tbuckley/cabot-search huggingface dataset:
Transforming Growth Factor-β Regulator SnoN Modulates Mammary Gland Branching Morphogenesis, Postlactational Involution, and Mammary Tumorigenesis
Authors: Nadine S. Jahchan, Young-Hyun You, William J. Muller, Kunxin Luo
Journal: Cancer Research (2010)

Abstract SnoN is an important negative regulator of transforming growth factor-β (TGF-β) signaling that was originally identified as a transforming oncogene in chicken embryonic fibroblasts. Both pro-oncogenic and antioncogenic activities of SnoN have been reported, but its function in normal epithelial cells has not been defined. In the mouse mammary gland, SnoN is expressed at relatively low levels, but it is transiently upregulated at late gestation before being downregulated during lactation and early involution. To assess the effects of elevated levels of SnoN, we generated transgenic mice expressing a SnoN fragment under the control of the mouse mammary tumor virus promoter. In this model system, SnoN elevation increased side-branching and lobular-alveolar proliferation in virgin glands, while accelerating involution in postlactation glands. Increased proliferation stimulated by SnoN was insufficient to induce mammary tumorigenesis. In contrast, elevated levels of SnoN cooperated with polyoma middle T antigen to accelerate the formation of aggressive multifocal adenocarcinomas and to increase the formation of pulmonary metastases. Our studies define functions of SnoN in mammary epithelial cell proliferation and involution, and provide the first in vivo evidence of a pro-oncogenic role for SnoN in mammalian tumorigenesis. Cancer Res; 70(10); 4204–13. ©2010 AACR.
Climate, traffic-related air pollutants and allergic rhinitis prevalence in middle-school children in Taiwan
Authors: Y-L. Lee, C-K. Shaw, H-J. Su, J-S. Lai, Y-C. Ko, S-L. Huang, F-C. Sung, Y.L. Guo
Journal: European Respiratory Journal (2003)

The prevalence of allergic rhinitis, a common respiratory disorder, may be rapidly increasing. Epidemiological studies, however, indicate little about its association with climatic factors and air pollution. The relationship between traffic-related air pollutants and allergic rhinitis in middle-school students was therefore investigated. In a nationwide survey of middle-school students in Taiwan conducted in 1995/1996, the lifetime prevalence of physician-diagnosed allergic rhinitis and typical symptoms of allergic rhinitis were compared with air-monitoring station data on temperature, relative humidity, sulphur dioxide (SO<sub>2</sub>), nitrogen oxides (NOx), ozone (O<sub>3</sub>), carbon monoxide (CO) and particulate matter with a 50% cut-off aerodynamic diameter of 10 µm (PM<sub>10</sub>). A total of 331,686 nonsmoking children attended schools located within 2 km of 55 stations. Mean (range) annual exposures were: CO 853 (381–1,610) parts per billion (ppb), NOx 35.1 (10.2–72.4) ppb, SO<sub>2</sub> 7.57 (0.88–21.2) ppb, PM<sub>10</sub> 69.2 (40.1–116.2) µg·m<sup>−3</sup>, O<sub>3</sub> 21.3 (12.4–34.1) ppb, temperature 22.9 (19.6–25.1)°C, and relative humidity 76.2 (64.8–86.2)%. The prevalence of physician-diagnosed allergic rhinitis was 28.6 and 19.5% in males and females, respectively, with prevalence of questionnaire-determined allergic rhinitis 42.4 and 34.0%. After adjustment for age, parental education and history of atopic eczema, physician-diagnosed allergic rhinitis was found to be associated with higher nonsummer (September–May) warmth and traffic-related air pollutants, including CO, NOx and O<sub>3</sub>. Questionnaire-determined allergic rhinitis correlated only with traffic-related air pollutants. Nonsummer warmth and traffic-related air pollution, probably mediated through exposure to common allergens such as dust mites, are possible risk factors for allergic rhinitis in middle-school-aged children.
SF-36 summary and subscale scores are reliable outcomes of neuropsychiatric events in systemic lupus erythematosus
Authors: J G Hanly, M B Urowitz, D Jackson, S C Bae, C Gordon, D J Wallace, A Clarke, S Bernatsky, A Vasudevan, D Isenberg, A Rahman, J Sanchez-Guerrero, J Romero-Diaz, J T Merrill, P R Fortin, D D Gladman, I N Bruce, K Steinsson, M Khamashta, G S Alarcón, B Fessler, M Petri, S Manzi, O Nived, G Sturfelt, R Ramsey-Goldman, M A Dooley, C Aranow, R Van Vollenhoven, M Ramos-Casals, A Zoma, K Kalunian, V Farewell
Journal: Annals of the Rheumatic Diseases (2011)

