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  • 1
    Language: English
    In: The New phytologist, 2018-05-01, Vol.218 (3), p.1247-1259
    Description: Barley ( ) is an established model to study domestication of the Fertile Crescent cereals. Recent molecular data suggested that domesticated barley genomes consist of the ancestral blocks descending from multiple wild barley populations. However, the relationship between the mosaic ancestry patterns and the process of domestication itself remained unclear. To address this knowledge gap, we identified candidate domestication genes using selection scans based on targeted resequencing of 433 wild and domesticated barley accessions. We conducted phylogenetic, population structure, and ancestry analyses to investigate the origin of the domesticated barley haplotypes separately at the neutral and candidate domestication loci. We discovered multiple selective sweeps that occurred on all barley chromosomes during domestication in the background of several ancestral wild populations. The ancestry analyses demonstrated that, although the ancestral blocks of the domesticated barley genomes were descended from all over the Fertile Crescent, the candidate domestication loci originated specifically in its eastern and western parts. These findings provided the first molecular evidence implicating multiple wild or protodomesticated lineages in the process of barley domestication initiated in the Levantine and Zagros clusters of the origin of agriculture.
    Subject(s): Analysis ; ancestry analysis ; Barley ; cereals ; domestication ; Full Paper ; Full papers ; Research ; selection scan ; targeted resequencing
    ISSN: 0028-646X
    E-ISSN: 1469-8137
    Source: JSTOR Life Sciences
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 2
    Language: English
    In: Nature genetics, 2013-05, Vol.45 (5), p.531-536
    Description: Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ɛ) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.
    Subject(s): Acute Kidney Injury - genetics ; Age ; Amino acids ; Atypical Hemolytic Uremic Syndrome ; Care and treatment ; Child ; Child, Preschool ; Confidence intervals ; Databases ; Diacylglycerol Kinase - genetics ; Exome - genetics ; Female ; Gene mutations ; Genealogy ; Genes, Recessive - genetics ; Genetic aspects ; Genetics ; Genomes ; Health aspects ; Hemolytic-uremic syndrome ; Hemolytic-Uremic Syndrome - etiology ; Hemolytic-Uremic Syndrome - pathology ; Humans ; Immunoenzyme Techniques ; Infant ; Life Sciences ; Male ; Molecular Sequence Data ; Mutation ; Mutation - genetics ; Pediatrics ; Proteins ; Renal Insufficiency, Chronic ; Research ; Risk factors ; Siblings ; Studies ; Thrombocytopenia - genetics ; Thrombotic Microangiopathies - genetics ; Von Willebrand factor
    ISSN: 1061-4036
    E-ISSN: 1546-1718
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 3
    Language: English
    In: The Plant cell, 2018-02, Vol.30 (2), p.300-323
    Description: The maize smut fungus is a model organism for elucidating host colonization strategies of biotrophic fungi. Here, we performed an in depth transcriptional profiling of the entire plant-associated development of wild-type strains. In our analysis, we focused on fungal metabolism, nutritional strategies, secreted effectors, and regulatory networks. Secreted proteins were enriched in three distinct expression modules corresponding to stages on the plant surface, establishment of biotrophy, and induction of tumors. These modules are likely the key determinants for virulence. With respect to nutrient utilization, we observed that expression of several nutrient transporters was tied to these virulence modules rather than being controlled by nutrient availability. We show that oligopeptide transporters likely involved in nitrogen assimilation are important virulence factors. By measuring the intramodular connectivity of transcription factors, we identified the potential drivers for the virulence modules. While known components of the mating type cascade emerged as inducers for the plant surface and biotrophy module, we identified a set of yet uncharacterized transcription factors as likely responsible for expression of the tumor module. We demonstrate a crucial role for leaf tumor formation and effector gene expression for one of these transcription factors.
    Subject(s): Analysis ; Biomass ; Colonization ; Corn ; DNA binding proteins ; Fungal Proteins - genetics ; Fungi ; Gene expression ; Gene Expression Profiling ; Genetic transcription ; Large-Scale Biology ; Membrane Transport Proteins - genetics ; Metabolism ; Modules ; Nitrogen - metabolism ; Nutrient availability ; Nutrient utilization ; Nutrients ; Nutrition ; Plant Diseases - microbiology ; Plant Tumors - microbiology ; Proteins ; Ribonucleic acid ; RNA ; RNA sequencing ; Sequence Analysis, RNA ; Smut ; Transcription factors ; Transcription Factors - genetics ; Transcriptome ; Tumors ; Ustilago - genetics ; Ustilago - growth & development ; Ustilago - pathogenicity ; Ustilago - physiology ; Ustilago maydis ; Virulence ; Virulence - genetics ; Virulence factors ; Virulence Factors - genetics ; Zea mays - microbiology
    ISSN: 1040-4651
    E-ISSN: 1532-298X
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 4
    Language: English
    In: American journal of human genetics, 2016-08-04, Vol.99 (2), p.337-351
    Description: In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319−1G〉A, c.2760delC, and c.3001−2A〉C) was indicated at the RNA and protein levels. Analysis of the diseased individuals’ tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.
