tbuckley/cabot-search huggingface dataset:
Comparative genomics of the pathogenic ciliate Ichthyophthirius multifiliis, its free-living relatives and a host species provide insights into adoption of a parasitic lifestyle and prospects for disease control
Authors: Robert S Coyne, Linda Hannick, Dhanasekaran Shanmugam, Jessica B Hostetler, Daniel Brami, Vinita S Joardar, Justin Johnson, Diana Radune, Irtisha Singh, Jonathan H Badger, Ujjwal Kumar, Milton Saier, Yufeng Wang, Hong Cai, Jianying Gu, Michael W Mather, Akhil B Vaidya, David E Wilkes, Vidyalakshmi Rajagopalan, David J Asai, Chad G Pearson, Robert C Findly, Harry W Dickerson, Martin Wu, Cindy Martens, Yves Van de Peer, David S Roos, Donna M Cassidy-Hanley, Theodore G Clark
Journal: Genome biology (2011)

Abstract Background Ichthyophthirius multifiliis , commonly known as Ich, is a highly pathogenic ciliate responsible for 'white spot', a disease causing significant economic losses to the global aquaculture industry. Options for disease control are extremely limited, and Ich's obligate parasitic lifestyle makes experimental studies challenging. Unlike most well-studied protozoan parasites, Ich belongs to a phylum composed primarily of free-living members. Indeed, it is closely related to the model organism Tetrahymena thermophila . Genomic studies represent a promising strategy to reduce the impact of this disease and to understand the evolutionary transition to parasitism. Results We report the sequencing, assembly and annotation of the Ich macronuclear genome. Compared with its free-living relative T. thermophila , the Ich genome is reduced approximately two-fold in length and gene density and three-fold in gene content. We analyzed in detail several gene classes with diverse functions in behavior, cellular function and host immunogenicity, including protein kinases, membrane transporters, proteases, surface antigens and cytoskeletal components and regulators. We also mapped by orthology Ich's metabolic pathways in comparison with other ciliates and a potential host organism, the zebrafish Danio rerio . Conclusions Knowledge of the complete protein-coding and metabolic potential of Ich opens avenues for rational testing of therapeutic drugs that target functions essential to this parasite but not to its fish hosts. Also, a catalog of surface protein-encoding genes will facilitate development of more effective vaccines. The potential to use T. thermophila as a surrogate model offers promise toward controlling 'white spot' disease and understanding the adaptation to a parasitic lifestyle.
Complement Factor H Polymorphism, Complement Activators, and Risk of Age-Related Macular Degeneration
Authors: Dominiek D. G. Despriet, Caroline C. W. Klaver, Jacqueline C. M. Witteman, Arthur A. B. Bergen, Isabella Kardys, Moniek P. M. de Maat, Sharmila S. Boekhoorn, Johannes R. Vingerling, Albert Hofman, Ben A. Oostra, André G. Uitterlinden, Theo Stijnen, Cornelia M. van Duijn, Paulus T. V. M. de Jong
Journal: JAMA (2006)

