tbuckley/cabot-search huggingface dataset:
Conservation of the binding site for the arginine repressor in all bacterial lineages
Authors: Kira S Makarova, Andrey A Mironov, Mikhail S Gelfand
Journal: Genome biology (2001)

The arginine repressor ArgR/AhrC is a transcription factor universally conserved in bacterial genomes. Its recognition signal (the ARG box), a weak palindrome, is also conserved between genomes, despite a very low degree of similarity between individual sites within a genome. Thus, the arginine repressor is different from two other universal transcription factors - HrcA, whose recognition signal is very strongly conserved both within and between genomes, and LexA/DinR, whose signal is strongly conserved within, but not between, genomes. The arginine regulon is well studied in Escherichia coli and to some extent in Bacillus subtilis and some other genomes. Here, we apply the comparative genomic approach to the prediction of the ArgR-binding sites in all completely sequenced bacterial genomes. Orthologs of ArgR/AhrC were identified in the complete genomes of E. coli, Haemophilus influenzae, Vibrio choleras, B. subtilis, Mycobacterium tuberculosis, Thermotoga maritima, Chlamydia pneumoniae and Deinococcus radiodurans. Candidate arginine repressor binding sites were identified upstream of arginine transport and metabolism genes. We found that the ArgR/AhrC recognition signal is conserved in all genomes that contain genes encoding orthologous transcription factors of this family. All genomes studied except M. tuberculosis contain ABC transport cassettes (related to the Art system of E. coli) belonging to the candidate arginine regulons.
Tularemia as a Biological Weapon
Authors: David T. Dennis, Thomas V. Inglesby, Donald A. Henderson, John G. Bartlett, Michael S. Ascher, Edward Eitzen, Anne D. Fine, Arthur M. Friedlander, Jerome Hauer, Marcelle Layton, Scott R. Lillibridge, Joseph E. McDade, Michael T. Osterholm, Tara O'Toole, Gerald Parker, Trish M. Perl, Philip K. Russell, Kevin Tonat, None for the Working Group on Civilian Biodefense
Journal: JAMA (2001)

The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if tularemia is used as a biological weapon against a civilian population.The working group included 25 representatives from academic medical centers, civilian and military governmental agencies, and other public health and emergency management institutions and agencies.MEDLINE databases were searched from January 1966 to October 2000, using the Medical Subject Headings Francisella tularensis, Pasteurella tularensis, biological weapon, biological terrorism, bioterrorism, biological warfare, and biowarfare. Review of these references led to identification of relevant materials published prior to 1966. In addition, participants identified other references and sources.Three formal drafts of the statement that synthesized information obtained in the formal evidence-gathering process were reviewed by members of the working group. Consensus was achieved on the final draft.A weapon using airborne tularemia would likely result 3 to 5 days later in an outbreak of acute, undifferentiated febrile illness with incipient pneumonia, pleuritis, and hilar lymphadenopathy. Specific epidemiological, clinical, and microbiological findings should lead to early suspicion of intentional tularemia in an alert health system; laboratory confirmation of agent could be delayed. Without treatment, the clinical course could progress to respiratory failure, shock, and death. Prompt treatment with streptomycin, gentamicin, doxycycline, or ciprofloxacin is recommended. Prophylactic use of doxycycline or ciprofloxacin may be useful in the early postexposure period.
IQGAP1, a Novel Vascular Endothelial Growth Factor Receptor Binding Protein, Is Involved in Reactive Oxygen Species—Dependent Endothelial Migration and Proliferation
Authors: Minako Yamaoka-Tojo, Masuko Ushio-Fukai, Lula Hilenski, Sergey I. Dikalov, Yuqing E. Chen, Taiki Tojo, Tohru Fukai, Mitsuaki Fujimoto, Nikolay A. Patrushev, Ningning Wang, Christopher D. Kontos, George S. Bloom, R. Wayne Alexander
Journal: Circulation Research (2004)

Endothelial cell (EC) proliferation and migration are important for reendothelialization and angiogenesis. We have demonstrated that reactive oxygen species (ROS) derived from the small GTPase Rac1-dependent NAD(P)H oxidase are involved in vascular endothelial growth factor (VEGF)-mediated endothelial responses mainly through the VEGF type2 receptor (VEGFR2). Little is known about the underlying molecular mechanisms. IQGAP1 is a scaffolding protein that controls cellular motility and morphogenesis by interacting directly with cytoskeletal, cell adhesion, and small G proteins, including Rac1. In this study, we show that IQGAP1 is robustly expressed in ECs and binds to the VEGFR2. A pulldown assay using purified proteins demonstrates that IQGAP1 directly interacts with active VEGFR2. In cultured ECs, VEGF stimulation rapidly promotes recruitment of Rac1 to IQGAP1, which inducibly binds to VEGFR2 and which, in turn, is associated with tyrosine phosphorylation of IQGAP1. Endogenous IQGAP1 knockdown by siRNA shows that IQGAP1 is involved in VEGF-stimulated ROS production, Akt phosphorylation, endothelial migration, and proliferation. Wound assays reveal that IQGAP1 and phosphorylated VEGFR2 accumulate and colocalize at the leading edge in actively migrating ECs. Moreover, we found that IQGAP1 expression is dramatically increased in the VEGFR2-positive regenerating EC layer in balloon-injured rat carotid artery. These results suggest that IQGAP1 functions as a VEGFR2-associated scaffold protein to organize ROS-dependent VEGF signaling, thereby promoting EC migration and proliferation, which may contribute to repair and maintenance of the functional integrity of established blood vessels.
Managing Medications in Clinically Complex Elders
Authors: Michael A. Steinman, Joseph T. Hanlon
Journal: JAMA (2010)

