tbuckley/cabot-search huggingface dataset:
Hearts from mice lacking desmin have a myopathy with impaired active force generation and unaltered wall compliance
Authors: J Balogh, M Merisckay, Z Li, D Paulin, A Arner
Journal: Cardiovascular Research (2002)

Objective: Desmin intermediate filaments are key structures in the cytoskeleton of cardiac muscle. Since they are associated with Z-discs and intercalated discs, they may have a role in sarcomere alignment or force transmission. We have explored the mechanical function of the desmin filaments in the cardiac wall by comparing desmin-deficient (Des−/−) and wild-type (Des+/+) mice. Methods: The Langendorff technique was used to examine the contractility of the whole heart. Rate of force generation, Ca2+-sensitivity and force per cross-sectional area were measured in skinned ventricle muscle preparations. Results:Des−/− mice have a cardiomyopathy with increased heart weight. Diastolic pressure was increased at all filling volumes in the Des−/− group. Since passive wall stress (i.e. force per area) was unchanged, the alteration in diastolic pressure is a consequence of the thicker ventricle wall. Developed pressure, rate of pressure increase and developed wall stress were significantly reduced, suggesting that active force generation of the contractile apparatus is reduced in Des−/−. Concentrations of actin and myosin in the ventricle were unaltered. Measurements in skinned muscle preparations showed a lower active force development with unaltered Ca2+-sensitivity and rate of tension development. Conclusion: It is suggested that the intermediate filaments have a role in active force generation of cardiac muscle, possibly by supporting sarcomere alignment or force transmission. The desmin filaments do not contribute the passive elasticity of the ventricle wall. Des−/− mice provide a model for genetic cardiomyopathy where the main factor contributing to altered cardiac performance is a decrease in active force generation, possibly in combination with a loss of functional contractile units.
Applications of Errorless Learning for Improving Work Performance in Persons With Schizophrenia
Authors: Robert S. Kern, Robert P. Liberman, Alex Kopelowicz, Jim Mintz, Michael F. Green
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Until recently, few training methods used in the psychosocial rehabilitation of persons with schizophrenia have taken into account the neurocognitive deficits common to this illness. The present study tested a training method called errorless learning (which theoretically compensates for neurocognitive impairments) for efficacy at teaching entry-level job tasks to persons with serious and persistent mental illness. METHOD: Sixty-five unemployed, clinically stable outpatients with schizophrenia or schizoaffective disorder were randomly assigned to training by means of either errorless learning or conventional instruction for two entry-level job tasks (index card filing and toilet tank assembly). Training was conducted in small groups of four subjects for 90–120 minutes in a simulated workshop. Efficacy—as measured by accuracy, speed, and overall productivity—was assessed immediately after training and at a 3-month follow-up evaluation. RESULTS: Significant group differences in accuracy that favored errorless learning were found on both job tasks. In terms of productivity, the errorless learning group was superior to the conventional instruction group on the card filing task, and differences for the tank assembly task approached significance. There were no significant group differences in speed. Both groups showed significant drops in accuracy and productivity on the tank assembly task from immediately after training to the 3-month follow-up evaluation; performance levels were more stable for both groups on the card filing task. CONCLUSIONS: Errorless learning appears to be a useful training method for establishing introductory high levels of performance in the work rehabilitation of persons with schizophrenia. Future studies may wish to test its long-term durability by embedding it within supported employment programs.
The Polyamine Catabolic Enzyme SAT1 Modulates Tumorigenesis and Radiation Response in GBM
Authors: Adina Brett-Morris, Bradley M. Wright, Yuji Seo, Vinay Pasupuleti, Junran Zhang, Jun Lu, Raffaella Spina, Eli E. Bar, Maneesh Gujrati, Rebecca Schur, Zheng-Rong Lu, Scott M. Welford
Journal: Cancer Research (2014)

