scholarly journals Predicting the Impact of cis-Regulatory Variation on Alternative Polyadenylation

2018 ◽  
Author(s):  
Nicholas Bogard ◽  
Johannes Linder ◽  
Alexander B. Rosenberg ◽  
Georg Seelig
Keyword(s):  
Random Sequence ◽  
Alternative Polyadenylation ◽  
Expression Data ◽  
Sequence Motifs ◽  
Network Layers ◽  
Pathogenic Variants ◽  
Wide Range ◽  
The Impact ◽  
Transcriptome Diversity ◽  
Unknown Sequence

Alternative polyadenylation (APA) is a major driver of transcriptome diversity in human cells. Here, we use deep learning to predict APA from DNA sequence alone. We trained our model (APARENT, APA REgression NeT) on isoform expression data from over three million APA reporters, built by inserting random sequence into twelve distinct 3’UTR contexts. Predictions are highly accurate across both synthetic and genomic contexts; when tasked with inferring APA in human 3’UTRs, APARENT outperforms models trained exclusively on endogenous data. Visualizing features learned across all network layers reveals that APARENT recognizes sequence motifs known to recruit APA regulators, discovers previously unknown sequence determinants of cleavage site selection, and integrates these features into a comprehensive, interpretable cis-regulatory code. Finally, we use APARENT to quantify the impact of genetic variants on APA. Our approach detects pathogenic variants in a wide range of disease contexts, expanding our understanding of the genetic origins of disease.

scholarly journals One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation

2021 ◽  
Author(s):  
Stephen E. Lincoln ◽  
Tina Hambuch ◽  
Justin M. Zook ◽  
Sara L. Bristow ◽  
Kathryn Hatchell ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Copy Number Variants ◽  
Low Complexity ◽  
Clinical Genetic ◽  
Clinical Sensitivity ◽  
Pathogenic Variants ◽  
Wide Range ◽  
Large Indels ◽  
Next Generation Sequencing Ngs ◽  
The Impact

Abstract Purpose To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions. Methods An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)–based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients. Results In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests. Conclusion The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.

scholarly journals Impact of a Random Sequence of Debris Flows on Torrential Fan Formation

Geosciences ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 64 ◽  
Author(s):  
Nejc Bezak ◽  
Jošt Sodnik ◽  
Matjaž Mikoš
Keyword(s):  
Debris Flow ◽  
Numerical Simulations ◽  
Rheological Properties ◽  
Debris Flows ◽  
Random Sequence ◽  
Rheological Parameters ◽  
Model Parameters ◽  
Maximum Height ◽  
Wide Range ◽  
The Impact

Debris flows with different magnitudes can have a large impact on debris fan characteristics such as height or slope. Moreover, knowledge about the impact of random sequences of debris flows of different magnitudes on debris fan properties is sparse in the literature and can be improved using numerical simulations of debris fan formation. Therefore, in this paper we present the results of numerical simulations wherein we investigated the impact of a random sequence of debris flows on torrential fan formation, where the total volume of transported debris was kept constant, but different rheological properties were used. Overall, 62 debris flow events with different magnitudes from 100 m3 to 20,000 m3 were selected, and the total volume was approximately 225,000 m3. The sequence of these debris flows was randomly generated, and selected debris fan characteristics after the 62 events were compared. For modeling purposes, we applied the Rapid Mass Movement Simulations (RAMMS) software and its debris flow module (RAMMS-DF). The modeling was carried out using (a) real fan topography from an alpine environment (i.e., an actual debris fan in north-west (NW) Slovenia formed by the Suhelj torrent) and (b) an artificial surface with a constant slope. Several RAMMS model parameters were tested. The simulation results confirm that the random sequence of debris flow events has only some minor effects on the fan formation (e.g., slope, maximum height), even when changing debris flow rheological properties in a wide range. After the 62 events, independent of the selected sequence of debris flows, the final fan characteristics were not significantly different from each other. Mann–Whitney (MW) tests and t-tests were used for this purpose, and the selected significance level was 0.05. Moreover, this conclusion applies for artificial and real terrain and for a wide range of tested RAMMS model rheological parameters. Further testing of the RAMMS-DF model in real situations is proposed in order to better understand its applicability and limitations under real conditions for debris flow hazard assessment or the planning of mitigation measures.

