tbuckley/cabot-search huggingface dataset:
A Comprehensive Analysis of Mammalian Mitochondrial Genome Base Composition and Improved Phylogenetic Methods
Authors: Andrew Gibson, Vivek Gowri-Shankar, Paul G. Higgs, Magnus Rattray
Journal: Molecular Biology and Evolution (2004)

Phylogenetic analysis of mammalian species using mitochondrial protein genes has proved to be problematic in many previous studies. The high mutation rate of mitochondrial DNA and unusual base composition of several species has prompted us to conduct a detailed study of the composition of 69 mammalian mitochondrial genomes. Most major changes in base composition between lineages can be attributed to shifts between the proportions of C and T on the L-strand. These changes are significant at all codon positions and are shown to affect amino acid composition. Correlated changes in the base composition of the RNA loops and stems are also observed. Following up from previous studies, we investigate changes in the base composition of all 12 H-strand proteins and find that variability in proportions of C and T is correlated with location on the genome. Variation in base composition across genes and species is known to adversely affect the performance of phylogenetic inference methods. We have, therefore, developed a customized three-state general time-reversible DNA substitution model, implemented in the PHASE phylogenetic inference package, which lumps C and T into a composite pyrimidine state. We compare the phylogenetic tree obtained using the new three-state model with that obtained using a standard four-state model. Results using the three-state model are more congruent with recent studies using large sets of nuclear genes and help resolve some of the apparent conflicts between studies using nuclear and mitochondrial proteins.
The Electrical Detection of Lead Ions Using Gold‐Nanoparticle‐ and DNAzyme‐Functionalized Graphene Device
Authors: Yanqin Wen, Fabien Yi Li, Xiaochen Dong, Jun Zhang, Qihua Xiong, Peng Chen
Journal: Advanced Healthcare Materials (2012)

An electronic Pb2+ sensor, with high sensitivity and specificity, was developed based on DNAzyme- and gold-nanoparticle-functionalized graphene transistor.
Research misconduct: the poisoning of the well
Authors: R. Smith
Journal: Journal of the Royal Society of Medicine (2006)

Richard Smith was editor of the BMJ and chief executive of the BMJ Publishing Group for 13 years. In his last year at the journal he retreated to a 15th century palazzo in Venice to write a book. This is a much shortened chapter from the author's book provisionally entitled The Trouble With Medical Journals that the RSM Press will publish in the autumn [www.rsmpress.co.uk], and this is the fourth in a series of extracts that will be published in the JRSM.
THE IMMUNOGENICITY OF ANTIGEN BOUND TO THE PLASMA MEMBRANE OF MACROPHAGES
Authors: Emil R. Unanue, Jean-Charles Cerottini
Journal: The Journal of Experimental Medicine (1970)

Macrophages were cultured for several hours after a brief exposure to radio-iodinated keyhole limpet hemocyanin. Most of the hemocyanin taken up by the macrophages was rapidly catabolized and eliminated from the cell. A few molecules were retained on the plasma membrane of the cells for prolonged periods and were not subject to endocytosis and catabolism. These few molecules of hemocyanin bound to the plasma membrane were identified by observing the fixation of antibody fragments to macrophages at low temperature. The membrane-bound antigen, which could be removed by trypsin or EDTA, was of large molecular size, though heterogeneous. A great part of the immune responses of mice to hemocyanin bound to live macrophages could be abrogated by treatment of the macrophages in vitro with antibody or trypsin. Hence, most of the immunogenicity of hemocyanin bound to macrophages was attributed to the few molecules of antigen bound to the plasma membrane.
Angiotensin IV has mixed effects on left ventricle systolic function and speeds relaxation
Authors: B Slinker
Journal: Cardiovascular Research (1999)