    Subject(s): adenomatous polyposis ; Adenomatous Polyposis Coli - genetics ; Adolescent ; Adult ; Alleles ; candidate genes ; Child, Preschool ; Colorectal cancer ; Colorectal Neoplasms - genetics ; DNA Mutational Analysis ; DNA sequencing ; DNA-Binding Proteins - deficiency ; DNA-Binding Proteins - genetics ; Exome - genetics ; exome sequencing ; familial colorectal cancer ; Female ; Gene mutations ; Genes, Recessive - genetics ; Genetic aspects ; Genetics ; Germ-Line Mutation - genetics ; Health aspects ; hereditary tumor syndromes ; Humans ; Male ; massive parallel sequencing ; Methods ; Middle Aged ; mismatch repair ; Mismatch Repair Endonuclease PMS2 - genetics ; Mutation ; MutS Homolog 3 Protein ; Nucleotide sequencing ; Pedigree ; Ribonucleic acid ; RNA ; Tumors
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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  • 5
    Language: English
    In: Nature communications, 2018-02-20, Vol.9 (1), p.727-8
    Description: Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions.
    Subject(s): Aberration ; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use ; Cancer ; Chronic lymphatic leukemia ; Cyclin-Dependent Kinase Inhibitor p15 - genetics ; Cyclin-Dependent Kinase Inhibitor p15 - metabolism ; Cyclin-Dependent Kinase Inhibitor p18 - genetics ; Cyclin-Dependent Kinase Inhibitor p18 - metabolism ; Data processing ; Drug Resistance, Neoplasm ; Female ; Humans ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Lymphatic leukemia ; Male ; Mutation ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Patients ; PD-L1 protein ; Sulfonamides - therapeutic use ; Therapeutic applications
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 6
    Language: English
    In: PloS one, 2015, Vol.10 (6), p.e0128951-e0128951
    Description: The chemosensory capacity of the somatosensory system relies on the appropriate expression of chemoreceptors, which detect chemical stimuli and transduce sensory information into cellular signals. Knowledge of the complete repertoire of the chemoreceptors expressed in human sensory ganglia is lacking. This study employed the next-generation sequencing technique (RNA-Seq) to conduct the first expression analysis of human trigeminal ganglia (TG) and dorsal root ganglia (DRG). We analyzed the data with a focus on G-protein coupled receptors (GPCRs) and ion channels, which are (potentially) involved in chemosensation by somatosensory neurons in the human TG and DRG. For years, transient receptor potential (TRP) channels have been considered the main group of receptors for chemosensation in the trigeminal system. Interestingly, we could show that sensory ganglia also express a panel of different olfactory receptors (ORs) with putative chemosensory function. To characterize OR expression in more detail, we performed microarray, semi-quantitative RT-PCR experiments, and immunohistochemical staining. Additionally, we analyzed the expression data to identify further known or putative classes of chemoreceptors in the human TG and DRG. Our results give an overview of the major classes of chemoreceptors expressed in the human TG and DRG and provide the basis for a broader understanding of the reception of chemical cues.
