and reads generated by DNA or RNA sequencing and is thus well suited to resolve the phase of rare variants. To inform the user about the reliability of a phasing prediction, it computes a confidence score which is essential to select error-free predictions. It incorporates existing haplotype information and applies logical rules to determine variants that can be excluded as causing a recessive, monogenic disease. SmartPhase can phase either all possible variant pairs in predefined genetic loci or preselected variant pairs of interest, thus keeping the focus on clinically relevant results. We compared SmartPhase to WhatsHap, one of the leading comparable phasing tools, using simulated data and a real clinical cohort of 921 patients. On both data sets, SmartPhase generated error-free predictions using our derived confidence score threshold. It outperformed WhatsHap with regard to the percentage of resolved pairs when parental genotype information is available. On the cohort data, SmartPhase enabled on average the exclusion of approximately 22% of the input variant pairs in each singleton patient and 44% in each trio patient. SmartPhase is implemented as an open-source Java tool and freely available at http://ibis.helmholtz-muenchen.de/smartphase/.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Physical training improves insulin sensitivity and can prevent type 2 diabetes (T2D). However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-β, identified as a ...possible upstream regulator involved in this low response, is also a potent regulator of microRNAs (miRNAs). The aim of this study was to elucidate the potential impact of TGF-β-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-β1-treated human skeletal muscle cells corroborated the effects of TGF-β1 on muscle cell differentiation, the induction of extracellular matrix components, and identified several TGF-β1-regulated miRNAs. qPCR validated a potent upregulation of miR-143-3p/145-5p and miR-181a2-5p by TGF-β1 in both human myoblasts and differentiated myotubes. Healthy subjects who were overweight or obese participated in a supervised 8-week endurance training intervention (
= 40) and were categorized as responder or low responder in glycemic control based on fold change ISIMats (≥+1.1 or <+1.1, respectively). In skeletal muscle biopsies of low responders, TGF-β signaling and miR-143/145 cluster levels were induced by training at much higher rates than among responders. Target-mining revealed HDACs, MYHs, and insulin signaling components INSR and IRS1 as potential miR-143/145 cluster targets. All these targets were down-regulated in TGF-β1-treated myotubes. Transfection of miR-143-3p/145-5p mimics in differentiated myotubes validated
,
, and
as miR-143/145 cluster targets. Elevated TGF-β signaling and miR-143/145 cluster induction in skeletal muscle of low responders might obstruct improvements in insulin sensitivity by training in two ways: by a negative impact of miR-143-3p on muscle cell fusion and myofiber functionality and by directly impairing insulin signaling via a reduction in INSR by TGF-β and finetuned
suppression by miR-143-3p.
In diesem Open-Access-Buch sind aktuelle Praxisbeispiele und Handlungsempfehlungen zur Gestaltung von Arbeit und Produktivität in der digitalisierten Welt beschrieben. Die Beispiele wurden von ...Unternehmen und wissenschaftlichen Instituten in mehreren Forschungsprojekten entwickelt und in der Praxis erprobt. Jedes Praxisbeispiel umfasst konkrete Bedarfe und Ziele, ein schrittweises Vorgehen, die Auswirkungen auf die Arbeitsgestaltung und die Produktivität sowie die zu beachtenden Erfolgsfaktoren. So sind aktuelle Gestaltungslösungen für Unternehmen beschrieben, die die Potenziale der Digitalisierung für die Arbeitswelt und das Produktivitätsmanagement praxisnah aufzeigen.
An increasing networking of IT systems as well as the use of cyber-physical systems in the industrial environment are raising the current amount of data. To process this enormous amount of data and ...derive conclusions companies use Artificial Intelligence (AI) more frequently. The increasing application and use of AI have a significant impact on socio-technical work systems. In particular, challenges and requirements for leaders and leadership can be identified. Accordingly, leaders and leadership are crucial for implementing and using AI successfully. This and the dynamic development of AI require further research on its impact on leaders and leadership for supporting companies with practice-proven guidelines and recommendations. For developing those a comprehensive analysis of existing literature has been conducted and will be the basis for further steps. The literature analysis’ results were grouped into four main clusters: Strategic Transformation Process, Qualification and Competencies, Culture and Human-AI Interaction. The results are presented in detail and an outlook on the further steps of research and development will be given.
