tbuckley/cabot-search huggingface dataset:
Evolution of RAG-1 in Polyploid Clawed Frogs
Authors: B. J. Evans
Journal: Molecular Biology and Evolution (2005)

Possible genetic fates of a gene duplicate are silencing, redundancy, subfunctionalization, or novel function. These different fates can be realized at the DNA, RNA, or protein level, and their genetic determinants are poorly understood. We explored molecular evolution of duplicated RAG-1 genes in African clawed frogs (Xenopus and Silurana) (1) to examine the fate of paralogs of this gene at the DNA level in terms of recombination, positive selection, and gene degeneration and in the absence of extensive recombination among alleles at different paralogs, (2) to test phylogenetic hypotheses about the origins of polyploid species. We found that recombination between different RAG-1 paralogs is infrequent, that degeneration of some paralogs has occurred via stop codons and frameshift mutations, and that this degeneration occurred in paralogs inherited from only one diploid progenitor species. Simulations and phylogenetic analyses of RAG-1 and mitochondrial DNA support one origin of extant tetraploids in Xenopus and at least one origin in Silurana, five allopolyploid origins of extant octoploids, and two allopolyploid origins of extant dodecaploids. In allopolyploid species, which inherit a complete genome from two different ancestors, genes inherited from the same ancestor have a longer period of coevolution than genes inherited from different ancestors. Because of this, gene ancestry could potentially influence gene fate: interacting paralogs derived from the same lower ploidy ancestor might have similar genetic destinies.
Cholesterol Policy and the Primary Prevention of Coronary Disease: Reflections on Clinical and Population Strategies
Authors: C D Naylor, J M Paterson
Journal: Annual Review of Nutrition (1996)

Despite billions of dollars spent on targeted and population-wide strategies aimed at reducing human consumption of saturated fat and cholesterol, aspects of the diet-heart connection remain a source of debate. At least part of the uncertainty arises from a growing appreciation that the relationship between dietary habits, serum lipids, and atherosclerosis is more complex than was previously thought. While we wait for answers from clinical and basic research, what is to be done? This review examines evidence about clinical policies and population strategies for the primary prevention of coronary disease, with specific reference to diet and dyslipidemias. It also summarizes some current policies and offers conclusions about broad directions for further policy development.
Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors
Authors: Michele De Palma, Mary Anna Venneri, Rossella Galli, Lucia Sergi Sergi, Letterio S. Politi, Maurilio Sampaolesi, Luigi Naldini
Journal: Cancer Cell (2005)
Some Implications of Population Control
Authors: A C Barnes
Journal: Annual Review of Medicine (1976)

Despite the growing awareness that unchecked population growth is 1 of mankind's most serious threats, all nations are still growing because of the sharp drop in the death rate. This is of special interest to the physician, largely the result of the implementation of medical knowledge and technology. A new approach is now necessary where family planning workers and the instillation of attitude changes will replace the traditional methods. The approach in China is unique, where enforcement and motivation come from the grass roots, the communes and work brigades. Investigation in contraceptive technology relating to the IUD, pill, and especially the release of steroids through silastics is being actively pursued. The objective, however, should not simply be greater efficacy but a method that will reach the uninformed and unmotivated.
Retinal Arteriolar Dilation Predicts Retinopathy in Adolescents With Type 1 Diabetes
Authors: Ning Cheung, Sophie L. Rogers, Kim C. Donaghue, Alicia J. Jenkins, Gabriella Tikellis, Tien Yin Wong
Journal: Diabetes Care (2008)

Alterations in retinal vascular caliber may reflect early subclinical microvascular dysfunction. In this study, we examined the association of retinal vascular caliber to incident retinopathy in young patients with type 1 diabetes.This was a prospective cohort study of 645 initially retinopathy-free type 1 diabetic patients, aged 12-20 years. Participants had seven-field stereoscopic retinal photographs taken of both eyes at baseline and follow-up. Retinal vascular caliber was measured from baseline photographs using a computer-based program following a standardized protocol. Incident retinopathy was graded according to the modified Airlie House classification from follow-up photographs.Over a median follow-up of 2.5 years, 274 participants developed retinopathy (14.8 per 100 person-years). After adjustments for age, sex, diabetes duration, glycemia, mean arterial blood pressure, BMI, and cholesterol levels, larger retinal arteriolar caliber (fourth versus first quartile) was associated with a more than threefold higher risk of retinopathy (hazard rate ratio 3.44 [95% CI 2.08-5.66]). Each SD increase in retinal arteriolar caliber was associated with a 46% increase in retinopathy risk (1.46 [1.22-1.74]). This association was stronger in female than in male participants. After similar adjustments, retinal venular caliber was not consistently associated with incident retinopathy.Retinal arteriolar dilatation predicts retinopathy development in young patients with type 1 diabetes. Our data suggest that arteriolar dysfunction may play a critical role in the pathogenesis of early diabetic retinopathy and that computer-based retinal vascular caliber measurements may provide additional prognostic information regarding risk of diabetes microvascular complications.
Enhanced Release of Prostaglandins Contributes to Flow-Induced Arteriolar Dilation in eNOS Knockout Mice
Authors: Dong Sun, An Huang, Carolyn J. Smith, Christopher J. Stackpole, Joseph A. Connetta, Edward G. Shesely, Akos Koller, Gabor Kaley
Journal: Circulation Research (1999)