Glioblastoma multiforme (GBM) is the most common and severe form of brain cancer. The median survival time of patients is approximately 12 months due to poor responses to surgery and chemoradiation. To understand the mechanisms involved in radioresistance, we conducted a genetic screen using an shRNA library to identify genes in which inhibition would sensitize cells to radiation. The results were cross-referenced with the Oncomine and Rembrandt databases to focus on genes that are highly expressed in GBM tumors and associated with poor patient outcomes. Spermidine/spermine-N1-acetyltransferase 1 (SAT1), an enzyme involved in polyamine catabolism, was identified as a gene that promotes resistance to ionizing radiation (IR), is overexpressed in brain tumors, and correlates with poor outcomes. Knockdown of SAT1 using shRNA and siRNA approaches in multiple cell and neurosphere lines resulted in sensitization of GBM cells to radiation in colony formation assays and tumors, and decreased tumorigenesis in vivo. Radiosensitization occurred specifically in G2-M and S phases, suggesting a role for SAT1 in homologous recombination (HR) that was confirmed in a DR-GFP reporter system. Mechanistically, we found that SAT1 promotes acetylation of histone H3, suggesting a new role of SAT1 in chromatin remodeling and regulation of gene expression. In particular, SAT1 depletion led to a dramatic reduction in BRCA1 expression, explaining decreased HR capacity. Our findings suggest that the biologic significance of elevated SAT1 expression in GBM lies in its contribution to cell radioresistance and that SAT1 may potentially be a therapeutic target to sensitize GBM to cancer therapies.
An Osteoprotegerin-like Peptidomimetic Inhibits Osteoclastic Bone Resorption and Osteolytic Bone Disease in Myeloma
Authors: Deborah J. Heath, Karin Vanderkerken, Xin Cheng, Orla Gallagher, Matthew Prideaux, Ramachandran Murali, Peter I. Croucher
Journal: Cancer Research (2007)

Abstract Multiple myeloma is a B-cell malignancy characterized by the uncontrolled growth of plasma cells in the bone marrow and the development of osteolytic bone disease. Myeloma cells express the receptor activator of nuclear factor κB ligand (RANKL), induce RANKL expression in the bone marrow, and down-regulate expression of the decoy receptor osteoprotegerin, thereby promoting bone resorption. Targeting this system in myeloma has clear therapeutic potential. However, osteoprotegerin also binds tumor necrosis factor–related apoptosis inducing ligand (TRAIL) and prevents TRAIL-induced apoptosis of myeloma cells. Whether or not osteoprotegerin can bind TRAIL and prevent apoptosis in vivo and the relative importance of osteoprotegerin binding to TRAIL and RANKL are unclear. In the present study, we have investigated the ability of an osteoprotegerin-like peptidomimetic (OP3-4), designed to block the RANKL/RANK interaction, to inhibit osteoclastic bone resorption and TRAIL-induced apoptosis in vitro and myeloma bone disease in vivo. OP3-4 inhibited osteoclast formation (P &amp;lt; 0.01) and bone resorption (P &amp;lt; 0.01) in vitro. However, OP3-4 had no effect on TRAIL-induced apoptosis of RPMI 8226 myeloma cells. Treatment of 5T2MM myeloma–bearing mice with OP3-4 decreased osteoclast number and the proportion of bone surface covered by osteoclasts (P &amp;lt; 0.05). Treatment also prevented the tumor-induced decrease in cancellous bone area and the development of osteolytic lesions (P &amp;lt; 0.05). OP3-4 also reduced tumor burden when compared with the control (P &amp;lt; 0.05). These data suggest that OP3-4 and the selective inhibition of RANKL, but not TRAIL activity, are effective in preventing myeloma bone disease and offer a novel therapeutic approach to treating this aspect of myeloma. [Cancer Res 2007;67(1):202–8]
Quantitative morphology and water distribution of bronchial biopsy samples.
Authors: D R Baldwin, R Wise, J M Andrews, D Honeybourne
Journal: Thorax (1992)