Objective: A novel angiotensin receptor has been described and named AT4. Ligands for this receptor include the angiotensin II (Ang II) metabolite Ang II (3–8), known as angiotensin IV (Ang IV). There is 10-fold more AT4 receptor than AT1 receptor in rabbit myocardium. The AT4 receptor has a high affinity for Ang IV (Ki in rabbit myocardium <2×10−9) and similar ligands, but very low affinity for Ang II (Ki in rabbit myocardium >10−6). Although several functions have been attributed to the novel Ang IV peptide/AT4 receptor system, the effect of this system on left ventricular (LV) function has not been studied. We hypothesized (1) that Ang IV would affect LV function and (2) that any effects would be opposite to those of Ang II. Methods: Using the buffer-perfused (30°C) isolated rabbit heart, we studied the effect of the AT4 agonist Nle1-Ang IV on LV systolic function, quantified using both Frank–Starling and end-systolic pressure–volume relationships, and relaxation. We also studied the effect of the AT1/AT2 agonist, Sar1-Ang II on LV function. Finally, because the profile of effect of Nle1-Ang IV was similar to the reported effect of nitric oxide (NO), we also studied the effect of Nle1-Ang IV in the presence of the NO synthase inhibitor NG-monomethyl-l-arginine. Results: Nle1-Ang IV reduced LV pressure-generating capability at any volume but increased the sensitivity of pressure development to volume change. Nle1-Ang IV reduced LV ejection capability. Sar1-Ang II had the opposite effect – increasing both pressure generation and ejection capability. Finally, both Sar1-Ang II and Nle1-Ang IV speeded LV relaxation. Inhibition of NO synthase did not alter the effect of Nle1-Ang IV on LV systolic function or relaxation. Conclusions: AT4 receptor agonism has mixed effects on LV systolic function, depressing pressure-generation and ejection capabilities, but enhancing the sensitivity of pressure development to volume change. It also speeds relaxation. The effect of Ang IV on systolic function is generally opposite to the effect of Ang II, whereas the Ang IV influence on relaxation is similar to the effect of Ang II.
Copy number variants are a common cause of non-syndromic hearing loss
Authors: A Shearer, Diana L Kolbe, Hela Azaiez, Christina M Sloan, Kathy L Frees, Amy E Weaver, Erika T Clark, Carla J Nishimura, E Black-Ziegelbein, Richard J H Smith
Journal: Genome Medicine (2014)

Copy number variants (CNVs) are a well-recognized cause of genetic disease; however, methods for their identification are often gene-specific, excluded as 'routine' in screens of genetically heterogeneous disorders, and not implemented in most next-generation sequencing pipelines. For this reason, the contribution of CNVs to non-syndromic hearing loss (NSHL) is most likely under-recognized. We aimed to incorporate a method for CNV identification as part of our standard analysis pipeline and to determine the contribution of CNVs to genetic hearing loss.We used targeted genomic enrichment and massively parallel sequencing to isolate and sequence all exons of all genes known to cause NSHL. We completed testing on 686 patients with hearing loss with no exclusions based on type of hearing loss or any other clinical features. For analysis we used an integrated method for detection of single nucleotide changes, indels and CNVs. CNVs were identified using a previously published method that utilizes median read-depth ratios and a sliding-window approach.Of 686 patients tested, 15.2% (104) carried at least one CNV within a known deafness gene. Of the 38.9% (267) of individuals for whom we were able to determine a genetic cause of hearing loss, a CNV was implicated in 18.7% (50). We identified CNVs in 16 different genes including 7 genes for which no CNVs have been previously reported. CNVs of STRC were most common (73% of CNVs identified) followed by CNVs of OTOA (13% of CNVs identified).CNVs are an important cause of NSHL and their detection must be included in comprehensive genetic testing for hearing loss.
MEDICAL SCHOOL ELECTIVES ON FAMILY ATTITUDES, SEXUAL BEHAVIOR, AND MARRIAGE COUNSELING
Authors: KENNETH E. APPEL, EMILY HARTSHORNE MUDD, PHILIP Q. ROCHE
Journal: American Journal of Psychiatry (1955)

On the basis of a 3-year experiment, we believe that there is a body of scientific data on family attitudes and sexual behavior sufficiently developed for communication to medical students as part of the regular medical curriculum and in supervised marriage counseling. Student response indicates interest and receptivity, which become correlated not only with the theory and practice of medicine, but also with the personal needs of the students. These electives make a contribution to the medical student's vocabulary, to his concepts of the personality in social interactions, and to his grasp of many symptomatic configurations expressive of the tensions of our times, particularly in the area of marriage. We plan in 1955 to focus the material more intensively on the senior medical student who is about to emerge in his professional role, and, at appropriate opportunities, to emphasize what he can do to be helpful to his patient. The experiment so far supports the suggestion that the medical curriculum may in time properly devise means for supervised participation of a majority of senior students in the study and counseling of marital problems as they relate to the practice of medicine.
Kupffer cell activation and endothelial cell damage after storage of rat livers: Effects of reperfusion
Authors: Jane C. Caldwell-Kenkel, Robert T. Currin, Yukio Tanaka, Ronald G. Thurman, John J. Lemasters
Journal: Hepatology (1991)