Nitric oxide and prostaglandins were shown to contribute to the endothelial mediation of flow-induced dilation of skeletal muscle arterioles of rats. Thus, we hypothesized that flow-induced dilation and its mediation are altered in gracilis muscle arterioles of mice deficient in the gene for endothelial nitric oxide synthase (eNOS-KO) compared with control wild-type (WT) mice. Gracilis muscle arterioles ( approximately 80 micrometer) of male mice were isolated, then cannulated and pressurized in a vessel chamber. The increases in diameter elicited by increases in perfusate flow from 0 to 10 microq/min were similar in arterioles from eNOS-KO (n=28) and WT (n=22) mice ( approximately 20 micrometer at 10 microL/min flow). Removal of the endothelium eliminated flow-induced dilations in vessels of both strains of mice. N(omega)-nitro-L-arginine (L-NNA, 10(-4) mol/L) significantly inhibited flow-induced dilation in arterioles of WT mice by approximately 51% but had no effect on responses of arterioles from eNOS-KO mice. Indomethacin (INDO, 10(-5) mol/L) inhibited flow-induced dilation of WT mice by approximately 49%, whereas it completely abolished this response in arterioles of eNOS-KO mice. Simultaneous administration of INDO and L-NNA eliminated flow-induced responses in arterioles of WT mice. Dilations to carbaprostacyclin were similar at concentrations of 10(-8) and 3x10(-8) mol/L but decreased significantly at 10(-7) mol/L in arterioles of eNOS-KO compared with those of WT mice. These findings demonstrate that, despite the lack of nitric oxide mediation, flow-induced dilation is close to normal in arterioles of eNOS-KO mice because of an enhanced release of endothelial dilator prostaglandins and suggest that this vascular adaptation may contribute to the regulation of peripheral resistance in eNOS-KO mice.
Testing Spatiotemporal Hypothesis of Bacterial Evolution Using Methicillin-Resistant Staphylococcus aureus ST239 Genome-wide Data within a Bayesian Framework
Authors: R. R. Gray, A. J. Tatem, J. A. Johnson, A. V. Alekseyenko, O. G. Pybus, M. A. Suchard, M. Salemi
Journal: Molecular Biology and Evolution (2010)

Staphylococcus aureus is a common cause of infections that has undergone rapid global spread over recent decades. Formal phylogeographic methods have not yet been applied to the molecular epidemiology of bacterial pathogens because the limited genetic diversity of data sets based on individual genes usually results in poor phylogenetic resolution. Here, we investigated a whole-genome single nucleotide polymorphism (SNP) data set of health care-associated Methicillin-resistant S. aureus sequence type 239 (HA-MRSA ST239) strains, which we analyzed using Markov spatial models that incorporate geographical sampling distributions. The reconstructed timescale indicated a temporal origin of this strain shortly after the introduction of Methicillin, followed by global pandemic spread. The estimate of the temporal origin was robust to the molecular clock, coalescent prior, full/intergenic/synonymous SNP inclusion, and correction for excluded invariant site patterns. Finally, phylogeographic analyses statistically supported the role of human movement in the global dissemination of HA-MRSA ST239, although it was unable to conclusively resolve the location of the root. This study demonstrates that bacterial genomes can indeed contain sufficient evolutionary information to elucidate the temporal and spatial dynamics of transmission. Future applications of this approach to other bacterial strains may provide valuable epidemiological insights that may justify the cost of genome-wide typing.
Inhaled Fenoterol–Ipratropium Bromide in Mechanically Ventilated Patients with Chronic Obstructive Pulmonary Disease
Authors: CLAUDE GUERIN, ARNAUD CHEVRE, PIERRE DESSIRIER, THIERRY PONCET, MARIE-HELENE BECQUEMIN, PIERRE FRANÇOIS DEQUIN, CHANTAL LE GUELLEC, DIDIER JACQUES, GERARD FOURNIER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

