keyword
https://read.qxmd.com/read/32838340/point-of-care-nucleic-acid-testing-for-sars-cov-2-in-hospitalized-patients-a-clinical-validation-trial-and-implementation-study
#21
JOURNAL ARTICLE
Dami A Collier, Sonny M Assennato, Ben Warne, Nyarie Sithole, Katherine Sharrocks, Allyson Ritchie, Pooja Ravji, Matthew Routledge, Dominic Sparkes, Jordan Skittrall, Anna Smielewska, Isobel Ramsey, Neha Goel, Martin Curran, David Enoch, Rhys Tassell, Michelle Lineham, Devan Vaghela, Clare Leong, Hoi Ping Mok, John Bradley, Kenneth G C Smith, Vivienne Mendoza, Nikos Demiris, Martin Besser, Gordon Dougan, Paul J Lehner, Mark J Siedner, Hongyi Zhang, Claire S Waddington, Helen Lee, Ravindra K Gupta
There is an urgent need for rapid SARS-CoV-2 testing in hospitals to limit nosocomial spread. We report an evaluation of point of care (POC) nucleic acid amplification testing (NAAT) in 149 participants with parallel combined nasal and throat swabbing for POC versus standard lab RT-PCR testing. Median time to result is 2.6 (IQR 2.3-4.8) versus 26.4 h (IQR 21.4-31.4, p < 0.001), with 32 (21.5%) positive and 117 (78.5%) negative. Cohen's κ correlation between tests is 0.96 (95% CI 0.91-1.00). When comparing nearly 1,000 tests pre- and post-implementation, the median time to definitive bed placement from admission is 23...
August 25, 2020: Cell reports medicine
https://read.qxmd.com/read/32799905/dimsum-an-error-model-and-pipeline-for-analyzing-deep-mutational-scanning-data-and-diagnosing-common-experimental-pathologies
#22
JOURNAL ARTICLE
Andre J Faure, Jörn M Schmiedel, Pablo Baeza-Centurion, Ben Lehner
Deep mutational scanning (DMS) enables multiplexed measurement of the effects of thousands of variants of proteins, RNAs, and regulatory elements. Here, we present a customizable pipeline, DiMSum, that represents an end-to-end solution for obtaining variant fitness and error estimates from raw sequencing data. A key innovation of DiMSum is the use of an interpretable error model that captures the main sources of variability arising in DMS workflows, outperforming previous methods. DiMSum is available as an R/Bioconda package and provides summary reports to help researchers diagnose common DMS pathologies and take remedial steps in their analyses...
August 17, 2020: Genome Biology
https://read.qxmd.com/read/32558644/effective-control-of-sars-cov-2-transmission-between-healthcare-workers-during-a-period-of-diminished-community-prevalence-of-covid-19
#23
JOURNAL ARTICLE
Nick K Jones, Lucy Rivett, Dominic Sparkes, Sally Forrest, Sushmita Sridhar, Jamie Young, Joana Pereira-Dias, Claire Cormie, Harmeet Gill, Nicola Reynolds, Michelle Wantoch, Matthew Routledge, Ben Warne, Jack Levy, William David Córdova Jiménez, Fathima Nisha Begum Samad, Chris McNicholas, Mark Ferris, Jane Gray, Michael Gill, Martin D Curran, Stewart Fuller, Afzal Chaudhry, Ashley Shaw, John R Bradley, Gregory J Hannon, Ian G Goodfellow, Gordon Dougan, Kenneth Gc Smith, Paul J Lehner, Giles Wright, Nicholas J Matheson, Stephen Baker, Michael P Weekes
Previously, we showed that 3% (31/1032)of asymptomatic healthcare workers (HCWs) from a large teaching hospital in Cambridge, UK, tested positive for SARS-CoV-2 in April 2020. About 15% (26/169) HCWs with symptoms of coronavirus disease 2019 (COVID-19) also tested positive for SARS-CoV-2 (Rivett et al., 2020). Here, we show that the proportion of both asymptomatic and symptomatic HCWs testing positive for SARS-CoV-2 rapidly declined to near-zero between 25th April and 24th May 2020, corresponding to a decline in patient admissions with COVID-19 during the ongoing UK 'lockdown'...