The evidence that inflammation is an important pathway in age-related macular degeneration (AMD) is growing. Recent case-control studies demonstrated an association between the complement factor H (CFH) gene, a regulator of complement, and AMD.To assess the associations between the CFH gene and AMD in the general population and to investigate the modifying effect of smoking, serum inflammatory markers, and genetic variation of C-reactive protein (CRP).Population-based, prospective cohort study of individuals aged 55 years or older (enrollment between March 20, 1990, and July 31, 1993, and 3 follow-up examinations that were performed between September 1, 1993, and December 31, 2004) in Rotterdam, the Netherlands. The CFH Y402H polymorphism was determined in a total of 5681 individuals. Information on smoking, erythrocyte sedimentation rate, CRP serum levels, and haplotypes of the CRP gene were assessed at baseline.All severity stages of prevalent and incident AMD, graded according to the international classification and grading system for AMD.The frequency of CFH Y402H was 36.2% (4116/11,362 alleles). At baseline, there were 2062 persons (36.3%) with any type of AMD (prevalent cases), including 78 (1.4%) with late AMD (stage 4). During follow-up (mean, 8 years; median, 10 years), 1649 (35.5%) of 4642 participants progressed to a higher stage of AMD (incident cases), including 93 (5.6%) who developed late AMD. The odds ratio (OR) of AMD increased in an allele-dose manner with 2.00 (95% confidence interval [CI], 1.56-2.55) for stage 2 AMD, 4.58 (95% CI, 2.82-7.44) for stage 3 AMD, and 11.02 (95% CI, 6.82-11.81) for stage 4 (late, vision threatening) AMD for homozygous persons. Cumulative risks calculated by Kaplan-Meier analysis of late AMD by age 95 years were 48.3% for homozygotes, 42.6% for heterozygotes, and 21.9% for noncarriers. The population-attributable risk for CFH Y402H was 54.0%. Elevated erythrocyte sedimentation rates further increased the OR to 20.2 (95% CI, 9.5-43.0), elevated serum CRP levels to 27.7 (95% CI, 10.7-72.0), and smoking to 34.0 (95% CI, 13.0-88.6) for homozygotes compared with noncarriers without these determinants. The CRP haplotypes conferring high levels of CRP significantly increased the effect of CFH Y402H (P<.01).The CFH Y402H polymorphism may account for a substantial proportion of AMD in individuals similar to those in the Rotterdam Study and may confer particular risk in the presence of environmental and genetic stimulators of the complement cascade.
Clinical Sports Medicine
Authors: R. G. Hackney
Journal: British Journal of Sports Medicine (1993)

This volume is another comprehensive and authoritative publication for the Encyclopaedia of Sports Medicine, the result of collaboration between the IOC Medical Commission and the International Federation of Sports Medicine.The editors present a well organized total of 57 contributions, grouped into seven different sections, covering many aspects of aerobic endurance and its application to sport.The first section contains semantic and physiological definitions and notes that the lengths both of competition and of training determine whether an event can be classified as 'endurance'.The second section, entitled 'General Scientific Considerations' consists of . . .
DNAzyme-mediated Inhibition of Japanese Encephalitis Virus Replication in Mouse Brain
Authors: Mohan Babu Appaiahgari, Sudhanshu Vrati
Journal: Molecular Therapy (2007)

Japanese encephalitis virus (JEV) is an arthropod-borne flavivirus with a single-stranded RNA genome containing non-coding regions (NCRs) at its 5′ and 3′-ends. The NCRs have flavivirus-conserved sequences that are important for virus replication. Here we describe DNAzymes (Dzs) that cleave the RNA sequence of the 3′-NCR of JEV genome in vitro. The nuclease-resistant Dzs, containing phosphorothioate linkages, were efficiently taken up by mouse neuronal and glial cells, and addition of a continuous stretch of 10 guanosine residues (poly-(G)10) to the 3′-end of a Dz led to its enhanced delivery to cells containing scavenger receptors (ScRs). These novel Dzs inhibited JEV replication in cultured mouse cells of neuronal and macrophage origin. JEV is a neurotropic virus that actively replicates in mouse brain. Here we show that intra-cerebral (i.c.) administration of a poly-(G)10-tethered, phosphorothioated Dz in JEV-infected mice led to more than 99.99% inhibition of virus replication in brain, resulting in a dose-dependent extended lifespan or complete recovery of the infected animals. This is the first report of in vivo application of a Dz to control a virus infection in an animal model. Japanese encephalitis virus (JEV) is an arthropod-borne flavivirus with a single-stranded RNA genome containing non-coding regions (NCRs) at its 5′ and 3′-ends. The NCRs have flavivirus-conserved sequences that are important for virus replication. Here we describe DNAzymes (Dzs) that cleave the RNA sequence of the 3′-NCR of JEV genome in vitro. The nuclease-resistant Dzs, containing phosphorothioate linkages, were efficiently taken up by mouse neuronal and glial cells, and addition of a continuous stretch of 10 guanosine residues (poly-(G)10) to the 3′-end of a Dz led to its enhanced delivery to cells containing scavenger receptors (ScRs). These novel Dzs inhibited JEV replication in cultured mouse cells of neuronal and macrophage origin. JEV is a neurotropic virus that actively replicates in mouse brain. Here we show that intra-cerebral (i.c.) administration of a poly-(G)10-tethered, phosphorothioated Dz in JEV-infected mice led to more than 99.99% inhibition of virus replication in brain, resulting in a dose-dependent extended lifespan or complete recovery of the infected animals. This is the first report of in vivo application of a Dz to control a virus infection in an animal model.
Transforming Growth Factor-β as a Therapeutic Target in Hepatocellular Carcinoma
Authors: Gianluigi Giannelli, Erica Villa, Michael Lahn
Journal: Cancer Research (2014)