scholarly journals One in seven pathogenic variants can be challenging to detect by NGS: An analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation

2020 ◽  
Author(s):  
Stephen E Lincoln ◽  
Tina Hambuch ◽  
Justin M Zook ◽  
Sara L Bristow ◽  
Kathryn Hatchell ◽  
...  
Keyword(s):  
Genetic Test ◽  
Diagnostic Yield ◽  
Low Complexity ◽  
Clinical Genetic ◽  
Clinical Sensitivity ◽  
Pathogenic Variants ◽  
Wide Range ◽  
Large Indels ◽  
The Impact ◽  
Selection Of

Purpose: To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small CNVs, complex alterations, and variants in low-complexity or segmentally duplicated regions. Methods: An interlaboratory pilot study used novel synthetic specimens to assess detection of challenging variant types by various NGS-based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients. Results: In the interlaboratory study, only two of 13 challenging variants were detected by all 10 workflows, and just three workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests. Conclusion: The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.

EXTRACTION OF CO-BEHAVING GENES BY SIMILARITY ENSEMBLES

2017 ◽  
Vol 25 (03) ◽  
pp. 479-494
Author(s):  
MOSLEM MOHAMMADI-JENGHARA ◽  
HOSSEIN EBRAHIMPOUR-KOMLEH
Keyword(s):  
Gene Expression ◽  
Candidate Genes ◽  
Biological Information ◽  
Data Sets ◽  
Expression Data ◽  
Yeast Gene ◽  
Ensemble Technique ◽  
Wide Range ◽  
The Impact

Microarray technology is used as a source of data for a wide range of biology studies. Useful biological information can be extracted from the analysis of microarray data, namely, the impact of a particular gene expression on the expression of other genes or the determination of expressed genes under different conditions. The purpose of this paper is to find co-behavioral genes in different data sets for different times and conditions. In other words, genes with similar behavior, same increase or decrease, under different medical, stress, and time conditions in terms of expression are determined. Multi-valued discretization of expression data was used for extracting genes with identical behavior. The algorithm proposed in this study is based on data and methods ensemble. The data ensemble technique was used to extract candidate genes with identical behavior. Other methods were also applied on all the data sets; as a result, many co-behavioral candidate genes with different similarity and correlation values were identified. Finally, the ultimate output was created from the ensemble of different methods. By applying the algorithm on yeast gene expression data, meaningful relations among genes were extracted.

THE IMPACT OF LEADERSHIP PRACTICES TO TEAM MEMBERS’ SATISFACTION

2009 ◽  
Vol 8 (1) ◽  
Author(s):  
Chalimah .
Keyword(s):  
Conflict Resolution ◽  
Leadership Practices ◽  
Hotel Industry ◽  
Leader Behavior ◽  
Team Leader ◽  
Shop Floor ◽  
Team Members ◽  
Top Executives ◽  
Wide Range ◽  
The Impact

eamwork is becoming increasingly important to wide range of operations. It applies to all levels of the company. It is just as important for top executives as it is to middle management, supervisors and shop floor workers. Poor teamwork at any level or between levels can seriously damage organizational effectiveness. The focus of this paper was therefore to examine whether leadership practices consist of team leader behavior, conflict resolution style and openness in communication significantly influenced the team member’s satisfaction in hotel industry. Result indicates that team leader behavior and the conflict resolution style significantly influenced team member satisfaction. It was surprising that openness in communication did not affect significantly to the team members’ satisfaction.