An approach to the study of the pharmacokinetics of drugs in the lung is to measure their concentrations in bronchial biopsy specimens. The main criticism of this technique is that bronchial biopsy specimens consist of more than one tissue type and that drugs are often not distributed evenly. The morphology of bronchial biopsy specimens and the distribution of water between the extracellular and the intracellular compartments is therefore important.Fifteen subjects undergoing fibreoptic bronchoscopy each had four bronchial biopsy samples taken. Thirty sections from 10 patients were examined and the proportion of tissue types noted, a morphometric analysis computer being used. The water distribution was investigated in the other biopsy specimens with radiolabelled markers.There was pronounced variation in the relative proportions of tissue types. Ciliated epithelium occupied a mean of 22.3% of the biopsy sample, submucosa 53.4%, muscle 17.6%, and glandular tissue 7.0%. There were no differences between second and the fourth generation subcarinae and macroscopic normality of the mucosa was a good predictor of histological normality. The extracellular water content was 40% of the total weight of the specimen and the total water content was 70%.These data provide the basis for pharmacokinetic study of drugs in bronchial mucosa. They show for pharmacokinetic study that macroscopically normal mucosa may be assumed to be histologically normal; that multiple biopsy specimens should be taken for any study, as there is considerable variation in the proportion of tissue types; that specimens from second and fourth generation subcarinae are the same; and that extracellular water contributes 40% to the total weight of the biopsy specimen.
High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells
Authors: Tomoko Hayashida, H. William Schnaper
Journal: Journal of the American Society of Nephrology (2004)

High ambient glucose activates intracellular signaling pathways to induce cytokines such as TGF-beta1 in the extracellular matrix accumulation of diabetic nephropathy. These same pathways also may directly modulate TGF-beta1 signaling. R-Smad phosphorylation, association with Smad4, and nuclear accumulation after TGF-beta1 treatment (1.0 ng/ml) were significantly higher in mesangial cells that were conditioned to 20 mM glucose for 72 h than mesangial cells in 6.5 mM glucose, suggesting that high glucose enhanced responsiveness to TGF-beta1. Neither TGF-beta1 bioactivity nor TGF-beta receptor binding was significantly different between in 6.5 and 20 mM glucose-conditioned cultures. Furthermore, adding a neutralizing anti-TGF-beta1 antibody during glucose conditioning did not affect the enhanced Smad responsiveness, indicating that enhancement likely did not result from increased TGF-beta expression. In contrast, a mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK inhibitor, PD98059, completely abrogated the effect of high glucose. Glucose stimulation of ERK was inhibited by the general protein kinase C (PKC) inhibitor calphostin C and by the PKCdelta-specific inhibitor rottlerin, whereas Gö6976, an inhibitor of conventional PKC, had no effect on ERK activity. Specificity of the PKC inhibitors was further verified by PKCbeta and delta kinase assay. High glucose increased expression of several PKC isozymes, but only PKCdelta showed proportionally increased membrane translocation and kinase activity in cells that were conditioned to 20 mM glucose. Finally, both ERK and PKCdelta inhibition during glucose conditioning abrogated enhanced alpha1(I) collagen mRNA and promoter induction by TGF-beta1. Taken together, these data strongly suggest that heightened ERK and PKCdelta activity in high ambient glucose conditions interact with the Smad pathway, leading to enhanced responsiveness to TGF-beta1 and increased extracellular matrix production in mesangial cells.
Chest Compression Fraction Determines Survival in Patients With Out-of-Hospital Ventricular Fibrillation
Authors: Jim Christenson, Douglas Andrusiek, Siobhan Everson-Stewart, Peter Kudenchuk, David Hostler, Judy Powell, Clifton W. Callaway, Dan Bishop, Christian Vaillancourt, Dan Davis, Tom P. Aufderheide, Ahamed Idris, John A. Stouffer, Ian Stiell, Robert Berg
Journal: Circulation (2009)

Quality cardiopulmonary resuscitation contributes to cardiac arrest survival. The proportion of time in which chest compressions are performed in each minute of cardiopulmonary resuscitation is an important modifiable aspect of quality cardiopulmonary resuscitation. We sought to estimate the effect of an increasing proportion of time spent performing chest compressions during cardiac arrest on survival to hospital discharge in patients with out-of-hospital ventricular fibrillation or pulseless ventricular tachycardia.
A single eubacterial origin of eukaryotic pyruvate: ferredoxin oxidoreductase genes: implications for the evolution of anaerobic eukaryotes
Authors: D. S. Horner, R. P. Hirt, T. M. Embley
Journal: Molecular Biology and Evolution (1999)