June 19, 2020: ELife
https://read.qxmd.com/read/32046365/the-secretion-of-toxins-and-other-exoproteins-of-cronobacter-role-in-virulence-adaption-and-persistence
#24
REVIEW
Hyein Jang, Gopal R Gopinath, Athmanya Eshwar, Shabarinath Srikumar, Scott Nguyen, Jayanthi Gangiredla, Isha R Patel, Samantha B Finkelstein, Flavia Negrete, JungHa Woo, YouYoung Lee, Séamus Fanning, Roger Stephan, Ben D Tall, Angelika Lehner
: Cronobacter species are considered an opportunistic group of foodborne pathogenic bacteria capable of causing both intestinal and systemic human disease. This review describes common virulence themes shared among the seven Cronobacter species and describes multiple exoproteins secreted by Cronobacter , many of which are bacterial toxins that may play a role in human disease. The review will particularly concentrate on the virulence factors secreted by C. sakazakii , C. malonaticus , and C. turicensis , which are the primary human pathogens of interest...
February 8, 2020: Microorganisms
https://read.qxmd.com/read/31659324/the-impact-of-nonsense-mediated-mrna-decay-on-genetic-disease-gene-editing-and-cancer-immunotherapy
#25
JOURNAL ARTICLE
Rik G H Lindeboom, Michiel Vermeulen, Ben Lehner, Fran Supek
Premature termination codons (PTCs) can result in the production of truncated proteins or the degradation of messenger RNAs by nonsense-mediated mRNA decay (NMD). Which of these outcomes occurs can alter the effect of a mutation, with the engagement of NMD being dependent on a series of rules. Here, by applying these rules genome-wide to obtain a resource called NMDetective, we explore the impact of NMD on genetic disease and approaches to therapy. First, human genetic diseases differ in whether NMD typically aggravates or alleviates the effects of PTCs...
November 2019: Nature Genetics
https://read.qxmd.com/read/31551797/vitellogenins-yolk-gene-function-and-regulation-in-caenorhabditis-elegans
#26
REVIEW
Marcos Francisco Perez, Ben Lehner
Vitellogenins are a family of yolk proteins that are by far the most abundant among oviparous animals. In the model nematode Caenorhabditis elegans , the 6 vitellogenins are among the most highly expressed genes in the adult hermaphrodite intestine, which produces copious yolk to provision eggs. In this article we review what is known about the vitellogenin genes and proteins in C. elegans , in comparison with vitellogenins in other taxa. We argue that the primary purpose of abundant vitellogenesis in C. elegans is to support post-embryonic development and fertility, rather than embryogenesis, especially in harsh environments...
2019: Frontiers in Physiology
https://read.qxmd.com/read/31530808/author-correction-changes-in-gene-expression-predictably-shift-and-switch-genetic-interactions
#27
Xianghua Li, Jasna Lalić, Pablo Baeza-Centurion, Riddhiman Dhar, Ben Lehner
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
September 17, 2019: Nature Communications
https://read.qxmd.com/read/31519910/the-mutational-landscape-of-a-prion-like-domain
#28
JOURNAL ARTICLE
Benedetta Bolognesi, Andre J Faure, Mireia Seuma, Jörn M Schmiedel, Gian Gaetano Tartaglia, Ben Lehner
Insoluble protein aggregates are the hallmarks of many neurodegenerative diseases. For example, aggregates of TDP-43 occur in nearly all cases of amyotrophic lateral sclerosis (ALS). However, whether aggregates cause cellular toxicity is still not clear, even in simpler cellular systems. We reasoned that deep mutagenesis might be a powerful approach to disentangle the relationship between aggregation and toxicity. We generated >50,000 mutations in the prion-like domain (PRD) of TDP-43 and quantified their toxicity in yeast cells...
