PubMed Central (PMC3 - NLM DTD)
Archive of life sciences journal literature at the U.S. National Institutes of Health (NIH), developed and managed by NIH's National Center for Biotechnology Information (NCBI) in the National Library of Medicine (NLM).
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Mostrando recursos 1 - 20 de 384,244
Genomics and the classification of mental illness: focus on broader categories - Uher, Rudolf
Coinciding with the release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, two recently published molecular genetics analyses suggest large overlaps in genetic liability to schizophrenia, bipolar disorder and major depressive disorder. This indicates that a broader category of severe mental illness may be an important target for future large-scale etiological and therapeutic investigations. Studies of patient groups not restricted to current diagnostic categories may lead to a genetically informed nosology.
Mesenchymal stem cells to augment therapeutic angiogenesis in hind-limb ischemia models: how important is their source? - Duffy, Garry P; Herron, Caroline C
Murine models of hind-limb ischemia are frequently used to assess interventions aimed at improving therapeutic angiogenesis in critical limb ischemia. Much of the current focus of angiogenesis lies with mesenchymal stem cells (MSCs). Important considerations when using these models include the strain of mouse, because some strains recover from ischemia more rapidly than others, and the MSC source. MSCs derived from certain strains generate increased levels of growth factors such as vascular endothelial growth factor. This may significantly affect the limb?s ability to generate collateral vessels.
Guidelines for investigating causality of sequence variants in human disease - MacArthur, D. G.; Manolio, T. A.; Dimmock, D. P.; Rehm, H. L.; Shendure, J.; Abecasis, G. R.; Adams, D. R.; Altman, R. B.; Antonarakis, S. E.; Ashley, E. A.; Barrett, J. C.; Biesecker, L. G.; Conrad, D. F.; Cooper, G. M.; Cox, N. J.; Daly, M. J.; Gerstein, M. B.; Goldstein, D. B.; Hirschhorn, J. N.; Leal, S. M.; Pennacchio, L. A.; Stamatoyannopoulos, J. A.; Sunyaev, S. R.; Valle, D.; Voight, B. F.; Winckler, W.; Gunter, C.
The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource...
Targeted genomic rearrangements using CRISPR/Cas technology - Choi, Peter S.; Meyerson, Matthew
Genomic rearrangements are frequently observed in cancer cells but have been difficult to generate in a highly specific manner for functional analysis. Here we report the application of CRISPR/Cas technology to successfully generate several types of chromosomal rearrangements implicated as driver events in lung cancer, including the CD74-ROS1 translocation event and the EML4-ALK and KIF5B-RET inversion events. Our results demonstrate that Cas9-induced DNA breaks promote efficient rearrangement between pairs of targeted loci, providing a highly tractable approach for the study of genomic rearrangements.
Mammalian Y chromosomes retain widely expressed dosage-sensitive
regulators - Bellott, Daniel W.; Hughes, Jennifer F.; Skaletsky, Helen; Brown, Laura G.; Pyntikova, Tatyana; Cho, Ting-Jan; Koutseva, Natalia; Zaghlul, Sara; Graves, Tina; Rock, Susie; Kremitzki, Colin; Fulton, Robert S.; Dugan, Shannon; Ding, Yan; Morton, Donna; Khan, Ziad; Lewis, Lora; Buhay, Christian; Wang, Qiaoyan; Watt, Jennifer; Holder, Michael; Lee, Sandy; Nazareth, Lynne; Alföldi, Jessica; Rozen, Steve; Muzny, Donna M.; Warren, Wesley C.; Gibbs, Richard A.; Wilson, Richard K.; Page, David C.
The human X and Y chromosomes evolved from an ordinary pair of autosomes, but
millions of years ago genetic decay ravaged the Y chromosome, and only three percent of
its ancestral genes survived. We reconstructed the evolution of the Y chromosome across
eight mammals to identify biases in gene content and the selective pressures that
preserved the surviving ancestral genes. Our findings indicate that survival was
non-random, and in two cases, convergent across placental and marsupial mammals. We
conclude that the Y chromosome's gene content became specialized through selection
to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly
expressed regulators of transcription, translation...