The iron sulfur protein pyruvate: ferredoxin oxidoreductase (PFO) is central to energy metabolism in amitochondriate eukaryotes, including those with hydrogenosomes. Thus, revealing the evolutionary history of PFO is critical to understanding the origin(s) of eukaryote anaerobic energy metabolism. We determined a complete PFO sequence for Spironucleus barkhanus, a large fragment of a PFO sequence from Clostridium pasteurianum, and a fragment of a new PFO from Giardia lamblia. Phylogenetic analyses of eubacterial and eukaryotic PFO genes suggest a complex history for PFO, including possible gene duplications and horizontal transfers among eubacteria. Our analyses favor a common origin for eukaryotic cytosolic and hydrogenosomal PFOs from a single eubacterial source, rather than from separate horizontal transfers as previously suggested. However, with the present sampling of genes and species, we were unable to infer a specific eubacterial sister group for eukaryotic PFO. Thus, we find no direct support for the published hypothesis that the donor of eukaryote PFO was the common alpha-proteobacterial ancestor of mitochondria and hydrogenosomes. We also report that several fungi and protists encode proteins with PFO domains that are likely monophyletic with PFOs from anaerobic protists. In Saccharomyces cerevisiae, PFO domains combine with fragments of other redox proteins to form fusion proteins which participate in methionine biosynthesis. Our results are consistent with the view that PFO, an enzyme previously considered to be specific to energy metabolism in amitochondriate protists, was present in the common ancestor of contemporary eukaryotes and was retained, wholly or in part, during the evolution of oxygen-dependent and mitochondrion-bearing lineages.
Approaches to uninvestigated dyspepsia
Authors: R H Jones
Journal: Gut (2002)

Uninvestigated dyspepsia refers to patients with new or recurrent dyspeptic symptoms in whom no investigations have previously been undertaken. These patients are much more likely to present in primary than in secondary care. It is particularly important to be able to offer effective symptom relief to support the explanation, reassurance, and advice provided to patients, and low dose or standard dose proton pump inhibitor therapy appears to offer the most effective approach to empirical therapy of this kind.
Hair keratin mutations in tooth enamel increase dental decay risk
Authors: Olivier Duverger, Takahiro Ohara, John R. Shaffer, Danielle Donahue, Patricia Zerfas, Andrew Dullnig, Christopher Crecelius, Elia Beniash, Mary L. Marazita, Maria I. Morasso
Journal: Journal of Clinical Investigation (2014)

Tooth enamel is the hardest substance in the human body and has a unique combination of hardness and fracture toughness that protects teeth from dental caries, the most common chronic disease worldwide. In addition to a high mineral content, tooth enamel comprises organic material that is important for mechanical performance and influences the initiation and progression of caries; however, the protein composition of tooth enamel has not been fully characterized. Here, we determined that epithelial hair keratins, which are crucial for maintaining the integrity of the sheaths that support the hair shaft, are expressed in the enamel organ and are essential organic components of mature enamel. Using genetic and intraoral examination data from 386 children and 706 adults, we found that individuals harboring known hair disorder–associated polymorphisms in the gene encoding keratin 75 (KRT75), KRT75A161T and KRT75E337K, are prone to increased dental caries. Analysis of teeth from individuals carrying the KRT75A161T variant revealed an altered enamel structure and a marked reduction of enamel hardness, suggesting that a functional keratin network is required for the mechanical stability of tooth enamel. Taken together, our results identify a genetic locus that influences enamel structure and establish a connection between hair disorders and susceptibility to dental caries.
Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci
Authors: Kerstin U Ludwig, Elisabeth Mangold, Stefan Herms, Stefanie Nowak, Heiko Reutter, Anna Paul, Jessica Becker, Ruth Herberz, Taofik AlChawa, Entessar Nasser, Anne C Böhmer, Manuel Mattheisen, Margrieta A Alblas, Sandra Barth, Nadine Kluck, Carola Lauster, Bert Braumann, Rudolf H Reich, Alexander Hemprich, Simone Pötzsch, Bettina Blaumeiser, Nikolaos Daratsianos, Thomas Kreusch, Jeffrey C Murray, Mary L Marazita, Ingo Ruczinski, Alan F Scott, Terri H Beaty, Franz-Josef Kramer, Thomas F Wienker, Regine P Steegers-Theunissen, Michele Rubini, Peter A Mossey, Per Hoffmann, Christoph Lange, Sven Cichon, Peter Propping, Michael Knapp, Markus M Nöthen
Journal: Nature Genetics (2012)
Regulation of sarcoplasmic reticulum Ca2+ ATPase pump expression and its relevance to cardiac muscle physiology and pathology
Authors: M. Periasamy, P. Bhupathy, G. J. Babu
Journal: Cardiovascular Research (2007)