Reperfusion injury characterized by loss of endothelial cell viability occurs after cold ischemic storage of livers for transplantation surgery. Here, ultrastructural changes in stored rat livers were examined by scanning and transmission electron microscopy. With increasing times of storage in Euro-Collins solution (4 to 24 hr) followed by 15 min of reperfusion at 37 degrees C, a sequence of structural alterations was observed involving endothelial and Kupffer cells. Widening of endothelial fenestrations occurred after 4 hr and progressed over 8 to 24 hr to retraction of cellular processes, ball-like rounding, sinusoidal denudation and ultrastructural derangements consistent with loss of cell viability. Kupffer cells exhibited progressive rounding, ruffling of the cell surface, polarization, appearance of wormlike densities, vacuolization and degranulation over a similar time course. By contrast, the structures of parenchymal and fat-storing cells were relatively undisturbed by cold storage and reperfusion. Alterations to endothelial and Kupffer cells were also studied as a function of time of reperfusion. After 24 hr of storage, endothelial cells showed retraction of cytoplasm before reperfusion that progressed quickly to loss of viability and denudation during reperfusion. Kupffer cell activation (ruffling, degranulation) during reperfusion was slower and occurred after deterioration of endothelial cells. Livers stored in Euro-Collins solution were also compared with livers stored in University of Wisconsin cold storage solution, an improved preservation medium for transplantation. University of Wisconsin solution provided better preservation of endothelial structure and markedly reduced parenchymal cell blebbing and swelling before reperfusion. University of Wisconsin solution also reduced Kupffer cell activation and release of lysosomal enzymes. In conclusion, endothelial cell deterioration followed by Kupffer cell activation occurred after increasing times of cold ischemic storage and reperfusion of rat livers. Both changes may contribute to the pathophysiology of graft failure caused by reperfusion-mediated storage injury.
A systematic screen reveals new elements acting at the G2/M cell cycle control
Authors: Francisco J Navarro, Paul Nurse
Journal: Genome biology (2012)

Abstract Background The major cell cycle control acting at the G2 to mitosis transition is triggered in all eukaryotes by cyclin-dependent kinases (CDKs). In the fission yeast Schizosaccharomyces pombe the activation of the G2/M CDK is regulated primarily by dephosphorylation of the conserved residue Tyr15 in response to the stress-nutritional response and cell geometry sensing pathways. To obtain a more complete view of the G2/M control we have screened systematically for gene deletions that advance cells prematurely into mitosis. Results A screen of 82% of fission yeast non-essential genes, comprising approximately 3,000 gene deletion mutants, identified 18 genes that act negatively at mitotic entry, 7 of which have not been previously described as cell cycle regulators. Eleven of the 18 genes function through the stress response and cell geometry sensing pathways, both of which act through CDK Tyr15 phosphorylation, and 4 of the remaining genes regulate the G2/M transition by inputs from hitherto unknown pathways. Three genes act independently of CDK Tyr15 phosphorylation and define additional uncharacterized molecular control mechanisms. Conclusions Despite extensive investigation of the G2/M control, our work has revealed new components of characterized pathways that regulate CDK Tyr15 phosphorylation and new components of novel mechanisms controlling mitotic entry.
Inhibition of Toll-like Receptor 4 With Eritoran Attenuates Myocardial Ischemia-Reperfusion Injury
Authors: Akira Shimamoto, Albert J. Chong, Masaki Yada, Shin Shomura, Hiroo Takayama, Ani J. Fleisig, Matthew L. Agnew, Craig R. Hampton, Christine L. Rothnie, Denise J. Spring, Timothy H. Pohlman, Hideto Shimpo, Edward D. Verrier
Journal: Circulation (2006)