In 18 patients with chronic obstructive pulmonary disease intubated and mechanically ventilated, we prospectively randomized 200 μ g fenoterol-80 μ g ipratropium bromide (four puffs) from a metered-dose inhaler (MDI) versus 1.25 mg fenoterol-500 μ g ipratropium bromide in 5 ml saline from a nebulizer (NEB). Respiratory mechanics were assessed before and 30 min after the end of each delivery by the rapid end-inspiratory airway occlusion technique. We did vary on single breaths the inflation flow (V˙) from 0.2 to 1.2 L · s− 1, at constant inflation volume. The total respiratory resistance of the respiratory system (Rrs) was partitioned into airway (Rint,rs) and tissue ( Δ Rrs) resistances. We found that Rrs was equivalently reduced, from 16.49 ± 1.37 to 14.85 ± 1.88 cm H2O · L− 1 · s with MDI (p < 0.05) and from 18.04 ± 1.85 to 15.15 ± 1.33 cm H2O · L− 1 · s with NEB (p < 0.01). Whereas the prevailing effect of MDI was to reduce Rint,rs, that of NEB was to decrease Δ Rrs. In addition, the V˙ resistance of the respiratory system over the whole range of V˙ was significantly affected by NEB but not by MDI.
Nuclear DNA content of isolated crypts of background colonic mucosa from patients with familial adenomatous polyposis and sporadic colorectal cancer.
Authors: S Nakamura, I Kino, S Baba
Journal: Gut (1993)

The DNA content of the upper one third of the crypt epithelium was compared with that of the lower two thirds in the background colorectal mucosa of eight cases of familial adenomatous polyposis (FAP) and eight control cases of sporadic colorectal cancer (SCRC). Intact crypts were isolated by incubating fresh lesion free colorectal mucosa in calcium and magnesium free Hanks9 balanced salt solution (CMFH) containing 30 mM EDTA for 30 minutes at 37 degrees C and then agitating in CMFH. The crypts were then separated from the lamina propria, fixed in 70% ethanol and under a dissecting microscope divided manually into upper and lower portions. Each portion was digested with pepsin to obtain a suspension of single nuclei, and smears of the nuclei were stained with 49,6,-diamidino-2-phenylindole dihydrochloride (DAPI). Nuclear DNA was determined using a cytophotometric microscope. Results showed that the DNA content of the epithelium of the upper one third of crypts was diploid in both FAP and SCRC cases, and that proliferative fractions with diploid peaks were present in the lower two thirds of the crypts in both groups. These results support our previous finding that the proliferative compartment of background crypts is confined to the lower two thirds and does not extend to the upper parts of the crypts.
Induction of a ragweed-specific allergic state in Ir-gene-restricted nonresponder mice.
Authors: N Chiorazzi, A S Tung, D H Katz
Journal: The Journal of Experimental Medicine (1977)

Mice of the inbred strains, C57BL/6 and C57BL/10 (H-2b), are genetically incapable of developing IgE antibody responses to ragweed pollen extract (RE) or its dinitrophenylated derivative, DNP-RE. This nonresponsiveness has previously been thought to reflect the absence of a relevant H-2-linked Ir genes controlling responses of inbred mice to these antigens. However, pretreatment of H-2b mice with either low doses of ionizing X irradiation or cyclophosphamide abrogates the nonresponder status of such animals, apparently by removal of a suppressive mechanism normally inhibiting development of IgE responses to these antigens. The implications of these findings for mechanisms of genetic control of IgE antibody synthesis and the Ir-gene concept are discussed.
Development of a Type 2 Diabetes Risk Model From a Panel of Serum Biomarkers From the Inter99 Cohort
Authors: Janice A. Kolberg, Torben Jørgensen, Robert W. Gerwien, Sarah Hamren, Michael P. McKenna, Edward Moler, Michael W. Rowe, Mickey S. Urdea, Xiaomei M. Xu, Torben Hansen, Oluf Pedersen, Knut Borch-Johnsen
Journal: Diabetes Care (2009)