Abstract Hepatocellular carcinoma arises in patients as a consequence of long-standing preexisting liver illnesses, including viral hepatitis, alcohol abuse, or metabolic disease. In such preexisting liver diseases, TGF-β plays an important role in orchestrating a favorable microenvironment for tumor cell growth and promoting epithelial–mesenchymal transition (EMT). TGF-β signaling promotes hepatocellular carcinoma progression by two mechanisms: first, via an intrinsic activity as an autocrine or paracrine growth factor and, second, via an extrinsic activity by inducing microenvironment changes, including cancer-associated fibroblasts, T regulatory cells, and inflammatory mediators. Although there is an increasing understanding on how TGF-β signaling is associated with tumor progression in hepatocellular carcinoma, it is not clear whether TGF-β signaling is limited to a certain subgroup of patients with hepatocellular carcinoma or is a key driver of hepatocellular carcinoma during the entire tumorigenesis of hepatocellular carcinoma. Inhibitors of the TGF-β signaling have been shown to block hepatocellular carcinoma growth and progression by modulating EMT in different experimental models, leading to the clinical investigation of the TGF-β inhibitor LY2157299 monohydrate in hepatocellular carcinoma. Preliminary results from a phase II clinical trial have shown improved clinical outcome and also changes consistent with a reduction of EMT. Cancer Res; 74(7); 1890–4. ©2014 AACR.
Contribution of Monocytes/Macrophages to Compensatory Neovascularization
Authors: Nicanor I. Moldovan, Pascal J. Goldschmidt-Clermont, Jan Parker-Thornburg, Steven D. Shapiro, Pappachan E. Kolattukudy
Journal: Circulation Research (2000)

Abstract —In a transgenic model of ischemic cardiomyopathy in which monocytes are attracted to the myocardium by the targeted overexpression of monocyte chemoattractant protein-1 (MCP-1), we have observed the presence of endothelial NO synthase and platelet endothelial cell adhesion molecule-1–negative tunnels, occasionally containing blood-derived cells, that probe the cardiac tissue. Immunohistochemical data show that monocytes/macrophages (MCs/Mphs) drill tunnels using the broad-spectrum mouse macrophage metalloelastase. 5-Bromo-2′-deoxyuridine incorporation and neo-endothelial markers present in the microvasculature of MCP-1 mouse hearts suggest an active angiogenic process. Further studies will be required to establish that the MC-/Mph-drilled tunnels evolve to become capillaries, connected to the existing vessels and colonized by circulating endothelial cell progenitors. This possibility is supported by the availability of these cells, which is demonstrated by cell tagging with β-galactosidase placed under an active endothelial Tie-2 promoter. This phenomenon might represent another mechanism, in addition to the secretion of the angiogenic factors, by which MCs/MPhs may participate in the elaboration of new blood vessels in adult tissues.
JunD protects against chronic kidney disease by regulating paracrine mitogens
Authors: Evangéline Pillebout, Jonathan B. Weitzman, Martine Burtin, Carla Martino, Pierre Federici, Moshe Yaniv, Gérard Friedlander, Fabiola Terzi
Journal: Journal of Clinical Investigation (2003)