Background— We previously reported that the functional mutation of Toll-like receptor 4 (TLR4) in C3H/HeJ mice subjected to myocardial ischemia-reperfusion (MI/R) injury resulted in an attenuation of myocardial infarction size. To investigate the ligand-activating TLR4 during MI/R injury, we evaluated the effect of eritoran, a specific TLR4 antagonist, on MI/R injury, with the goal of defining better therapeutic options for MI/R injury. Methods and Results— C57BL/6 mice received eritoran (5 mg/kg) intravenously 10 minutes before 30 minutes of in situ of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. Infarct size was measured using triphenyltetrazoliumchloride staining. A c-Jun NH 2 -terminal kinase (JNK) activation was determined by Western blotting, nuclear factor (NF)-κB activity was detected by gel-shift assay, and cytokine expression was measured by ribonuclease protection assay. Mice treated with eritoran developed significantly smaller infarcts when compared with mice treated with vehicle alone (21.0±6.4% versus 30.9±13.9%; P =0.041). Eritoran pretreatment resulted in a reduction in JNK phosphorylation (eritoran versus vehicle: 3.98±0.81 versus 7.01±2.21-fold increase; P =0.020), less nuclear NF-κB translocation (2.70±0.35 versus 7.75±0.60-fold increase; P =0.00007), and a decrease in cytokine expression ( P &lt;0.05). Conclusions— We conclude that inhibition of TLR4 with eritoran in an in situ murine model significantly reduces MI/R injury and markers of an inflammatory response.
PERSISTENCE OF CIRCULATING HBsAg/IgM COMPLEXES IN ACUTE VIRAL HEPATITIS, TYPE B: AN EARLY MARKER OF CHRONIC EVOLUTION
Authors: Franco Careoda, Roberto De Franchis, Antonella D'Arminio Monforte, Maurizio Vecchi, Massimo Primignani, Elio Rossi, Mario Palla, Nicola Dioguardi
Journal: The Lancet (1982)
Comparative Effects of Castration and Antiandrogen Treatment on the Aortas of Hypertensive and Normotensive Male Rats
Authors: HARVEY WOLINSKY
Journal: Circulation Research (1973)

Lowering androgen levels by gonadectomy or inhibiting circulating androgen by administration of the antiandrogen, BOMT, did not affect morphological or compositional changes induced by hypertension in the thoracic aorta of male rats. However, treatment with cyproterone acetate, another antiandrogenic drug, did result in the maintenance of total elastin and collagen at levels the same as those for the normotensive group and significantly lower than those for other treated and untreated hypertensive groups. In rapidly growing normotensive rats, neither castration nor administration of an antiandrogenic drug had any detectable effect on aortic wall morphology or composition regardless of whether the latter was expressed in absolute or relative terms. These findings suggest that growth and hypertension result in the accumulation of connective tissue proteins, elastin, and collagen in the blood vessel wall by different, independent mechanisms.
Vascular complications after percutaneous coronary interventions following hemostasis with manual compression versus arteriotomy closure devices
Authors: George Dangas, Roxana Mehran, Spyros Kokolis, Dmitriy Feldman, Lowell F Satler, Augusto D Pichard, Kenneth M Kent, Alexandra J Lansky, Gregg W Stone, Martin B Leon
Journal: Journal of the American College of Cardiology (2001)
Antiproteases are increased in bronchoalveolar lavage in interstitial lung disease
Authors: Y Sibille, JB Martinot, P Staquet, L Delaunois, B Chatelain, DL Delacroix
Journal: European Respiratory Journal (1988)

The present study evaluates different cellular and soluble components in the bronchoalveolar lavage (BAL) from patients with interstitial lung disease. We observed an increased T4/T8 lymphocyte ratio in BAL but not in blood from 24 patients with active pulmonary sarcoidosis compared to sixteen normal individuals and to eleven patients with inactive pulmonary sarcoidosis. Seven patients with hypersensitivity pneumonitis had a normal T4/T8 ratio. In the active sarcoidosis and hypersensitivity pneumonitis groups, alpha 1-Protease Inhibitor (alpha 1 PI) in BAL is significantly higher than in the normal group and a significant correlation between the two antiproteases (alpha 2-macroglobulin and alpha 1 PI) is observed. These data demonstrate that antiprotease levels (alpha 1 PI and alpha 2 M) are increased in the lower respiratory tract of patients with interstitial lung disease and that among cellular and soluble components of BAL, alpha 2 M represents a sensitive marker of the alveolitis.
Genetic Fate Mapping Identifies Second Heart Field Progenitor Cells As a Source of Adipocytes in Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Raffaella Lombardi, Jinjiang Dong, Gabriela Rodriguez, Achim Bell, Tack Ki Leung, Robert J. Schwartz, James T. Willerson, Ramon Brugada, Ali J. Marian
Journal: Circulation Research (2009)