The purpose of this study was to develop a model for assessing the 5-year risk of developing type 2 diabetes from a panel of 64 circulating candidate biomarkers.Subjects were selected from the Inter99 cohort, a longitudinal population-based study of approximately 6,600 Danes in a nested case-control design with the primary outcome of 5-year conversion to type 2 diabetes. Nondiabetic subjects, aged >or=39 years, with BMI >or=25 kg/m(2) at baseline were selected. Baseline fasting serum samples from 160 individuals who developed type 2 diabetes and from 472 who did not were tested. An ultrasensitive immunoassay was used to measure of 58 candidate biomarkers in multiple diabetes-associated pathways, along with six routine clinical variables. Statistical learning methods and permutation testing were used to select the most informative biomarkers. Risk model performance was estimated using a validated bootstrap bias-correction procedure.A model using six biomarkers (adiponectin, C-reactive protein, ferritin, interleukin-2 receptor A, glucose, and insulin) was developed for assessing an individual's 5-year risk of developing type 2 diabetes. This model has a bootstrap-estimated area under the curve of 0.76, which is greater than that for A1C, fasting plasma glucose, fasting serum insulin, BMI, sex-adjusted waist circumference, a model using fasting glucose and insulin, and a noninvasive clinical model.A model incorporating six circulating biomarkers provides an objective and quantitative estimate of the 5-year risk of developing type 2 diabetes, performs better than single risk indicators and a noninvasive clinical model, and provides better stratification than fasting plasma glucose alone.
Enhancement of cardiovascular effects of glucagon by aminophylline
Authors: S. AFONSO, C. E. HANSING, T. J. ANSFIELD, T. B. BERNDT, G. G. ROWE
Journal: Cardiovascular Research (1972)

Journal Article Enhancement of cardiovascular effects of glucagon by aminophylline Get access SKODA AFONSO, SKODA AFONSO From the Cardiovascular Research Laboratory, Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin 53706, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar CHARLES E. HANSING, CHARLES E. HANSING From the Cardiovascular Research Laboratory, Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin 53706, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar THOMAS J. ANSFIELD, THOMAS J. ANSFIELD From the Cardiovascular Research Laboratory, Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin 53706, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar THEODORE B. BERNDT, THEODORE B. BERNDT From the Cardiovascular Research Laboratory, Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin 53706, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar GEORGE G. ROWE GEORGE G. ROWE From the Cardiovascular Research Laboratory, Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin 53706, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 6, Issue 3, May 1972, Pages 235–239, https://doi.org/10.1093/cvr/6.3.235 Published: 01 May 1972
Local anaesthesia for pain control during outpatient hysteroscopy: systematic review and meta-analysis
Authors: N. A M Cooper, K. S Khan, T J. Clark
Journal: BMJ (2010)

<b>Objective</b> To compare the effects of different types of local anaesthetic for pain control during outpatient hysteroscopy. <b>Design</b> Systematic review and meta-analysis of randomised controlled trials. <b>Setting</b> Outpatient hysteroscopy clinics. <b>Participants</b> Women undergoing diagnostic or operative hysteroscopy as outpatients—that is, without general anaesthesia. <b>Study selection criteria</b> Medline, Embase, CINAHL, the Cochrane library, and reference lists of relevant studies. Two reviewers independently selected trials. Data were abstracted on quality, characteristics, and results. <b>Results</b> There were 20 trials (2851 participants). Data from 15 of these were meta-analysed in subgroups defined by type of intervention and study quality. Intracervical (standardised mean difference −0.36, 95% confidence interval −0.61 to −0.10, I<sup>2</sup>=0%) and paracervical (−1.28, −2.22 to −0.35, I<sup>2</sup>=97%) injections of local anaesthetic significantly reduced the pain in women undergoing hysteroscopy as outpatients, whereas transcervical (−0.11, −0.31 to 0.10, I<sup>2</sup>=27%) and topical application (−0.32, −0.97 to 0.33, I<sup>2</sup>= 90%) did not. Meta-regression showed that paracervical injection was superior to the other anaesthetic methods (P=0.04), a finding that was supported by the high quality subgroup of studies. Use of local anaesthetic did not have a significant effect on the incidence of vasovagal episodes (P=0.09). <b>Conclusions</b> Paracervical local anaesthetic injection is the best method of pain control for women undergoing hysteroscopy as outpatients.
Sphingolipid Mediators in Cardiovascular Cell Biology and Pathology
Authors: Thierry Levade, Nathalie Augé, Robert Jan Veldman, Olivier Cuvillier, Anne Nègre-Salvayre, Robert Salvayre
Journal: Circulation Research (2001)