The AP-1 transcription factor, composed of Jun and Fos proteins, plays a crucial role in the fine tuning of cell proliferation. We showed previously that AP-1 complexes are activated during the proliferative response that parallels the development of renal lesions after nephron reduction, but little is known about the specific role of individual Jun/Fos components in the deterioration process. Here we used JunD knockout (JunD-/-) mice and an experimental model of chronic renal injury (75% nephron reduction) to explore the role of JunD. Nephron reduction resulted in an initial compensatory growth phase that did not require JunD. JunD, however, was essential to inhibit a second wave of cell proliferation and to halt the development of severe glomerular sclerosis, tubular dilation, and interstitial fibrosis. We show that the effects of junD inactivation are not cell autonomous and involve upregulation of the paracrine mitogen, TGF-alpha. Expression of a transgene (REM) encoding a dominant negative isoform of the EGFR, the receptor for TGF-alpha, prevented the second wave of cell proliferation and the development of renal lesions in bitransgenic JunD-/-/REM mice. We propose that JunD is part of a regulatory network that controls proliferation to prevent pathological progression in chronic renal diseases.
Water Supply Interruptions and Suspected Cholera Incidence: A Time-Series Regression in the Democratic Republic of the Congo
Authors: Aurélie Jeandron, Jaime Mufitini Saidi, Alois Kapama, Manu Burhole, Freddy Birembano, Thierry Vandevelde, Antonio Gasparrini, Ben Armstrong, Sandy Cairncross, Jeroen H. J. Ensink
Journal: PLoS Medicine (2015)

Background The eastern provinces of the Democratic Republic of the Congo have been identified as endemic areas for cholera transmission, and despite continuous control efforts, they continue to experience regular cholera outbreaks that occasionally spread to the rest of the country. In a region where access to improved water sources is particularly poor, the question of which improvements in water access should be prioritized to address cholera transmission remains unresolved. This study aimed at investigating the temporal association between water supply interruptions and Cholera Treatment Centre (CTC) admissions in a medium-sized town. Methods and Findings Time-series patterns of daily incidence of suspected cholera cases admitted to the Cholera Treatment Centre in Uvira in South Kivu Province between 2009 and 2014 were examined in relation to the daily variations in volume of water supplied by the town water treatment plant. Quasi-poisson regression and distributed lag nonlinear models up to 12 d were used, adjusting for daily precipitation rates, day of the week, and seasonal variations. A total of 5,745 patients over 5 y of age with acute watery diarrhoea symptoms were admitted to the CTC over the study period of 1,946 d. Following a day without tap water supply, the suspected cholera incidence rate increased on average by 155% over the next 12 d, corresponding to a rate ratio of 2.55 (95% CI: 1.54–4.24), compared to the incidence experienced after a day with optimal production (defined as the 95th percentile—4,794 m3). Suspected cholera cases attributable to a suboptimal tap water supply reached 23.2% of total admissions (95% CI 11.4%–33.2%). Although generally reporting less admissions to the CTC, neighbourhoods with a higher consumption of tap water were more affected by water supply interruptions, with a rate ratio of 3.71 (95% CI: 1.91–7.20) and an attributable fraction of cases of 31.4% (95% CI: 17.3%–42.5%). The analysis did not suggest any association between levels of residual chlorine in the water fed to the distribution network and suspected cholera incidence. Laboratory confirmation of cholera was not available for this analysis. Conclusions A clear association is observed between reduced availability of tap water and increased incidence of suspected cholera in the entire town of Uvira in Eastern Democratic Republic of the Congo. Even though access to piped water supplies is low in Uvira, improving the reliability of tap water supply may substantially reduce the incidence of suspected cholera, in particular in neighbourhoods having a higher access to tap water. These results argue in favour of water supply investments that focus on the delivery of a reliable and sustainable water supply, and not only on point-of-use water quality improvements, as is often seen during cholera outbreaks.
Sympathectomy for Raynaud's Phenomenon
Authors: RAY W. GIFFORD, EDGAR A. HINES, WINCHELL MCK. CRAIG
Journal: Circulation (1958)

Follow-up information has been obtained from 70 women with Raynaud's disease and 54 women with secondary Raynaud's phenomenon who were subjected to surgical sympathetic denervation of one extremity or more. The results of sympathectomy in the upper and lower extremities are described. The effect of operation on the subsequent course, the complications and sequelae are presented and compared with the reports of others.
Solid lipid dispersion of calcitriol with enhanced dissolution and stability
Authors: Ting Yuan, Lingzhen Qin, Zhouhua Wang, Jinyuan Nie, Zhefei Guo, Ge Li, Chuanbin Wu
Journal: Asian Journal of Pharmaceutical Sciences (2013)