September 13, 2019: Nature Communications
https://read.qxmd.com/read/31467279/changes-in-gene-expression-predictably-shift-and-switch-genetic-interactions
#29
JOURNAL ARTICLE
Xianghua Li, Jasna Lalic, Pablo Baeza-Centurion, Riddhiman Dhar, Ben Lehner
Non-additive interactions between mutations occur extensively and also change across conditions, making genetic prediction a difficult challenge. To better understand the plasticity of genetic interactions (epistasis), we combine mutations in a single protein performing a single function (a transcriptional repressor inhibiting a target gene). Even in this minimal system, genetic interactions switch from positive (suppressive) to negative (enhancing) as the expression of the gene changes. These seemingly complicated changes can be predicted using a mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype...
August 29, 2019: Nature Communications
https://read.qxmd.com/read/31413260/harmonious-genetic-combinations-rewire-regulatory-networks-and-flip-gene-essentiality
#30
JOURNAL ARTICLE
Aaron M New, Ben Lehner
We lack an understanding of how the full range of genetic variants that occur in individuals can interact. To address this shortcoming, here we combine diverse mutations between genes in a model regulatory network, the galactose (GAL) switch of budding yeast. The effects of thousands of pairs of mutations fall into a limited number of phenotypic classes. While these effects are mostly predictable using simple rules that capture the 'stereotypical' genetic interactions of the network, some double mutants have unexpected outcomes including constituting alternative functional switches...
August 14, 2019: Nature Communications
https://read.qxmd.com/read/31320634/empirical-mean-noise-fitness-landscapes-reveal-the-fitness-impact-of-gene-expression-noise
#31
JOURNAL ARTICLE
Jörn M Schmiedel, Lucas B Carey, Ben Lehner
The effects of cell-to-cell variation (noise) in gene expression have proven difficult to quantify because of the mechanistic coupling of noise to mean expression. To independently quantify the effects of changes in mean expression and noise we determine the fitness landscapes in mean-noise expression space for 33 genes in yeast. For most genes, short-lived (noise) deviations away from the expression optimum are nearly as detrimental as sustained (mean) deviations. Fitness landscapes can be classified by a combination of each gene's sensitivity to protein shortage or surplus...
July 18, 2019: Nature Communications
https://read.qxmd.com/read/31307927/scales-and-mechanisms-of-somatic-mutation-rate-variation-across-the-human-genome
#32
REVIEW
Fran Supek, Ben Lehner
Cancer genome sequencing has revealed that somatic mutation rates vary substantially across the human genome and at scales from megabase-sized domains to individual nucleotides. Here we review recent work that has both revealed the major mutation biases that operate across the genome and the molecular mechanisms that cause them. The default mutation rate landscape in mammalian genomes results in active genes having low mutation rates because of a combination of factors that increase DNA repair: early DNA replication, transcription, active chromatin modifications and accessible chromatin...
July 8, 2019: DNA Repair
https://read.qxmd.com/read/31209395/determining-protein-structures-using-deep-mutagenesis
#33
JOURNAL ARTICLE
Jörn M Schmiedel, Ben Lehner
Determining the three-dimensional structures of macromolecules is a major goal of biological research, because of the close relationship between structure and function; however, thousands of protein domains still have unknown structures. Structure determination usually relies on physical techniques including X-ray crystallography, NMR spectroscopy and cryo-electron microscopy. Here we present a method that allows the high-resolution three-dimensional backbone structure of a biological macromolecule to be determined only from measurements of the activity of mutant variants of the molecule...
July 2019: Nature Genetics
https://read.qxmd.com/read/31082279/the-causes-and-consequences-of-genetic-interactions-epistasis
#34
REVIEW
Júlia Domingo, Pablo Baeza-Centurion, Ben Lehner
The same mutation can have different effects in different individuals. One important reason for this is that the outcome of a mutation can depend on the genetic context in which it occurs. This dependency is known as epistasis. In recent years, there has been a concerted effort to quantify the extent of pairwise and higher-order genetic interactions between mutations through deep mutagenesis of proteins and RNAs. This research has revealed two major components of epistasis: nonspecific genetic interactions caused by nonlinearities in genotype-to-phenotype maps, and specific interactions between particular mutations...
