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Human genetic

Deepthi Alapati, Edward E Morrisey
While our understanding of the genetics and pathology of congenital lung diseases such as surfactant protein deficiency, cystic fibrosis and alpha 1 antitrypsin deficiency is extensive, treatment options are lacking. Since the lung is a barrier organ in direct communication with the external environment, targeted delivery of gene corrective technologies to the respiratory system via intra-tracheal or intranasal routes is an attractive option for therapy. CRISPR/Cas9 gene editing technology is a promising approach to repair or inactivate disease causing mutations...
October 25, 2016: American Journal of Respiratory Cell and Molecular Biology
Eildert Groeneveld, Helmut Lichtenberg
The fast development of high throughput genotyping has opened up new possibilities in genetics while at the same time producing considerable data handling issues. TheSNPpit is a database system for managing large amounts of multi panel SNP genotype data from any genotyping platform. With an increasing rate of genotyping in areas like animal and plant breeding as well as human genetics, already now hundreds of thousand of individuals need to be managed. While the common database design with one row per SNP can manage hundreds of samples this approach becomes progressively slower as the size of the data sets increase until it finally fails completely once tens or even hundreds of thousands of individuals need to be managed...
2016: PloS One
Wolfgang Enard
Humans are a remarkable species, especially because of the remarkable properties of their brain. Since the split from the chimpanzee lineage, the human brain has increased three-fold in size and has acquired abilities for vocal learning, language and intense cooperation. To better understand the molecular basis of these changes is of great biological and biomedical interest. However, all the about 16 million fixed genetic changes that occurred during human evolution are fully correlated with all molecular, cellular, anatomical and behavioral changes that occurred during this time...
October 24, 2016: Current Biology: CB
Adrian Guthals, Yutian Gan, Laura Murray, Yongmei Chen, Jeremy Stinson, Gerald R Nakamura, Jennie R Lill, Wendy Sandoval, Nuno Bandeira
One direct route for the discovery of therapeutic human monoclonal antibodies (mAbs) involves the isolation of peripheral B cells from survivors/sero-positive individuals after exposure to an infectious reagent or disease etiology followed by single-cell sequencing or hybridoma generation. Peripheral B cells, however, are not always easy to obtain and only represent a small percentage of the total B cell population across all bodily tissues. Although it has been demonstrated that tandem mass spectrometry (MS/MS) techniques can interrogate the expressed polyclonal antibody (pAb) response to an antigen in vivo, all current approaches identify MS/MS spectra against databases derived from genetic sequencing of B cells from the same patient...
October 25, 2016: Journal of Proteome Research
Jeng-Haur Chen, Weiyi Xu, David N Sheppard
Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-gated Cl(-) channel defective in the genetic disease cystic fibrosis (CF). The gating behaviour of CFTR is characterized by bursts of channel openings interrupted by brief, flickery closures, separated by long closures between bursts. Entry to and exit from an open burst is controlled by the interaction of ATP with two ATP-binding sites, sites 1 and 2 in CFTR. To understand better the kinetic basis of CFTR intraburst gating, we investigated the single-channel activity of human CFTR at different intracellular pH (pHi ) values...
October 25, 2016: Journal of Physiology
J L Baker, D Shriner, A R Bentley, C N Rotimi
As the common birthplace of all human populations, modern humans have lived longer on the African continent than in any other geographical region of the world. This long history, along with the evolutionary need to adapt to environmental challenges such as exposure to infectious agents, has led to greater genetic variation in Africans. The vast genetic variation in Africans also extends to genes involved in the absorption, distribution, metabolism and excretion of pharmaceuticals. Ongoing cataloging of these clinically relevant variants reveals huge allele-frequency differences within and between African populations...
October 25, 2016: Pharmacogenomics Journal
Carolina D'Alesio, Simona Punzi, Angelo Cicalese, Lorenzo Fornasari, Laura Furia, Laura Riva, Alessandro Carugo, Giuseppe Curigliano, Carmen Criscitiello, Giancarlo Pruneri, Pier Giuseppe Pelicci, Mario Faretta, Daniela Bossi, Luisa Lanfrancone
Epigenetic regulation plays an essential role in tumor development and epigenetic modifiers are considered optimal potential druggable candidates. In order to identify new breast cancer vulnerabilities and improve therapeutic chances for patients, we performed in vivo and in vitro shRNA screens in a human breast cancer cell model ( cell line) using epigenetic libraries. Among the genes identified in our screening, we deeply investigated the role of Chromodomain Helicase DNA binding Protein 4 (CHD4) in breast cancer tumorigenesis...