To examine change in health-related quality of life in association with clinical outcomes of neuropsychiatric events in systemic lupus erythematosus (SLE).
Reducing Emotional Distress Improves Prognosis in Coronary Heart Disease
Authors: Johan Denollet, Dirk L. Brutsaert
Journal: Circulation (2001)

The impact of treating emotional distress on prognosis in coronary heart disease (CHD) has not been documented convincingly. We tested the hypothesis that treatment-related changes in emotional distress may explain the beneficial effect of rehabilitation on prognosis.In this nonrandomized clinical trial, 150 men with CHD participated in rehabilitation (n=78) or received standard medical care (n=72). There were no differences between rehabilitation and control patients with regard to left ventricular ejection fraction (LVEF) or standard care. End points were reduction in distress after 3 months and mortality after 9 years. At the end of the 3-month trial, 64 patients (43%) reported improvement and 22 (15%) reported deterioration in negative affect. Rehabilitation patients improved more (P=0.004) and deteriorated less (P=0.001) than control patients; rehabilitation was effective in reducing distress. After 9 years of follow-up, 15 patients had died (13 cardiac and 2 cancer deaths). Mortality was associated with LVEF </=50% (P=0.038) and deterioration in negative affect (P=0.007). Rate of death was 17% (12/72) for control patients versus 4% (3/78) for rehabilitation patients (P=0.009); rehabilitation was effective in reducing mortality. LVEF </=50% (OR 3.2; 95% CI 1.1 to 9.8; P=0.041) and rehabilitation (OR 0.2; 95% CI 0.1 to 0.7; P=0.016) were independent predictors of mortality. Rehabilitation warded off the deleterious effect of deterioration in negative affect on prognosis.Deterioration in negative affect is associated with a high long-term mortality risk. Warding off deterioration in negative affect is a mechanism that may explain the beneficial effect of comprehensive rehabilitation on prognosis in patients with CHD.
HLA haplotypes in non-familial rheumatoid arthritis.
Authors: L Legrand, G M Lathrop, T Bardin, A Marcelli-Barge, A Dryll, N Debeyre, A Ryckewaert
Journal: Annals of the Rheumatic Diseases (1987)

The frequencies of HLA-A, B, C, DR, and BF haplotypes in 44 unrelated Caucasian patients with definite seropositive rheumatoid arthritis (RA) were compared with haplotype frequencies in controls. Overall, the patients had an increased risk for HLA-DR4, DR3, and DR2 antigens, but frequencies of certain DR4 or DR3 haplotypes were not increased, suggesting the importance of other HLA loci for the evaluation of risk. The presence of DR4 alone was not found to produce an increased risk for RA since the frequencies of certain DR4 haplotypes were similar in patients and controls. Increased frequencies of HLA-B18, DR4, HLA-B15, DR4, and HLA-A1, B8, Cw7, DR3 haplotypes were found in patients. RA susceptibility has been found to be associated with the last two haplotypes in some studies of multiple case families, suggesting that similar genetic mechanisms may underlie the disease in familial and sporadic forms.
A cloned Ca(2+)-sensing receptor
Authors: E M Brown, S C Hebert
Journal: Journal of the American Society of Nephrology (1995)

Changes in the extracellular calcium concentration [Ca2+]o modulate several aspects of renal function through unknown mechanism(s). cDNA encoding a Ca2+o-sensing receptor from bovine parathyroid and rat kidney that appears to mediate several of the known effects of Ca2+o on parathyroid and renal function were recently isolated. The expressed receptor activates phospholipase C, showing a pharmacologic profile very similar to that of the native receptor. Its deduced amino acid sequence identifies it as a member of the superfamily of G protein-coupled receptors. The physiologic relevance of the receptor has been established by the demonstration that mutations in it cause three inherited diseases of calcium metabolism. Two hypercalcemic disorders, familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, result from inactivating mutations when present in the heterozygous and homozygous states, respectively. An activating mutation, in contrast, causes an autosomal dominant form of hypocalcemia. In the kidney, the receptor is expressed most abundantly in the thick ascending limb, where it likely modulates sodium chloride, calcium, and magnesium reabsorption and, perhaps, urinary concentrating ability. Studies are currently underway to determine whether it also mediates the effects of Ca2+o on other parameters of kidney function, such as RBF, glomerular filtration, renin secretion, and vitamin D metabolism. Thus, this Ca2+o-sensing receptor permits extracellular calcium ions to act not only as an intracellular second messenger but also in a "hormone-like" role as an extracellular first messenger.
Group Occupational Health Service in a Developing Country
Authors: H. de Glanville
Journal: BMJ (1970)