    Subject(s): Analysis ; Chemical stimuli ; Chemoreception ; Chemoreceptors ; Data analysis ; Data processing ; Dorsal root ganglia ; Ganglia ; Ganglia, Spinal - cytology ; Ganglia, Spinal - metabolism ; Gene expression ; Gene Expression Regulation ; Gene sequencing ; Genomics ; Humans ; Immunohistochemistry ; Ion channels ; Ligands ; Mammals ; Migraine ; Neurons ; Odorant receptors ; Pain ; Physiology ; Polymerase chain reaction ; Proteins ; Receptor mechanisms ; Receptors ; Receptors, Odorant - biosynthesis ; Receptors, Odorant - genetics ; Ribonucleic acid ; RNA ; RNA - biosynthesis ; RNA - genetics ; Rodents ; Sensory neurons ; Sequence Analysis, RNA ; Software ; Somatosensory system ; Transient receptor potential proteins ; Trigeminal ganglion ; Trigeminal Ganglion - cytology ; Trigeminal Ganglion - metabolism ; Trigeminal nerve
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 7
    Language: English
    In: eLife, 2017-06-20, Vol.6
    Description: In the arcuate nucleus of the hypothalamus (ARH) satiety signaling (anorexigenic) pro-opiomelanocortin (POMC)-expressing and hunger signaling (orexigenic) agouti-related peptide (AgRP)-expressing neurons are key components of the neuronal circuits that control food intake and energy homeostasis. Here, we assessed whether the catecholamine noradrenalin directly modulates the activity of these neurons in mice. Perforated patch clamp recordings showed that noradrenalin changes the activity of these functionally antagonistic neurons in opposite ways, increasing the activity of the orexigenic NPY/AgRP neurons and decreasing the activity of the anorexigenic POMC neurons. Cell type-specific transcriptomics and pharmacological experiments revealed that the opposing effect on these neurons is mediated by the activation of excitatory α - and β- adrenergic receptors in NPY/AgRP neurons, while POMC neurons are inhibited via α - adrenergic receptors. Thus, the coordinated differential modulation of the key hypothalamic neurons in control of energy homeostasis assigns noradrenalin an important role to promote feeding.
    Subject(s): Adrenergic receptors ; Agouti-Related Protein - metabolism ; AgRP-neuron ; Animals ; Arcuate nucleus ; Arcuate Nucleus of Hypothalamus - drug effects ; Catecholamines ; Cellular signal transduction ; Data analysis ; Dopamine ; Energy ; Energy balance ; Experiments ; Food ; Food intake ; Gene Expression Profiling ; Health aspects ; Homeostasis ; Hunger ; Hypothalamus ; Intermedin ; Mice ; Mouse ; Muridae ; Neural circuitry ; neuromodulation ; Neurons ; Neurons - drug effects ; Neurons - metabolism ; Neuropeptide Y ; Neuroscience ; noradrenalin ; Norepinephrine - metabolism ; Patch-Clamp Techniques ; POMC-neuron ; Pro-Opiomelanocortin - metabolism ; Proopiomelanocortin ; Rodents ; Satiety
    ISSN: 2050-084X
    E-ISSN: 2050-084X
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 8
    Language: English
    In: American journal of human genetics, 2012-05-04, Vol.90 (5), p.871-878
    Description: Autosomal-recessive primary microcephaly (MCPH) is a rare congenital disorder characterized by intellectual disability, reduced brain and head size, but usually without defects in cerebral cortical architecture, and other syndromic abnormalities. MCPH is heterogeneous. The underlying genes of the seven known loci code for centrosomal proteins. We studied a family from northern Pakistan with two microcephalic children using homozygosity mapping and found suggestive linkage for regions on chromosomes 2, 4, and 9. We sequenced two positional candidate genes and identified a homozygous frameshift mutation in the gene encoding the 135 kDa centrosomal protein (CEP135), located in the linkage interval on chromosome 4, in both affected children. Post hoc whole-exome sequencing corroborated this mutation's identification as the causal variant. Fibroblasts obtained from one of the patients showed multiple and fragmented centrosomes, disorganized microtubules, and reduced growth rate. Similar effects were reported after knockdown of CEP135 through RNA interference; we could provoke them also by ectopic overexpression of the mutant protein. Our findings suggest an additional locus for MCPH at HSA 4q12 (MCPH8), further strengthen the role of centrosomes in the development of MCPH, and place CEP135 among the essential components of this important organelle in particular for a normal neurogenesis.