Sphingolipids have emerged as a new class of lipid mediators. In response to various extracellular stimuli, sphingolipid turnover can be stimulated in vascular cells and cardiac myocytes. Subsequent generation of sphingolipid molecules such as ceramide, sphingosine, and sphingosine-1-phosphate, is followed by regulation of ion fluxes and activation of various signaling pathways leading to smooth muscle cell proliferation, endothelial cell differentiation or apoptotic cell death, cell contraction, retraction, or migration. The importance of sphingolipids in cardiovascular signaling is illustrated by recent observations implicating them in physiological processes such as vasculogenesis as well as in frequent pathological conditions, including atherosclerosis and its complications.
Disarmed anthrax toxin delivers antisense oligonucleotides and siRNA with high efficiency and low toxicity
Authors: Paul D.R. Dyer, Thomas R. Shepherd, Alexander S. Gollings, Susan A. Shorter, Monique A.M. Gorringe-Pattrick, Chun-Kit Tang, Beatrice N. Cattoz, Les Baillie, Peter C. Griffiths, Simon C.W. Richardson
Journal: Journal of Controlled Release (2015)

Inefficient cytosolic delivery and vector toxicity contribute to the limited use of antisense oligonucleotides (ASOs) and siRNA as therapeutics. As anthrax toxin (Atx) accesses the cytosol, the purpose of this study was to evaluate the potential of disarmed Atx to deliver either ASOs or siRNA. We hypothesized that this delivery strategy would facilitate improved transfection efficiency while eliminating the toxicity seen for many vectors due to membrane destabilization. Atx complex formation with ASOs or siRNA was achieved via the in-frame fusion of either Saccharomyces cerevisiae GAL4 or Homo sapien sapien PKR (respectively) to a truncation of Atx lethal factor (LFn), which were used with Atx protective antigen (PA). Western immunoblotting confirmed the production of: LFN-GAL4, LFn-PKR and PA which were detected at ~45.9 kDa, ~37 kDa, and ~83 kDa respectively and small angle neutron scattering confirmed the ability of PA to form an annular structure with a radius of gyration of 7.0 ± 1.0 nm when placed in serum. In order to form a complex with LFn-GAL4, ASOs were engineered to contain a double-stranded region, and a cell free in vitro translation assay demonstrated that no loss of antisense activity above 30 pmol ASO was evident. The in vitro toxicity of both PA:LFn-GAL4:ASO and PA:LFn-PKR:siRNA complexes was low (IC50>100 μg/mL in HeLa and Vero cells) and subcellular fractionation in conjunction with microscopy confirmed the detection of LFn-GAL4 or LFn-PKR in the cytosol. Syntaxin5 (Synt5) was used as a model target gene to determine pharmacological activity. The PA:LFn-GAL4:ASO complexes had transfection efficiency approximately equivalent to Nucleofection® over a variety of ASO concentrations (24h post-transfection) and during a 72 h time course. In HeLa cells, at 200 pmol ASO (with PA:LFN-GAL4), 5.4 ± 2.0% Synt5 expression was evident relative to an untreated control after 24h. Using 200 pmol ASOs, Nucleofection® reduced Synt5 expression to 8.1 ± 2.1% after 24h. PA:LFn-GAL4:ASO transfection of non- or terminally-differentiated THP-1 cells and Vero cells resulted in 35.2 ± 19.1%, 36.4 ± 1.8% and 22.9 ± 6.9% (respectively) Synt5 expression after treatment with 200 pmol of ASO and demonstrated versatility. Nucleofection® with Stealth RNAi™ siRNA reduced HeLa Synt5 levels to 4.6 ± 6.1% whereas treatment with the PA:LFn-PKR:siRNA resulted in 8.5 ± 3.4% Synt5 expression after 24h (HeLa cells). These studies report for the first time an ASO and RNAi delivery system based upon protein toxin architecture that is devoid of polycations. This system may utilize regulated membrane back-fusion for the cytosolic delivery of ASOs and siRNA, which would account for the lack of toxicity observed. High delivery efficiency suggests further in vivo evaluation is warranted.
Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial
Authors: Ian E Krop, Sung-Bae Kim, Antonio González-Martín, Patricia M LoRusso, Jean-Marc Ferrero, Melanie Smitt, Ron Yu, Abraham C F Leung, Hans Wildiers
Journal: The Lancet Oncology (2014)