In 1967 an experimental group occupational health service was set up in Dar es Salaam to provide direct service to industrial firms. Larger companies were visited by a doctor, smaller firms in rotation by auxiliaries. After three years 65 companies had joined with over 15,000 employees, and workers were attending the group dispensaries at a rate of over 250,000 visits a year. Such an approach through direct service to the working community appears to be more appropriate to a developing country than a purely advisory central occupational health unit.
Next generation sequence analysis for mitochondrial disorders
Authors: Valeria Vasta, Sarah B Ng, Emily H Turner, Jay Shendure, Si Houn Hahn
Journal: Genome Medicine (2009)

Mitochondrial disorders can originate from mutations in one of many nuclear genes controlling the organelle function or in the mitochondrial genome (mitochondrial DNA (mtDNA)). The large numbers of potential culprit genes, together with the little guidance offered by most clinical phenotypes as to which gene may be causative, are a great challenge for the molecular diagnosis of these disorders.We developed a novel targeted resequencing assay for mitochondrial disorders relying on microarray-based hybrid capture coupled to next-generation sequencing. Specifically, we subjected the entire mtDNA genome and the exons and intron-exon boundary regions of 362 known or candidate causative nuclear genes to targeted capture and resequencing. We here provide proof-of-concept data by testing one HapMap DNA sample and two positive control samples.Over 94% of the targeted regions were captured and sequenced with appropriate coverage and quality, allowing reliable variant calling. Pathogenic mutations blindly tested in patients' samples were 100% concordant with previous Sanger sequencing results: a known mutation in Pyruvate dehydrogenase alpha 1 subunit (PDHA1), a novel splicing and a known coding mutation in Hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA) were correctly identified. Of the additional variants recognized, 90 to 94% were present in dbSNP while 6 to 10% represented new alterations. The novel nonsynonymous variants were all in heterozygote state and mostly predicted to be benign. The depth of sequencing coverage of mtDNA was extremely high, suggesting that it may be feasible to detect pathogenic mtDNA mutations confounded by low level heteroplasmy. Only one sequencing lane of an eight lane flow cell was utilized for each sample, indicating that a cost-effective clinical test can be achieved.Our study indicates that the use of next generation sequencing technology holds great promise as a tool for screening mitochondrial disorders. The availability of a comprehensive molecular diagnostic tool will increase the capacity for early and rapid identification of mitochondrial disorders. In addition, the proposed approach has the potential to identify new mutations in candidate genes, expanding and redefining the spectrum of causative genes responsible for mitochondrial disorders.
Lung function of school children with low levels of 1-antitrypsin and tobacco smoke exposure
Authors: O.S. von Ehrenstein, E. von Mutius, E. Maier, T. Hirsch, D. Carr, W. Schaal, A.A. Roscher, B. Olgemoller, T. Nicolai, S.K. Weiland
Journal: European Respiratory Journal (2002)