August 31, 2019: Annual Review of Genomics and Human Genetics
https://read.qxmd.com/read/30860479/single-cell-rna-seq-identifies-the-origins-of-heterogeneity-in-efficient-cell-transdifferentiation-and-reprogramming
#35
JOURNAL ARTICLE
Mirko Francesconi, Bruno Di Stefano, Clara Berenguer, Luisa de Andrés-Aguayo, Marcos Plana-Carmona, Maria Mendez-Lago, Amy Guillaumet-Adkins, Gustavo Rodriguez-Esteban, Marta Gut, Ivo G Gut, Holger Heyn, Ben Lehner, Thomas Graf
Forced transcription factor expression can transdifferentiate somatic cells into other specialized cell types or reprogram them into induced pluripotent stem cells (iPSCs) with variable efficiency. To better understand the heterogeneity of these processes, we used single-cell RNA sequencing to follow the transdifferentation of murine pre-B cells into macrophages as well as their reprogramming into iPSCs. Even in these highly efficient systems, there was substantial variation in the speed and path of fate conversion...
March 12, 2019: ELife
https://read.qxmd.com/read/30661752/combinatorial-genetics-reveals-a-scaling-law-for-the-effects-of-mutations-on-splicing
#36
JOURNAL ARTICLE
Pablo Baeza-Centurion, Belén Miñana, Jörn M Schmiedel, Juan Valcárcel, Ben Lehner
Despite a wealth of molecular knowledge, quantitative laws for accurate prediction of biological phenomena remain rare. Alternative pre-mRNA splicing is an important regulated step in gene expression frequently perturbed in human disease. To understand the combined effects of mutations during evolution, we quantified the effects of all possible combinations of exonic mutations accumulated during the emergence of an alternatively spliced human exon. This revealed that mutation effects scale non-monotonically with the inclusion level of an exon, with each mutation having maximum effect at a predictable intermediate inclusion level...
January 24, 2019: Cell
https://read.qxmd.com/read/30638445/single-cell-functional-genomics-reveals-the-importance-of-mitochondria-in-cell-to-cell-phenotypic-variation
#37
JOURNAL ARTICLE
Riddhiman Dhar, Alsu M Missarova, Ben Lehner, Lucas B Carey
Mutations frequently have outcomes that differ across individuals, even when these individuals are genetically identical and share a common environment. Moreover, individual microbial and mammalian cells can vary substantially in their proliferation rates, stress tolerance, and drug resistance, with important implications for the treatment of infections and cancer. To investigate the causes of cell-to-cell variation in proliferation, we used a high-throughput automated microscopy assay to quantify the impact of deleting >1,500 genes in yeast...
January 14, 2019: ELife
https://read.qxmd.com/read/30602724/intergenerational-and-transgenerational-epigenetic-inheritance-in-animals
#38
REVIEW
Marcos Francisco Perez, Ben Lehner
Animals transmit not only DNA but also other molecules, such as RNA, proteins and metabolites, to their progeny via gametes. It is currently unclear to what extent these molecules convey information between generations and whether this information changes according to their physiological state and environment. Here, we review recent work on the molecular mechanisms by which 'epigenetic' information is transmitted between generations over different timescales, and the importance of this information for development and physiology...
January 2, 2019: Nature Cell Biology
https://read.qxmd.com/read/30559457/memory-of-ancestral-mitochondrial-stress
#39
JOURNAL ARTICLE
Sarah-Lena Offenburger, Marcos Francisco Perez, Ben Lehner
No abstract text is available yet for this article.
December 17, 2018: Nature Cell Biology
https://read.qxmd.com/read/30542989/cancer-gene-discovery-by-network-analysis-of-somatic-mutations-using-the-muffinn-server
#40
JOURNAL ARTICLE
Heonjong Han, Ben Lehner, Insuk Lee
Identifying genes that are capable of inducing tumorigenesis has been a major challenge in cancer research. In many cases, such genes frequently show somatic mutations in tumor samples; thus various computational methods for predicting cancer genes have been developed based on "significantly mutated genes." However, this approach is intrinsically limited by the fact that there are many cancer genes infrequently mutated in cancer genomes. Therefore, we recently developed MUFFINN (Mutations For Functional Impact on Network Neighbors), a method for cancer gene prediction based not only on mutation occurrences in each gene but also those of neighbors in functional networks...
2019: Methods in Molecular Biology
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