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Phenotypic screen

Navaneetha Santhanam, Lee Kumanchik, Xiufang Guo, Frank Sommerhage, Yunqing Cai, Max Jackson, Candace Martin, George Saad, Christopher W McAleer, Ying Wang, Andrea Lavado, Christopher J Long, James J Hickman
There are currently no functional neuromuscular junction (hNMJ) systems composed of human cells that could be used for drug evaluations or toxicity testing in vitro. These systems are needed to evaluate NMJs for diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy or other neurodegenerative diseases or injury states. There are certainly no model systems, animal or human, that allows for isolated treatment of motoneurons or muscle capable of generating dose response curves to evaluate pharmacological activity of these highly specialized functional units...
February 27, 2018: Biomaterials
Anna Pellattiero, Luca Scorrano
Despite the significance of mitochondrial dynamics in many diseases, drugs that modulate it are lacking. In this issue of Cell Chemical Biology, Miret-Casals et al. (2018) use a phenotypic high-throughput screen to discover a pro-fusion role for the anti-inflammatory drug Leflunomide, paving the way to screen for mitochondrial pro-fusion drug candidates.
March 15, 2018: Cell Chemical Biology
Elodie Alessandri-Gradt, Fabienne De Oliveira, Marie Leoz, Véronique Lemee, David L Robertson, Felix Feyertag, Paul-Alain Ngoupo, Philippe Mauclere, François Simon, Jean-Christophe Plantier
OBJECTIVES: HIV/1 group P (HIV-1/P) is the last HIV/1 group discovered and to date, comprises only two strains. To obtain new insights into this divergent group, we screened for new infections by developing specific tools, and analysed phenotypic and genotypic properties of the prototypic strain RBF168. In addition, the follow-up of the unique patient monitored so far, has raised the knowledge of the natural history of this infection and its therapeutic management. DESIGN/METHODS: We developed an HIV-1/P specific sero-molecular strategy and screened over 29,498 specimen samples...
March 15, 2018: AIDS
Peter Stacey, Anne Mai Wassermann, Laura Kammonen, Emma Impey, Anna Wilbrey, Darren Cawkill
Screening against a disease-relevant phenotype to identify compounds that change the outcome of biological pathways, rather than just the activity of specific targets, offers an alternative approach to find modulators of disease characteristics. However, in pain research, use of in vitro phenotypic screens has been impeded by the challenge of sourcing relevant neuronal cell types in sufficient quantity and developing functional end-point measurements with a direct disease link. To overcome these hurdles, we have generated human induced pluripotent stem cell (hiPSC)-derived sensory neurons at a robust production scale using the concept of cryopreserved "near-assay-ready" cells to decouple complex cell production from assay development and screening...
March 1, 2018: SLAS Discovery
Florian Ferreri, Alexis Bourla, Stephane Mouchabac, Laurent Karila
Background: New technologies can profoundly change the way we understand psychiatric pathologies and addictive disorders. New concepts are emerging with the development of more accurate means of collecting live data, computerized questionnaires, and the use of passive data. Digital phenotyping , a paradigmatic example, refers to the use of computerized measurement tools to capture the characteristics of different psychiatric disorders. Similarly, machine learning-a form of artificial intelligence-can improve the classification of patients based on patterns that clinicians have not always considered in the past...
2018: Frontiers in Psychiatry
Yulei Zhao, Tess Montminy, Taha Azad, Elizabeth Lightbody, Yawei Hao, Sandip SenGupta, Eric Asselin, Christopher Jb Nicol, Xiaolong Yang
Breast cancer (BC) is a leading cause of death in women worldwide. Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB occur in many BC cases. In recent years, activation of the Transcriptional coactivator with PDZ binding motif (TAZ) and its paralog Yes-associated protein (YAP) have been found to be important for BC development and progression. However, there is no evidence that PI3K interacts with YAP/TAZ in mammary tumorigenesis. Using a systematic gain-of-function screen for kinases involved in mammary tumorigenesis, PIK3CB was identified as a transformation inducing kinase...
March 15, 2018: Molecular Cancer Research: MCR
Holger Winkels, Erik Ehinger, Melanie Vassallo, Konrad Buscher, Huy Dinh, Kouji Kobiyama, Anouk Hamers, Clément Cochain, Ehsan Vafadarnejad, Antoine-Emmanuel Saliba, Alma Zernecke, Akula Pramod, Amlan Ghosh, Nathaly Anto Michel, Natalie Hoppe, Ingo Hilgendorf, Andreas Zirlik, Catherine Hedrick, Klaus Ley, Dennis Wolf
<u>Rationale:</u> Atherosclerosis is a chronic inflammatory disease that is driven by the interplay of pro- and anti-inflammatory leukocytes in the aorta. Yet, the phenotypic and transcriptional diversity of aortic leukocytes is only poorly understood. <u>Objective:</u> We characterized leukocytes from healthy and atherosclerotic mouse aortas in-depth by single cell RNA-sequencing (scRNAseq) and mass cytometry (CyTOF) to define an atlas of the immune cell landscape in atherosclerosis...