Exposure to environmental tobacco smoke (ETS) and other air pollutants has been associated with small decrements in lung function. The susceptibility to pollution exposure may, however, vary substantially between individuals. Children with an impaired protease-antiprotease balance may be particularly vulnerable. Therefore this study aimed to investigate the effects of ETS exposure on children with reduced levels of α<sub>1</sub>-antitrypsin (α<sub>1</sub>-AT). Random samples of school children (aged 9–11 yrs) (n=3,526) were studied according to the International Study of Asthma and Allergies in Childhood (ISAAC) phase II protocol, including parental questionnaires, pulmonary function and allergy testing. Blood samples were obtained to measure plasma levels of α<sub>1</sub>-AT and to genotype for pleomorphic protein inhibitor (Pi)Z and PiS alleles. Children with low levels of α<sub>1</sub>-AT (≤116 mg·dL<sup>−1</sup>) showed significant, albeit small decrements in baseline lung function. When exposed to ETS, pronounced decrements of pulmonary function, particularly in measures of mid- to end-expiratory flow rates, were seen in these children as compared to exposed children with normal levels of α<sub>1</sub>-AT. The mean levels of % predicted±se in both groups were: maximum expiratory flow at 50% of vital capacity 79.4±7.2 <i>versus</i> 99.0±1.5, maximum expiratory flow at 25% of vital capacity 67.4±10.0 <i>versus</i> 100.3±2.1, maximal midexpiratory flow 73.7±8.6 <i>versus</i> 99.9±1.7. These findings suggest that school children with low levels of α<sub>1</sub>-antitrypsin are at risk of developing pronounced decrements in pulmonary function, particularly if they are exposed to environmental tobacco smoke. Parents of children with heterozygous α<sub>1</sub>-antitrypsin deficiency resulting in significantly reduced blood concentrations should be advised to prevent their children from being exposed to environmental tobacco smoke and dissuade them from taking up smoking.
High recombination rates and hotspots in a Plasmodium falciparum genetic cross
Authors: Hongying Jiang, Na Li, Vivek Gopalan, Martine M Zilversmit, Sudhir Varma, Vijayaraj Nagarajan, Jian Li, Jianbing Mu, Karen Hayton, Bruce Henschen, Ming Yi, Robert Stephens, Gilean McVean, Philip Awadalla, Thomas E Wellems, Xin-zhuan Su
Journal: Genome biology (2011)

The human malaria parasite Plasmodium falciparum survives pressures from the host immune system and antimalarial drugs by modifying its genome. Genetic recombination and nucleotide substitution are the two major mechanisms that the parasite employs to generate genome diversity. A better understanding of these mechanisms may provide important information for studying parasite evolution, immune evasion and drug resistance. Here, we used a high-density tiling array to estimate the genetic recombination rate among 32 progeny of a P. falciparum genetic cross (7G8 × GB4). We detected 638 recombination events and constructed a high-resolution genetic map. Comparing genetic and physical maps, we obtained an overall recombination rate of 9.6 kb per centimorgan and identified 54 candidate recombination hotspots. Similar to centromeres in other organisms, the sequences of P. falciparum centromeres are found in chromosome regions largely devoid of recombination activity. Motifs enriched in hotspots were also identified, including a 12-bp G/C-rich motif with 3-bp periodicity that may interact with a protein containing 11 predicted zinc finger arrays. These results show that the P. falciparum genome has a high recombination rate, although it also follows the overall rule of meiosis in eukaryotes with an average of approximately one crossover per chromosome per meiosis. GC-rich repetitive motifs identified in the hotspot sequences may play a role in the high recombination rate observed. The lack of recombination activity in centromeric regions is consistent with the observations of reduced recombination near the centromeres of other organisms.
The Anesthetic Hazards in Patients on Antihypertensive Therapy
Authors: D. LeRoy Crandell
Journal: JAMA (1962)

Antihypertensive drugs interfere with hemodynamic adjustments and can cause profound cardiovascular collapse when a patient is subjected to the stress of anesthesia and surgery. They constitute an insidious hazard to surgical patients. In patients who have received antihypertensive medication the primary problem is to determine the availability of the intrinsic catechol amines and the patient's ability to respond to them. This problem is solved by using the ephedrine response test (ERT). The test consists of 2 intravenous injections of ephedrine; the first injection of 10 mg. is followed promptly by additional 5 mg. If the ERT does not elicit a rise of at least 20 mm. Hg in blood pressure, the patient is believed to be unprepared for the cardiovascular stress of general, spinal, or spidural anesthesia.
Chemokine Receptor CXCR3 Mediates T Cell Recruitment and Tissue Injury in Nephrotoxic Nephritis in Mice
Authors: Ulf Panzer, Oliver M. Steinmetz, Hans-Joachim Paust, Catherine Meyer-Schwesinger, Anett Peters, Jan-Eric Turner, Gunther Zahner, Felix Heymann, Christian Kurts, Helmut Hopfer, Udo Helmchen, Friedrich Haag, André Schneider, Rolf A.K. Stahl
Journal: Journal of the American Society of Nephrology (2007)