The phenotypic hallmark of arrhythmogenic right ventricular cardiomyopathy, a genetic disease of desmosomal proteins, is fibroadipocytic replacement of the right ventricle. Cellular origin of excess adipocytes, the responsible mechanism(s) and the basis for predominant involvement of the right ventricle are unknown. We generated 3 sets of lineage tracer mice regulated by cardiac lineage promoters alpha-myosin heavy chain (alphaMyHC), Nkx2.5, or Mef2C. We conditionally expressed the reporter enhanced yellow fluorescent protein while concomitantly deleting the desmosomal protein desmoplakin in cardiac myocyte lineages using the Cre-LoxP technique. Lineage tracer mice showed excess fibroadiposis and increased numbers of adipocytes in the hearts. Few adipocytes in the hearts of alphaMyHC-regulated lineage tracer mice, but the majority of adipocytes in the hearts of Nkx2.5- and Mef2C-regulated lineage tracer mice, expressed enhanced yellow fluorescent protein. In addition, rare cells coexpressed adipogenic transcription factors and the second heart field markers Isl1 and Mef2C in the lineage tracer mouse hearts and in human myocardium from patients with arrhythmogenic right ventricular cardiomyopathy. To delineate the responsible mechanism, we generated transgenic mice expressing desmosomal protein plakoglobin in myocyte lineages. Transgene plakoglobin translocated to nucleus, detected by immunoblotting and immunofluorescence staining and coimmunoprecipitated with Tcf7l2, a canonical Wnt signaling transcription factor. Expression levels of canonical Wnt/Tcf7l2 targets bone morphogenetic protein 7 and Wnt5b, which promote adipogenesis, were increased and expression level of connective tissue growth factor, an inhibitor of adipogenesis, was decreased. We conclude adipocytes in arrhythmogenic right ventricular cardiomyopathy originate from the second heart field cardiac progenitors, which switch to an adipogenic fate because of suppressed canonical Wnt signaling by nuclear plakoglobin.
<i>STAT1</i>Mutations in Autosomal Dominant Chronic Mucocutaneous Candidiasis
Authors: Frank L. van de Veerdonk, Theo S. Plantinga, Alexander Hoischen, Sanne P. Smeekens, Leo A.B. Joosten, Christian Gilissen, Peer Arts, Diana C. Rosentul, Andrew J. Carmichael, Chantal A.A. Smits-van der Graaf, Bart Jan Kullberg, Jos W.M. van der Meer, Desa Lilic, Joris A. Veltman, Mihai G. Netea
Journal: New England Journal of Medicine (2011)

Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to candida infection of skin, nails, and mucous membranes. Patients with recessive CMC and autoimmunity have mutations in the autoimmune regulator AIRE. The cause of autosomal dominant CMC is unknown.We evaluated 14 patients from five families with autosomal dominant CMC. We incubated their peripheral-blood mononuclear cells with different combinations of stimuli to test the integrity of pathways that mediate immunity, which led to the selection of 100 genes that were most likely to contain the genetic defect. We used an array-based sequence-capture assay, followed by next-generation sequencing, to identify mutations.The mononuclear cells from the affected patients were characterized by poor production of interferon-γ, interleukin-17, and interleukin-22, suggesting that the defect lay within the interleukin-12 receptor and interleukin-23 receptor signaling pathways. We identified heterozygous missense mutations in the DNA sequence encoding the coiled-coil (CC) domain of signal transducer and activator of transcription 1 (STAT1) in the patients. These mutations lead to defective responses in type 1 and type 17 helper T cells (Th1 and Th17). The interferon-γ receptor pathway was intact in these patients.Mutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection. (Funded by the Netherlands Organization for Scientific Research and others.).