March 15, 2018: Circulation Research
Celeste Sassi, Michael A Nalls, Perry G Ridge, Jesse R Gibbs, Michelle K Lupton, Claire Troakes, Katie Lunnon, Safa Al-Sarraj, Kristelle S Brown, Christopher Medway, Jenny Lord, James Turton, Jose Bras, Sonja Blumenau, Mareike Thielke, Christa Josties, Dorette Freyer, Annette Dietrich, Monia Hammer, Michael Baier, Ulrich Dirnagl, Kevin Morgan, John F Powell, John S Kauwe, Carlos Cruchaga, Alison M Goate, Andrew B Singleton, Rita Guerreiro, Angela Hodges, John Hardy
Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively...
February 2, 2018: Neurobiology of Aging
Elizabeth A Winzeler
Phenotypic screening methods have had a profound impact on antimalarial drug development, but assays that predict which compounds might provide a radical cure have remained elusive. In this issue of Cell Host & Microbe, Gural et al. (2018) report hypnozoite culturing and systems to study these elusive, yet deadly, parasites.
March 14, 2018: Cell Host & Microbe
Christopher J Lambert, Briana C Freshner, Arlen Chung, Tamara J Stevenson, D Miranda Bowles, Raheel Samuel, Bruce K Gale, Joshua L Bonkowsky
Zebrafish are a valuable model organism in biomedical research. Their rapid development, ability to model human diseases, utility for testing genetic variants identified from next-generation sequencing, amenity to CRISPR mutagenesis, and potential for therapeutic compound screening, has led to their wide-spread adoption in diverse fields of study. However, their power for large-scale screens is limited by the absence of automated genotyping tools for live animals. This constrains potential drug screen options, limits analysis of embryonic and larval phenotypes, and requires raising additional animals to adulthood to ensure obtaining an animal of the desired genotype...
2018: PloS One
Jennifer Karmouch, Alexandros Protonotarios, Petros Syrris
PURPOSE OF REVIEW: To date 16 genes have been associated with arrhythmogenic cardiomyopathy (ACM). Mutations in these genes can lead to a broad spectrum of phenotypic expression ranging from disease affecting predominantly the right or left ventricle, to biventricular subtypes. Understanding the genetic causes of ACM is important in diagnosis and management of the disorder. This review summarizes recent advances in molecular genetics and discusses the application of next-generation sequencing technology in genetic testing in ACM...
March 14, 2018: Current Opinion in Cardiology
Per Strøman, Kim Ib Sørensen, Patrick M F Derkx, Ana Rute Neves
Biogenic amines have been widely studied because of their potential toxicity in fermented foods. Several lactic acid bacteria have the potential to decarboxylate the amino acid tyrosine to tyramine. In this work, we identified two strains of Lactobacillus curvatus, Lbc1 and Lbc2, endowed with the ability to produce tyramine, a metabolic feature that limits their application in starter cultures for fermented meat. To overcome this limitation, we set out to eliminate tyramine production from L. curvatus strains by using classical strain improvement...
March 15, 2018: Journal of Food Protection
Gregory J Kato, Frédéric B Piel, Clarice D Reid, Marilyn H Gaston, Kwaku Ohene-Frempong, Lakshmanan Krishnamurti, Wally R Smith, Julie A Panepinto, David J Weatherall, Fernando F Costa, Elliott P Vichinsky
Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB, which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system...
March 15, 2018: Nature Reviews. Disease Primers
(no author information available yet)
OBJECTIVES: To ascertain the proportion of neonates and infants presenting with suspicion of an inborn error of metabolism in the centers identified by ICMR for newborn screening. METHODS: A set of red flag signs suggestive IEM were listed by the Taskforce members. The age group was limited to one year as it was understood that most of the small molecules with a severe phenotype would present before the age of one year. Further investigations were tandem mass spectrometry, gas chromatography mass spectrometry and high performance liquid chromatography...
March 15, 2018: Indian Journal of Pediatrics
Ali J Marian, Yanli Tan, Lili Li, Jeffrey T Chang, Petros Syrris, Manouchehr Hessabi, Mohammad H Rahbar, James T Willerson, Benjamin Y Cheong, Chia-Ying Liu, Neal S Kleiman, David A Bluemke, Sherif F Nagueh
<u>Rationale:</u> Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy and interstitial fibrosis are important risk factors for sudden death and morbidity in HCM. Oxidative stress is implicated in the pathogenesis of cardiac hypertrophy and fibrosis. Treatment with anti-oxidant N-acetylcysteine (NAC) reverses cardiac hypertrophy and fibrosis in animal models of HCM. <u>Objective:</u> To determine effect sizes of NAC on indices of cardiac hypertrophy and fibrosis in patients with established HCM...