Solid dispersion of calcitriol with lipophilic surfactants and triglycerides was developed by melt-mixing method to modify the release and enhance stability of the drug. The solid dispersions were characterized by differential scanning calorimetry (DSC), hot stage polarized optical microscopy (HSPM), infrared spectroscopy (FTIR) and stability studies. The solid dispersion significantly enhanced the stability of calcitriol, which could be attributed to the high antioxidant activity of the solid lipid dispersion. The rapid dissolution rate from the solid dispersion was attributed to the amorphous or solid solution state of drug with improved specific surface area and wettability than the drug crystals. Therefore, solid dispersion of calcitriol with d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) offers a good approach to modify the release and enhance stability of calcitriol. The influence of lipophilic solid dispersion on drug bioavailability needs further investigation.
The proinflammatory mediator macrophage migration inhibitory factor induces glucose catabolism in muscle
Authors: Fabio Benigni, Toshiya Atsumi, Thierry Calandra, Christine Metz, Bernd Echtenacher, Tina Peng, Richard Bucala
Journal: Journal of Clinical Investigation (2000)

Severe infection or tissue invasion can provoke a catabolic response, leading to severe metabolic derangement, cachexia, and even death. Macrophage migration inhibitory factor (MIF) is an important regulator of the host response to infection. Released by various immune cells and by the anterior pituitary gland, MIF plays a critical role in the systemic inflammatory response by counterregulating the inhibitory effect of glucocorticoids on immune-cell activation and proinflammatory cytokine production. We describe herein an unexpected role for MIF in the regulation of glycolysis. The addition of MIF to differentiated L6 rat myotubes increased synthesis of fructose 2,6-bisphosphate (F2,6BP), a positive allosteric regulator of glycolysis. Increased expression of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) enhanced F2,6BP production and, consequently, cellular lactate production. The catabolic effect of TNF-α on myotubes was mediated by MIF, which served as an autocrine stimulus for F2,6BP production. TNF-α administered to mice decreased serum glucose levels and increased muscle F2,6BP levels; pretreatment with a neutralizing anti-MIF mAb completely inhibited these effects. Anti-MIF also prevented hypoglycemia and increased muscle F2,6BP levels in TNF-α–knockout mice that were administered LPS, supporting the intrinsic contribution of MIF to these inflammation-induced metabolic changes. Taken together with the recent finding that MIF is a positive, autocrine stimulator of insulin release, these data suggest an important role for MIF in the control of host glucose disposal and carbohydrate metabolism.
Glycemic Control and Blood Glucose Monitoring Over Time in a Sample of Young Australians With Type 1 Diabetes
Authors: Daniel Waller, Christine Johnston, Lynda Molyneaux, Lin Brown-Singh, Kristy Hatherly, Lorraine Smith, Jane Overland
Journal: Diabetes Care (2013)

OBJECTIVE To determine whether personality traits (conscientiousness, agreeableness, emotional regulation, extraversion, and openness to experience) are associated with glycemic control and blood glucose monitoring behavior, and change or stability of these outcomes over time, in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS A 3-year longitudinal study was conducted using data from 142 individuals with type 1 diabetes, 8–19 years of age. Personality was assessed at baseline using the Five-Factor Personality Inventory for Children. Data relating to glycemic control (HbA1c) and frequency of blood glucose monitoring (based on meter memory) were collected annually. Relationships between personality traits and HbA1c and monitoring frequency were examined using regression models and mixed-design ANOVA. RESULTS Three of the Five-Factor domains were independently associated with glycemic control. Individuals high in conscientiousness and agreeableness had a lower and more stable HbA1c across the 3-year study period. In contrast, the HbA1c of individuals scoring low on these traits was either consistently worse or deteriorated over time. Low or high emotional regulation scores were also associated with worse glycemic control. By the third year, these domains, together with initial HbA1c, accounted for 39% of HbA1c variance. Conscientiousness was the only personality factor associated with blood glucose monitoring behavior. CONCLUSIONS Results of this study underline the importance of personality in contributing to diabetes outcomes. Attention to a young person’s personality, and appropriate tailoring of diabetes management to ensure an individualized approach, may help to optimize diabetes outcomes.