Stress, anxiety, depression and burnout in frontline health care workers during COVID-19 pandemic: a brief systematic review and new data from Russia

2021 ◽  
Author(s):  
Ekaterina Mosolova ◽  
Dmitry Sosin ◽  
Sergey Mosolov
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Female Gender ◽  
Assessment Tools ◽  
Care Workers ◽  
Younger Age ◽  
Wide Range ◽  
Associated Risk Factors ◽  
Anxiety Depression ◽  
The Impact

During the COVID-19 pandemic, healthcare workers (HCWs) have been subject to increased workload while also exposed to many psychosocial stressors. In a systematic review we analyze the impact that the pandemic has had on HCWs mental state and associated risk factors. Most studies reported high levels of depression and anxiety among HCWs worldwide, however, due to a wide range of assessment tools, cut-off scores, and number of frontline participants in the studies, results were difficult to compare. Our study is based on two online surveys of 2195 HCWs from different regions of Russia during spring and autumn epidemic outbreaks revealed the rates of anxiety, stress, depression, emotional exhaustion and depersonalization and perceived stress as 32.3%, 31.1%, 45.5%, 74.2%, 37.7% ,67.8%, respectively. Moreover, 2.4% of HCWs reported suicidal thoughts. The most common risk factors include: female gender, nurse as an occupation, younger age, working for over 6 months, chronic diseases, smoking, high working demands, lack of personal protective equipment, low salary, lack of social support, isolation from families, the fear of relatives getting infected. These results demonstrate the need for urgent supportive programs for HCWs fighting COVID-19 that fall into higher risk factors groups.

A MODELING SYSTEM FOR CLIMATE CHANGE RISK ASSESSMENT, MANAGEMENT AND HEDGING IN COASTAL AREAS

2017 ◽  
Author(s):  
Sergei Soldatenko ◽  
Sergei Soldatenko ◽  
Genrikh Alekseev ◽  
Genrikh Alekseev ◽  
Alexander Danilov ◽  
...  
Keyword(s):  
Climate Change ◽  
Risk Assessment ◽  
Coastal Areas ◽  
Mitigation Strategies ◽  
System Structure ◽  
The Arctic ◽  
Risk Modeling ◽  
Wide Range ◽  
Adverse Weather ◽  
The Impact

Every aspect of human operations faces a wide range of risks, some of which can cause serious consequences. By the start of 21st century, mankind has recognized a new class of risks posed by climate change. It is obvious, that the global climate is changing, and will continue to change, in ways that affect the planning and day to day operations of businesses, government agencies and other organizations and institutions. The manifestations of climate change include but not limited to rising sea levels, increasing temperature, flooding, melting polar sea ice, adverse weather events (e.g. heatwaves, drought, and storms) and a rise in related problems (e.g. health and environmental). Assessing and managing climate risks represent one of the most challenging issues of today and for the future. The purpose of the risk modeling system discussed in this paper is to provide a framework and methodology to quantify risks caused by climate change, to facilitate estimates of the impact of climate change on various spheres of human activities and to compare eventual adaptation and risk mitigation strategies. The system integrates both physical climate system and economic models together with knowledge-based subsystem, which can help support proactive risk management. System structure and its main components are considered. Special attention is paid to climate risk assessment, management and hedging in the Arctic coastal areas.

The Management of Post-Tonsillectomy Morbidity in Patients With Sleep Apnoea

2019 ◽  
Vol 70 (10) ◽  
pp. 3738-3740
Keyword(s):  
Day Surgery ◽  
Sleep Apnoea ◽  
Integrative Approach ◽  
Multicenter Studies ◽  
Therapeutic Modalities ◽  
Advantages And Disadvantages ◽  
Obstructive Sleep ◽  
Wide Range ◽  
The Impact ◽  
Surgery Center

The Tonsillectomy in children or adults is an intervention commonly encountered in the ENT (Ear Nose and Throat) and Head and Neck surgeon practice. The current tendency is to perform this type of surgery in major ambulatory surgery centers. Two objectives are thus pursued: first of all, the increase of the patient quality of life through the reintegration into the family as quickly as possible and secondly, the expenses associated with continuous hospitalization are reduced. Any tertiary (multidisciplinary) sleep center must ensure the complete diagnosis and treatment (including surgery) of sleep respiratory disorders. Under these conditions the selection of patients and especially the implementation of the specific protocols in order to control the postoperative complications it becomes essential. The present paper describes our experience of tonsillectomy as treatment for selected patients with chronic rhonchopathy (snoring) and mild to moderate obstructive sleep apnoea. It was presented the impact of antibiotics protocols in reducing the main morbid outcomes following tonsillectomy, in our day surgery center. The obtained results can also be a prerequisite for the integrative approach of the patients with sleep apnoea who were recommended surgical treatment. Considering the wide range of therapeutic modalities used in sleep apnoea, each with its specific advantages and disadvantages, more extensive and multicenter studies are needed. Keywords: post-tonsillectomy morbidity, day surgery center, sleep disorders

Cognitive Impact of Cerebellar Damage: Is There a Future for Cognitive Rehabilitation?