The chemokine receptor CXCR3 is highly expressed on Th1 polarized T cells and has been predicted to play an important role in T cell recruitment and immune response in a number of inflammatory and autoimmune diseases. For testing whether CXCR3 plays a role in renal inflammation, CXCR3-deficient mice were generated and nephrotoxic nephritis was induced in C57BL/6 CXCR3−/− and C57BL/6 wild-type mice. Induction of the nephrotoxic nephritis leads to an increased renal mRNA expression of IP-10/CXCL10 (8.6-fold), Mig/CXCL9 (2.3-fold), and I-TAC/CXCL11 (4.9-fold) during the autologous phase at days 7 and 14. This increased chemokine expression was paralleled by the renal infiltration of T cells, followed by renal tissue injury, albuminuria, and loss of renal function. Compared with wild-type mice, CXCR3-deficient mice had significantly reduced renal T cell infiltrates. Moreover, CXCR3−/− mice developed less severe nephritis, with significantly lower albuminuria, better renal function, and a reduced frequency of glomerular crescent formation. Nephritic wild-type and CXCR3−/− mice both elicited an efficient systemic nephritogenic immune response in terms of antigen-specific IgG production and IFN-γ expression by splenocytes in response to the nephritogenic antigen. These findings indicate that the ameliorated nephritis in CXCR3-deficient mice is due to impaired renal trafficking of effector T cells rather than their inability to mount an efficient humoral or cellular immune response. The neutralization of CXCR3 might be a promising therapeutic strategy for Th1-dependent inflammatory renal disease.
Experimental characterization of the human non-sequence-specific nucleic acid interactome
Authors: Gerhard Dürnberger, Tilmann Bürckstümmer, Kilian Huber, Roberto Giambruno, Tobias Doerks, Evren Karayel, Thomas R Burkard, Ines Kaupe, André C Müller, Andreas Schönegger, Gerhard F Ecker, Hans Lohninger, Peer Bork, Keiryn L Bennett, Giulio Superti-Furga, Jacques Colinge
Journal: Genome biology (2013)

Abstract Background The interactions between proteins and nucleic acids have a fundamental function in many biological processes, including gene transcription, RNA homeostasis, protein translation and pathogen sensing for innate immunity. While our knowledge of the ensemble of proteins that bind individual mRNAs in mammalian cells has been greatly augmented by recent surveys, no systematic study on the non-sequence-specific engagement of native human proteins with various types of nucleic acids has been reported. Results We designed an experimental approach to achieve broad coverage of the non-sequence-specific RNA and DNA binding space, including methylated cytosine, and tested for interaction potential with the human proteome. We used 25 rationally designed nucleic acid probes in an affinity purification mass spectrometry and bioinformatics workflow to identify proteins from whole cell extracts of three different human cell lines. The proteins were profiled for their binding preferences to the different general types of nucleic acids. The study identified 746 high-confidence direct binders, 139 of which were novel and 237 devoid of previous experimental evidence. We could assign specific affinities for sub-types of nucleic acid probes to 219 distinct proteins and individual domains. The evolutionarily conserved protein YB-1, previously associated with cancer and drug resistance, was shown to bind methylated cytosine preferentially, potentially conferring upon YB-1 an epigenetics-related function. Conclusions The dataset described here represents a rich resource of experimentally determined nucleic acid-binding proteins, and our methodology has great potential for further exploration of the interface between the protein and nucleic acid realms.
Second‐phase hepatitis C virus RNA decline during telaprevir‐based therapy increases with drug effectiveness: Implications for treatment duration
Authors: Jeremie Guedj, Alan S. Perelson
Journal: Hepatology (2011)

Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase, followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase of decay to treatment effectiveness, whereas the second phase of decay is attributed to the progressive loss of infected cells. Here, we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found the second-phase slope of viral decline to be strongly correlated with treatment effectiveness and to be roughly four-fold more rapid than has been reported with interferon-based therapies. Because telaprevir is not known to increase the death rate of infected cells, our results suggest that the second-phase slope of viral decline is driven not only by the death of infected cells, but may also involve other mechanisms, such as a treatment-effectiveness-dependent degradation of intracellular viral RNA. As a result of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended.
Association of Nut Consumption with Total and Cause-Specific Mortality
Authors: Ying Bao, Jiali Han, Frank B. Hu, Edward L. Giovannucci, Meir J. Stampfer, Walter C. Willett, Charles S. Fuchs
Journal: New England Journal of Medicine (2013)

Increased nut consumption has been associated with a reduced risk of major chronic diseases, including cardiovascular disease and type 2 diabetes mellitus. However, the association between nut consumption and mortality remains unclear.