Inhibition of miR-25 Improves Cardiac Contractility in the Failing Heart - Wahlquist, Christine; Jeong, Dongtak; Rojas-Muñoz, Agustin; Kho, Changwon; Lee, Ahyoung; Mitsuyama, Shinichi; van Mil, Alain; Jin Park, Woo; Sluijter, Joost P. G.; Doevendans, Pieter A. F.; Hajjar, Roger J.; Mercola, Mark
Heart failure is characterized by a debilitating decline in cardiac function1, and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy2,3. microRNAs (miRs) are dysregulated with heart failure4,5 but whether they control contractility or constitute therapeutic targets remain speculative. Using high throughput, functional screening of the human microRNAome, we identified miRs that suppress intracellular calcium handling in heart muscle by interacting with mRNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a. Of 875 miRs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and...
Trogocytosis by Entamoeba histolytica contributes to cell killing and tissue invasion - Ralston, Katherine S.; Solga, Michael D.; Mackey-Lawrence, Nicole M.; Somlata,; Bhattacharya, Alok; Petri, William A.
Entamoeba histolytica is the causative agent of amoebiasis, a potentially fatal diarrheal disease in the developing world. The parasite was named “histolytica” for its ability to destroy host tissues, which is most likely driven by direct killing of human cells. The mechanism of human cell killing has been unclear, though the accepted model was that the parasites use secreted toxic effectors to kill cells prior to ingestion1. Here we report the surprising discovery that amoebae kill by biting off and ingesting distinct pieces of living human cells, resulting in intracellular calcium elevation and eventual cell death. After cell killing, amoebae...
Juno is the egg Izumo receptor and is essential for mammalian fertilisation - Bianchi, Enrica; Doe, Brendan; Goulding, David; ; Wright, Gavin J.
Fertilisation occurs when sperm and egg recognise each other and fuse to form a new, genetically distinct organism. The molecular basis of sperm-egg recognition is unknown, but is likely to require interactions between receptor proteins displayed on their surface. Izumo1 is an essential sperm cell surface protein, but its egg receptor has remained a mystery. Here, we identify Juno as the receptor for Izumo1 on mouse eggs, and show this interaction is conserved within mammals. Female mice lacking Juno are infertile and Juno-deficient eggs do not fuse with normal sperm. Rapid shedding of Juno from the oolemma after fertilisation suggests...
Small molecule inhibition of CBP/catenin interactions eliminates drug resistant clones in acute lymphoblastic leukemia - Gang, Eun Ji; Hsieh, Yao-Te; Pham, Jennifer; Zhao, Yi; Nguyen, Cu; Huantes, Sandra; Park, Eugene; Naing, Khatija; Klemm, Lars; Swaminathan, Srividya; Conway, Edward M.; Pelus, Louis M.; Crispino, John; Mullighan, Charles; McMillan, Michael; Müschen, Markus; Kahn, Michael; Kim, Yong-Mi
Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia, however little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CBP) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes...
Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression - Sato, Takahiro; Tran, Thai H.; Peck, Amy R.; Girondo, Melanie A.; Liu, Chengbao; Goodman, Chelain R.; Neilson, Lynn M.; Freydin, Boris; Chervoneva, Inna; Hyslop, Terry; Kovatich, Albert J.; Hooke, Jeffrey A.; Shriver, Craig D.; Fuchs, Serge Y.; Rui, Hallgeir
Prolactin controls the development and function of milk-producing breast epithelia but also supports growth and differentiation of breast cancer, especially luminal subtypes. A principal signaling mediator of prolactin, Stat5, promotes cellular differentiation of breast cancer cells in vitro, and loss of active Stat5 in tumors is associated with anti-estrogen therapy failure in patients. In luminal breast cancer progesterone induces a cytokeratin-5 (CK5)-positive basal cell-like population. This population possesses characteristics of tumor stem cells including quiescence, therapy-resistance, and tumor-initiating capacity. Here we report that prolactin counteracts induction of the CK5-positive population by the synthetic progestin R5020 in luminal breast cancer cells...
Ventriculo-atrial defect after bioprosthetic aortic valve replacement - Jainandunsing, Jayant S; Bergman, Remco; Wilkens, Jacob; Wang, Angela; Michielon, Guido; Natour, Ehsan
We present a case of a 71-year-old Caucasian male with a ventriculo-atrial defect due to infective endocarditis, originating from his aortic root near a bioprosthetic aortic valve, implanted 4 years earlier. Ventriculo-atrial defects are rare and can occur after endocarditis with abscess formation, usually in native tissue. We report a ventriculo-atrial defect due to a paravalvular aortic prosthetic defect, secondary to inflammation, a novel third type of a Gerbode defect. Case presentation, clinical decision making and surgical approach are discusses in this report.