2018 ◽  
Vol 17 (3) ◽  
pp. 199-206 ◽  
Author(s):  
Kim van Dun ◽  
Frank V. Overwalle ◽  
Mario Manto ◽  
Peter Marien
Keyword(s):  
Affective Disorders ◽  
Cognitive Rehabilitation ◽  
Therapeutic Interventions ◽  
Posterior Fossa Surgery ◽  
Daily Life Activities ◽  
Wide Range ◽  
Affective Deficits ◽  
Cerebellar Injury ◽  
Cognitive Therapies ◽  
The Impact

Background & Objective: During the past 3 decades, numerous neurophysiological, neuroimaging, experimental and clinical studies have evidenced a crucial role for the cerebellum in cognitive, affective and behavioral functions. As a result of the acknowledged modulatory role of the cerebellum upon remote structures such as the cerebral cortex, cerebellar injury may give rise to a constellation of behavioral, affective and cognitive symptoms (Schmahmann's Syndrome). In sharp contrast to the wide range of therapeutic interventions to treat cognitive and affective disorders following cerebral cortical lesions and despite the consequences of Schmahmann’s syndrome upon daily life activities, the literature is surprisingly only scantly documented with studies investigating the impact of cognitive therapies on cerebellar induced cognitive and affective disorders. This survey aims to present an overview of the therapeutic interventions available in the literature as a possible treatment for Schmahmann’s Syndrome after cerebellar injury, after posterior fossa surgery in children, and in children with neurodevelopmental disorders. Although systematical studies are clearly warranted, available evidence suggests that cerebellar-induced cognitive and affective disorders should be treated in a specific way. Approaches where the patients are explicitly made aware of their deficits and are considered to act as an “external cerebellum” are the most promising. Conclusion: The study of the anatomical connectivity of the cerebellar microcomplexes involved in cognitive/affective deficits is likely to play a major-role in the future.

Religion and Medicine

2020 ◽  
Author(s):  
Jeff Levin ◽  
Stephen G. Post
Keyword(s):  
Clinical Decision Making ◽  
Well Being ◽  
Clinical Decision ◽  
Religion And Medicine ◽  
Physical And Mental Health ◽  
Faith Based ◽  
Baylor University ◽  
Wide Range ◽  
History Of ◽  
The Impact

In Religion and Medicine, Dr. Jeff Levin, distinguished Baylor University epidemiologist, outlines the longstanding history of multifaceted interconnections between the institutions of religion and medicine. He traces the history of the encounter between these two institutions from antiquity through to the present day, highlighting a myriad of contemporary alliances between the faith-based and medical sectors. Religion and Medicine tells the story of: religious healers and religiously branded hospitals and healthcare institutions; pastoral professionals involved in medical missions, healthcare chaplaincy, and psychological counseling; congregational health promotion and disease prevention programs and global health initiatives; research studies on the impact of religious and spiritual beliefs and practices on physical and mental health, well-being, and healing; programs and centers for medical research and education within major universities and academic institutions; religiously informed bioethics and clinical decision-making; and faith-based health policy initiatives and advocacy for healthcare reform. Religion and Medicine is the first book to cover the full breadth of this subject. It documents religion-medicine alliances across religious traditions, throughout the world, and over the course of history. It summarizes a wide range of material of relevance to historians, medical professionals, pastors and theologians, bioethicists, scientists, public health educators, and policymakers. The product of decades of rigorous and focused research, Dr. Levin has produced the most comprehensive history of these developments and the finest introduction to this emerging field of scholarship.

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