Cardiac sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) plays a central role in myocardial contractility. SERCA2a actively transports Ca2+ into the SR and regulates cytosolic Ca2+ concentration, SR Ca2+ load, and the rate of contraction and relaxation of the heart. In the heart, SERCA pump activity is regulated by two small molecular weight proteins: phospholamban (PLB) and sarcolipin (SLN). Decreases in the expression levels of SERCA2a have been observed in a variety of pathological conditions. In addition, altered expression of PLB and SLN has been reported in many cardiac diseases. Thus, SERCA2a is a major regulator of intracellular Ca2+ homeostasis, and changes in the expression and activity of the SERCA pump contribute to the decreased SR Ca2+ content and cardiac dysfunction during pathogenesis. In this review, we discuss the mechanisms controlling SERCA pump expression and activity both during normal physiology and under pathological states.
The “Inverse Relationship Between Evolutionary Rate and Age of Mammalian Genes” Is an Artifact of Increased Genetic Distance with Rate of Evolution and Time of Divergence
Authors: Eran Elhaik, Niv Sabath, Dan Graur
Journal: Molecular Biology and Evolution (2005)

It has recently been claimed that older genes tend to evolve more slowly than newer ones (Alba and Castresana 2005). By simulation of genes of equal age, we show that the inverse correlation between age and rate is an artifact caused by our inability to detect homology when evolutionary distances are large. Since evolutionary distance increases with time of divergence and rate of evolution, homologs of fast-evolving genes are frequently undetected in distantly related taxa and are, hence, misclassified as "new." This misclassification causes the mean genetic distance of 'new' genes to be overestimated and the mean genetic distance of "old" genes to be underestimated.
Women's Mental Health Research: The Emergence of a Biomedical Field
Authors: Mary C. Blehar
Journal: Annual Review of Clinical Psychology (2006)

This review surveys the field of women's mental health, with particular emphasis on its evolution into a distinct area of biomedical research. The field employs a biomedical disease model but it also emphasizes social and cultural influences on health outcomes. In recent years, its scope has expanded beyond studies of disorders occurring in women at times of reproductive transitions and it now encompasses a broader study of sex and gender differences. Historical and conceptual influences on the field are discussed. The review also surveys gender differences in the prevalence and clinical manifestations of mental disorders. Epidemiological findings have provided a rich resource for theory development, but without research tools to test theories adequately, findings of gender differences have begged the question of their biological, social, and cultural origins. Clinical depression is used to exemplify the usefulness of a sex/gender perspective in understanding mental illness; and major theories proposed to account for gender differences are critically evaluated. The National Institutes of Health (NIH) is the primary federal funding source for biomedical women's mental health research. The review surveys areas of emphasis in women's mental health research at the NIH as well as some collaborative activities that represent efforts to translate research findings into the public health and services arenas. As new analytic methods become available, it is anticipated that a more fundamental understanding of the biological and behavioral mechanisms underlying sex and gender differences in mental illness will emerge. Nonetheless, it is also likely that integration of findings predicated on different conceptual models of the nature and causes of mental illness will remain a challenge. These issues are discussed with reference to their impact on the field of women's mental health research.