Progressing digitalization and the increasing opportunities for networking machines, products, services and a large amount of data in real time offer companies new potential for value creation – ...especially, to develop and establish innovative, hybrid business models. In the AnGeWaNt research project, such new business models are being developed and piloted with three companies that are established on the market with their physical products. Digitalization and upcoming hybridization are raising numerous challenges in the companies that need to be managed for successfully placing the new business models on the market. Within the project is investigated whether and how cross-company cooperation has the potential to solve these challenges together in a more efficient and effective way. The article describes the potential of cross-company cooperation for hybridization and the piloted procedure for establishing a cross-company cooperation structure.
Digitalization is a process that started already years ago and shows increasing dynamics. Since latest the year 2011 – when the vision of Industry 4.0 was presented – digitalization dynamics increase ...also in production industry. Simultaneously, manifold and partially far reaching expectations on the digitalization’s impact on productivity and its management as well as on employees and work design came up. To gain information on the current state of digitalization as well as the related experiences and expectations three studies have been conducted by ifaa in the years 2015, 2017 and 2019 in the German metal and electrical industry. Now integrated analyses of these studies and especially of some replicated questions have been conducted to recognize development tendencies and gain further knowledge on the digitalization’s development. In this way, several development tendencies were found, and assumptions were derived for explaining them. These include expectations on productivity gain, importance of digitalization for selected fields of application, the use of lean methods and holistic approaches as well as the impact on employees, their number, and their flexibility.
In diesem Open-Access-Buch sind aktuelle Praxisbeispiele und Handlungsempfehlungen zur Gestaltung von Arbeit und Produktivität in der digitalisierten Welt beschrieben. Die Beispiele wurden von ...Unternehmen und wissenschaftlichen Instituten in mehreren Forschungsprojekten entwickelt und in der Praxis erprobt. Jedes Praxisbeispiel umfasst konkrete Bedarfe und Ziele, ein schrittweises Vorgehen, die Auswirkungen auf die Arbeitsgestaltung und die Produktivität sowie die zu beachtenden Erfolgsfaktoren. So sind aktuelle Gestaltungslösungen für Unternehmen beschrieben, die die Potenziale der Digitalisierung für die Arbeitswelt und das Produktivitätsmanagement praxisnah aufzeigen.
•SRPRA and SRP19 are novel genes affected in congenital neutropenia and essential for granule protein processing.•Comparative proteomics in neutrophils of patients with defects in SRPRA, SRP19, ...SRP54, HAX1, and ELANE reveal genotype-specific alterations.
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The mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover 2 novel human genetic defects in signal recognition particle receptor alpha (SRPRA) and SRP19, constituents of the mammalian cotranslational targeting machinery, and characterize their roles in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the SRP genes, HAX1, and ELANE, and identify global as well as specific proteome aberrations. Using in vitro differentiation of human induced pluripotent stem cells and in vivo zebrafish models, we study the effects of SRP deficiency on neutrophil granulocyte development. In a heterologous cell–based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking, and homeostasis are critically important for the differentiation of neutrophil granulocytes.
Abstract
Summary
Despite their fundamental role in various biological processes, the analysis of small RNA sequencing data remains a challenging task. Major obstacles arise when short RNA sequences ...map to multiple locations in the genome, align to regions that are not annotated or underwent post-transcriptional changes which hamper accurate mapping. In order to tackle these issues, we present a novel profiling strategy that circumvents the need for read mapping to a reference genome by utilizing the actual read sequences to determine expression intensities. After differential expression analysis of individual sequence counts, significant sequences are annotated against user defined feature databases and clustered by sequence similarity. This strategy enables a more comprehensive and concise representation of small RNA populations without any data loss or data distortion.
Availability and implementation
Code and documentation of our R package at http://ibis.helmholtz-muenchen.de/deus/.
Supplementary information
Supplementary data are available at Bioinformatics online.
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