October 13, 2016: Oncotarget
Amy C Arnold, Emily M Garland, Jorge E Celedonio, Satish R Raj, Naji N Abumrad, Italo Biaggioni, David Robertson, James M Luther, Cyndya A Shibao
CONTEXT: Dopamine β-hydroxylase (DBH) deficiency is a rare genetic disorder characterized by failure to convert dopamine into norepinephrine. These patients have absence of sympathetic adrenergic function, predisposing to orthostatic hypotension. DBH deficient mice exhibit hyperinsulinemia, lower plasma glucose levels, and insulin resistance due to loss of tonic sympathetic inhibition of insulin secretion. The impact of DBH deficiency on glucose homeostasis in humans is unknown. CASE DESCRIPTION: We describe the metabolic profile of an adolescent female DBH deficient patient...
October 25, 2016: Journal of Clinical Endocrinology and Metabolism
Christopher Selleck, James A Larrabee, Jeffrey Harmer, Luke W Guddat, Nataša Mitić, Waleed Helweh, David L Ollis, Whitney R Craig, David L Tierney, Marcelo Monteiro Pedroso, Gerhard Schenk
Antibiotic resistance has emerged as a major threat to global health care. This is largely due to the fact that many pathogens have developed strategies to acquire resistance to antibiotics. Metallo-β-lactamases (MBL) have evolved to inactivate most of the commonly used β-lactam antibiotics. AIM-1 is one of only a few MBLs from the B3 subgroup that is encoded on a mobile genetic element in a major human pathogen. Here, its mechanism of action was characterised with a combination of spectroscopic and kinetic techniques and compared to that of other MBLs...
October 25, 2016: Chemistry: a European Journal
Anna Nolte, Aimara Bello, Michaela Drögemüller, Tosso Leeb, Eva Brockhaus, Wolfgang Baumgärtner, Peter Wohlsein
A female, 5-year-old American Staffordshire Terrier with severe progressive neurological deficits, particularly in terms of ataxia and keeping balance, was examined pathomorphologically and a genetic analysis was performed. In neurons of various localizations of the central nervous system an accumulation of a finely granular pale eosinophilic or light brown material was found. In addition, the cerebellum revealed marked degeneration and loss of Purkinje and inner granule cells. The accumulated PAS-positive, argyrophilic, autofluorescent material showed ultrastructurally a lamellar appearance suggestive of lipofuscin...
October 25, 2016: Tierärztliche Praxis. Ausgabe K, Kleintiere/Heimtiere
Armando Arias, Lucy Thorne, Elsa Ghurburrun, Dalan Bailey, Ian Goodfellow
Intrahost genetic diversity and replication error rates are intricately linked to RNA virus pathogenesis, with alterations in viral polymerase fidelity typically leading to attenuation during infections in vivo. We have previously shown that norovirus intrahost genetic diversity also influences viral pathogenesis using the murine norovirus model, as increasing viral mutation frequency using a mutagenic nucleoside resulted in clearance of a persistent infection in mice. Given the role of replication fidelity and genetic diversity in pathogenesis, we have now investigated whether polymerase fidelity can also impact virus transmission between susceptible hosts...
September 2016: MSphere
W S Hambright, Jie Deng, James M Tiedje, Ingrid Brettar, Jorge L M Rodrigues
In bacterial populations, subtle expressional differences may promote ecological specialization through the formation of distinct ecotypes. In a barrier-free habitat, this process most likely precedes population divergence and may predict speciation events. To examine this, we used four sequenced strains of the bacterium Shewanella baltica, OS155, OS185, OS195, and OS223, as models to assess transcriptional variation and ecotype formation within a prokaryotic population. All strains were isolated from different depths throughout a water column of the Baltic Sea, occupying different ecological niches characterized by various abiotic parameters...
September 2016: MSphere
Pomila Singh, Malaney O'Connell, Sarkar Shubhashish
Colorectal carcinogenesis is a multi-step process. While ~25% of colorectal cancers (CRCs) arise in patients with a family history (genetic predisposition), ~75% of CRCs are due to age-associated accumulation of epigenetic alterations which can result in the suppression of key tumor suppressor genes leading to mutations and activation of oncogenic pathways. Sporadic colon-carcinogenesis is facilitated by many molecular pathways of genomic instability which include chromosomal instability (CIN), micro-satellite instability (MSI) and CpG island methylator phenotype (CIMP), leading towards loss of homeostasis and onset of neoplastic transformation...
2016: Stem Cell Investigation
Chong Kun Cheon
The Prader-Willi syndrome (PWS) is a human imprinting disorder resulting from genomic alterations that inactivate imprinted, paternally expressed genes in human chromosome region 15q11-q13. This genetic condition appears to be a contiguous gene syndrome caused by the loss of at least 2 of a number of genes expressed exclusively from the paternal allele, including SNRPN, MKRN3, MAGEL2, NDN and several snoRNAs, but it is not yet well known which specific genes in this region are associated with this syndrome...