    Subject(s): Biological and medical sciences ; Brain ; Brain architecture ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Centrosome ; Centrosomes ; Child ; Children ; chromosome 2 ; chromosome 4 ; Chromosomes ; Chromosomes, Human, Pair 4 - genetics ; Chromosomes, Human, Pair 4 - metabolism ; Congenital diseases ; Diseases ; Exome ; Exons ; Female ; Fibroblasts ; Frameshift mutation ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Gene Knockdown Techniques ; Gene mapping ; Gene mutations ; General aspects. Genetic counseling ; Genes ; Genetic aspects ; Genetic disorders ; Genetic Linkage ; Genetic Loci ; Genetic research ; Genetically modified organisms ; Genetics of eukaryotes. Biological and molecular evolution ; Growth rate ; Head ; Homozygote ; Humans ; Intellectual Disability - genetics ; Intellectual Disability - physiopathology ; Male ; Malformations of the nervous system ; Medical genetics ; Medical sciences ; Mental retardation ; Microcephaly - genetics ; Microcephaly - physiopathology ; Microencephaly ; Microtubules ; Molecular and cellular biology ; Mutation ; Nervous system diseases ; Neurogenesis ; Neurological disorders ; Neurology ; Organelles ; Pakistan - epidemiology ; Pakistanis ; Pedigree ; Polymorphism, Single Nucleotide ; Proteins ; Report ; Research ; RNA ; RNA Interference ; RNA-mediated interference ; Sequence Analysis, DNA
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Cell Press Collection [ECCPC]
    Source: PubMed Central
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  • 9
    Language: English
    In: PloS one, 2017, Vol.12 (3), p.e0172491-e0172491
    Description: The analysis and functional characterization of ectopically expressed human olfactory receptors (ORs) is becoming increasingly important, as many ORs have been identified in several healthy and cancerous tissues. OR activation has been demonstrated to have influence on cancer cell growth and progression. Here, ORs were identified using RNA-Seq analyses and RT-PCR. We demonstrated the OR protein localization in HCT116 cells using immunocytochemistry (IHC). In order to analyze the physiological role of OR51B4, we deorphanized the receptor by the use of CRE-Luciferase assays, conducted calcium imaging experiments as well as scratch- and proliferation assays. Furthermore, western blot analyses revealed the involvement of different protein kinases in the ligand-dependent signaling pathway. Receptor knockdown via shRNA was used to analyze the involvement of OR51B4. We identified OR51B4, which is highly expressed in the colon cancer cell line HCT116 and in native human colon cancer tissues. We deorphanized the receptor and identified Troenan as an effective ligand. Troenan stimulation of HCT116 cells has anti-proliferative, anti-migratory and pro-apoptotic effects, mediated by changes in the intracellular calcium level upon PLC activation. These effects cause changes in the phosphorylation levels of p38, mTor and Akt kinases. Knockdown of the receptor via shRNA confirmed the involvement of OR51B4. This study emphasizes the importance of ectopically expressed ORs in the therapy for several diseases. The findings provide the basis for alternative treatments of colorectal cancer.
    Subject(s): Activation ; AKT protein ; Analysis ; Apoptosis ; Apoptosis - genetics ; Biology and Life Sciences ; Biomarkers ; Calcium ; Calcium (intracellular) ; Calcium imaging ; Calcium Signaling ; Cancer ; Cancer cells ; Caspase 3 - metabolism ; Cell cycle ; Cell growth ; Cell Line, Tumor ; Cell Proliferation ; Colon ; Colon cancer ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - metabolism ; Development and progression ; Ectopic Gene Expression ; Gene Expression ; Gene Expression Profiling ; Genomes ; Genomics ; HCT116 Cells ; Health aspects ; Humans ; Immunocytochemistry ; Kinases ; Ligands ; Localization ; Medicine and Health Sciences ; Models, Biological ; Motility ; Odorant receptors ; Olfactory receptors ; Phosphorylation ; Physical Sciences ; Physiology ; Polymerase chain reaction ; Prostate ; Proteins ; Proteomics ; Receptors ; Receptors, Odorant - genetics ; Receptors, Odorant - metabolism ; Research ; Research and Analysis Methods ; Ribonucleic acid ; RNA ; Rodents ; Signal Transduction ; Signaling ; Tissues ; TOR protein
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 10
    Language: English
    In: Nature genetics, 2014, Vol.46 (11), p.1239-1244
    Description: Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma
    Subject(s): Age ; Age of Onset ; Aging ; Animals ; Base Sequence ; Biopsy ; Carcinoma, Hepatocellular - genetics ; Chromosome Mapping ; Cloning, Molecular ; Colleges & universities ; Councils ; Deoxyribonucleic acid ; Development and progression ; DNA ; DNA Primers - genetics ; DNA Replication - genetics ; DNA-Binding Proteins - genetics ; Flow Cytometry ; Fluorescent Antibody Technique ; Gene mutations ; Genes ; Genes, cdc - genetics ; Genetic aspects ; Genetics ; Genomic Instability - genetics ; Genomics ; Germ-Line Mutation - genetics ; Grants ; Health aspects ; Hepatoma ; Humans ; Liver cancer ; Liver Neoplasms - genetics ; Male ; Molecular Sequence Data ; Mutation ; Patients ; Pedigree ; Progeria - genetics ; Proteins ; Research ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Analysis, DNA ; Zebrafish - genetics
    ISSN: 1061-4036
    E-ISSN: 1546-1718
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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