March 14, 2018: Circulation Research
Kristie Wrasman, Salvatore L Alioto, Yorke Zhang, Kyle Hoban, Marjon Khairy, Bruce L Goode, Beverly Wendland
Endocytosis is a fundamental process for internalizing material from the plasma membrane, including many transmembrane proteins that are selectively internalized depending on environmental conditions. In most cells, the main route of entry is clathrin-mediated endocytosis (CME), a process that involves the coordinated activity of over 60 proteins; however, there are likely as-yet unidentified proteins involved in cargo selection and/or regulation of endocytosis. We performed a mutagenic screen to identify novel endocytic genes in Saccharomyces cerevisiae expressing the methionine permease Mup1 tagged with pHluorin (pHl), a pH-sensitive GFP variant whose fluorescence is quenched upon delivery to the acidic vacuole lumen...
March 14, 2018: G3: Genes—Genomes—Genetics
Daniel W Yokom, Shabbir M H Alibhai, Schroder Sattar, Monika K Krzyzanowska, Martine T E Puts
INTRODUCTION: Screening tools in geriatric oncology have traditionally been studied for their ability to identify patients who have abnormal domains on a comprehensive geriatric assessment (CGA). However, an alternative outcome of identifying patients who would receive CGA-based interventions could improve selection of patients whose management will be altered by a CGA. The objective of this study was to assess the performance of three geriatric oncology screening tools for their ability to predict for CGA-based interventions...
March 12, 2018: Journal of Geriatric Oncology
C Krausz, Francesca Cioppi, Antoni Riera-Escamilla
Male infertility affects about 7% of the general male population, and it is a multifactorial, polygenic pathological condition. Known genetic factors, accounting for about 20-25% of male factor infertility, are present in each etiological category: i) hypothalamic-pituitary axis dysfunction; ii) quantitative and qualitative alterations of spermatogenesis; iii) ductal obstruction/dysfunction. Areas covered: All routinely available genetic tests are described. Indication for testing for chromosomal anomalies and Y chromosome microdeletions is based on sperm count (severe oligozoospermia/azoospermia)...
March 15, 2018: Expert Review of Molecular Diagnostics
Vicente Perez-Garcia, Elena Fineberg, Robert Wilson, Alexander Murray, Cecilia Icoresi Mazzeo, Catherine Tudor, Arnold Sienerth, Jacqueline K White, Elizabeth Tuck, Edward J Ryder, Diane Gleeson, Emma Siragher, Hannah Wardle-Jones, Nicole Staudt, Neha Wali, John Collins, Stefan Geyer, Elisabeth M Busch-Nentwich, Antonella Galli, James C Smith, Elizabeth Robertson, David J Adams, Wolfgang J Weninger, Timothy Mohun, Myriam Hemberger
Large-scale phenotyping efforts have demonstrated that approximately 25-30% of mouse gene knockouts cause intrauterine lethality. Analysis of these mutants has largely focused on the embryo and not the placenta, despite the crucial role of this extraembryonic organ for developmental progression. Here we screened 103 embryonic lethal and sub-viable mouse knockout lines from the Deciphering the Mechanisms of Developmental Disorders program for placental phenotypes. We found that 68% of knockout lines that are lethal at or after mid-gestation exhibited placental dysmorphologies...
March 14, 2018: Nature
Hugo Botha, William G Mantyh, Melissa E Murray, David S Knopman, Scott A Przybelski, Heather J Wiste, Jonathan Graff-Radford, Keith A Josephs, Christopher G Schwarz, Walter K Kremers, Bradley F Boeve, Ronald C Petersen, Mary M Machulda, Joseph E Parisi, Dennis W Dickson, Val Lowe, Clifford R Jack, David T Jones
Predicting underlying pathology based on clinical presentation has historically proven difficult, especially in older cohorts. Age-related hippocampal sclerosis may account for a significant proportion of elderly participants with amnestic dementia. Advances in molecular neuroimaging have allowed for detailed biomarker-based phenotyping, but in the absence of antemortem markers of hippocampal sclerosis, cases of mixed pathology remain problematic. We evaluated the utility of 18F-FDG-PET to differentiate flortaucipir tau PET negative from flortaucipir positive amnestic mild cognitive impairment and dementia and used an autopsy confirmed cohort to test the hypothesis that hippocampal sclerosis might account for the observed pattern...
March 12, 2018: Brain: a Journal of Neurology
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