September 2016: Annals of Pediatric Endocrinology & Metabolism
Catherine I Carty, Alison M Lee, Nathan A E Wienandt, Edward L Stevens, Derron A Alves, John A Browne, Jill Bryan, Eoin G Ryan, Joseph P Cassidy
BACKGROUND: An unusual presentation of skin disease was identified in two related neonatal Pedigree Limousin calves presented to University Veterinary Hospital, University College Dublin, following detailed post mortem examination a diagnosis of dermatosparaxis was made. Dermatosparaxis in animals or Ehlers Danlos Syndrome, which is the analogous condition seen in humans, is a connective tissue disorder characterised by extreme skin fragility. To the authors' knowledge this is the first report of such a diagnosis in the Limousin breed and the features of this lethal phenotype were severe in comparison to previous reports of the condition...
2016: Irish Veterinary Journal
Annie Gravel, Isabelle Dubuc, Angela Brooks-Wilson, Kristan J Aronson, Jacques Simard, Hector Velasquez-Garcia, John J Spinelli, Louis Flamand
Background Inherited chromosomally-integrated human herpesvirus 6 (iciHHV-6) is a condition observed in approximately 1% of the population. Whether such a genetic alteration predisposes to cancer development in currently unknown. Two studies were conducted to determine whether iciHHV-6 is associated with cancer development. Methods First, a screen of 19,597 people from the province of Quebec was conducted. A replication test, using data from a population-based case-control study of 1090 women with incident breast cancer and 1053 controls from British Columbia and Ontario was conducted...
October 24, 2016: Cancer Epidemiology, Biomarkers & Prevention
Erin L Rutherford, Laura Anne Lowery
Wolf-Hirschhorn syndrome (WHS) is a neurodevelopmental disorder characterized by mental retardation, craniofacial malformation, and defects in skeletal and heart development. The syndrome is associated with irregularities on the short arm of chromosome 4, including deletions of varying sizes and microduplications. Many of these genotypic aberrations in humans have been correlated with the classic WHS phenotype, and animal models have provided a context for mapping these genetic irregularities to specific phenotypes; however, there remains a significant knowledge gap concerning the cell biological mechanisms underlying these phenotypes...
October 21, 2016: Developmental Biology
Félix Javier Jiménez-Jiménez, Hortensia Alonso-Navarro, María Trinidad Herrero, Elena García-Martín, José A G Agúndez
BACKGROUND: The pathogenesis of Parkinson's disease (PD) is not fully understood. Together with some important physiological functions in the Central Nervous System (CNS), nitric oxide (NO) can have both, neuroprotective or neurotoxic actions, depending on its redox state. An important body of evidence suggests the involvement of NO in many of the processes leading to neurodegeneration in several neurological disorders including PD. OBJECTIVE: The main aim of this review is to update the data regarding the possible involvement of NO in the pathogenesis of PD...
2016: Current Medicinal Chemistry
Dennis Liang Fei, Hayley Motowski, Rakesh Chatrikhi, Sameer Prasad, Jovian Yu, Shaojian Gao, Clara L Kielkopf, Robert K Bradley, Harold Varmus
We have asked how the common S34F mutation in the splicing factor U2AF1 regulates alternative splicing in lung cancer, and why wild-type U2AF1 is retained in cancers with this mutation. A human lung epithelial cell line was genetically modified so that U2AF1S34F is expressed from one of the two endogenous U2AF1 loci. By altering levels of mutant or wild-type U2AF1 in this cell line and by analyzing published data on human lung adenocarcinomas, we show that S34F-associated changes in alternative splicing are proportional to the ratio of S34F:wild-type gene products and not to absolute levels of either the mutant or wild-type factor...
October 2016: PLoS Genetics
Pleun Hombrink, Christina Helbig, Ronald A Backer, Berber Piet, Anna E Oja, Regina Stark, Giso Brasser, Aldo Jongejan, René E Jonkers, Benjamin Nota, Onur Basak, Hans C Clevers, Perry D Moerland, Derk Amsen, René A W van Lier
Tissue-resident memory T cells (TRM cells) in the airways mediate protection against respiratory infection. We characterized TRM cells expressing integrin αE (CD103) that reside within the epithelial barrier of human lungs. These cells had specialized profiles of chemokine receptors and adhesion molecules, consistent with their unique localization. Lung TRM cells were poised for rapid responsiveness by constitutive expression of deployment-ready mRNA encoding effector molecules, but they also expressed many inhibitory regulators, suggestive of programmed restraint...
October 24, 2016: Nature Immunology
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