Multiple medication use is common in older adults and may ameliorate symptoms, improve and extend quality of life, and occasionally cure disease. Unfortunately, multiple medication use is also a major risk factor for prescribing and adherence problems, adverse drug events, and other adverse health outcomes. Using the case of an older patient taking multiple medications, this article summarizes the evidence-based literature about improving medication use and withdrawing specific drugs and drug classes. It also describes a systematic approach for how health professionals can assess and improve medication regimens to benefit patients and their caregivers and families.
Cystic fibrosis bone disease: is the CFTR corrector C18 an option for therapy?
Authors: Frédéric Velard, Martial Delion, Flora Lemaire, Olivier Tabary, Christine Guillaume, Françoise Le Pimpec Barthès, Lhousseine Touqui, Sophie Gangloff, Isabelle Sermet-Gaudelus, Jacky Jacquot
Journal: European Respiratory Journal (2014)

Mutations in the gene encoding the chloride ion channel CFTR (cystic fibrosis transmembrane conductance regulator) result in cystic fibrosis (CF), the most common lethal autosomal recessive genetic disease, which causes a number of long-term health problems, such as bone disease. Osteoporosis and increased vertebral fracture risk associated with CF disease are becoming more important as the life expectancy of patients continues to improve. The aetiology of low bone density is multifactorial, and is most probably a combination of inadequate peak bone mass during puberty and increased bone loss in adults [1]. Body mass index, male sex, advanced pulmonary disease, malnutrition and chronic therapies are established additional risk factors for CF-related bone disease. In multiple studies with a large cohort of adolescent and adult CF patients, the incidence of osteopenia and osteoporosis ranges from 34% to 79% [1, 2]. This further translated to a 100-fold greater risk of vertebral compression, which can decrease lung function, thus accelerating the course of the disease and decreasing the patient's quality of life. CFTR corrector–potentiators may be new therapies for CF bone disease <http://ow.ly/DSgyi> The authors thank all children who participated in this study. We also acknowledge the provision of CFTR corrector VRT-534/C18 by Vertex Pharmaceuticals (Boston, MA, USA).
Blockade of Interleukin-17A Results in Reduced Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Emily Smith, Konkal-Matt R. Prasad, Matthew Butcher, Anca Dobrian, Jay K. Kolls, Klaus Ley, Elena Galkina
Journal: Circulation (2010)

Background— T cells play an important role during the immune response that accompanies atherosclerosis. To date, the role for interleukin (IL)-17A in atherogenesis is not well defined. Here, we tested the hypothesis that atherosclerosis-prone conditions induce the differentiation of IL-17A–producing T cells, which in turn promote atherosclerosis. Methods and Results— IL-17A was found to be elevated in the plasma and tissues of apolipoprotein E–deficient ( Apoe −/− ) mice. IL-17A–expressing T cells were significantly increased in the aortas, spleen, and lamina propria of aged Apoe −/− mice compared with age-matched C57BL/6 mice. IL-17A + T cells resided in both adventitia and aortas of aged Apoe −/− mice fed a chow diet. Elevated levels of IL-17A + T cells were also detected in the aortas of 21-week-old Apoe −/− mice fed a Western diet for 15 weeks. IL-17A + T cells were characterized as predominantly CD4 + T helper 17 (Th17) cells and γδ + T cells. Blockade of IL-17A in Apoe −/− mice by use of adenovirus-produced IL-17 receptor A reduced plaque burden in Apoe −/− mice fed a Western diet for 15 weeks. In addition, the treatment diminished circulating IL-6 and granulocyte colony-stimulating factor levels and limited CXCL1 expression and macrophage content within the aortas. Conversely, IL-17A treatment of whole aorta isolated from Apoe −/− mice promoted aortic CXCL1 expression and monocyte adhesion in an ex vivo adhesion assay. Conclusions— These results demonstrate that atherosclerosis-prone conditions induce the differentiation of IL-17A–producing T cells. IL-17A plays a proatherogenic inflammatory role during atherogenesis by promoting monocyte/macrophage recruitment into the aortic wall.
Managed Care in Medicaid: Selected Issues in Program Origins, Design, and Research
Authors: D A Freund, R E Hurley
Journal: Annual Review of Public Health (1987)

The search for new methods to provide cost-effective medical care has become the principal concern of health service purchasers, providers, and researchers in the 1980s. This concern has led to bold and innovative strat­ egies in both the private and public sectors. These strategies are represented by initiatives that run the gamut from highly regulatory to avowedly market­ oriented competitive ones. Despite these wide variations, such strategies share a common goal of containing cost increases without reductions in service access and quality. In this paper we describe a set of the initiatives used currently in the Medicaid program and discuss how these new approaches are being evaluated to assess whether they attain their specific goals. We begin by discussing the environment that has fostered the search for alternative delivery methods and the legislative and executive activities that have enabled experimentation. We detail the theoretical foundations for these programs of prepaid and managed care and the characteristics of a selected set of them. With the programs broadly outlined, we then describe the evaluation design developed to assess them. Finally, we identify areas for additional research.
High diversity of hepatitis C viral quasispecies is associated with early virological response in patients undergoing antiviral therapy
Authors: Xiaofeng Fan, Qing Mao, Donghui Zhou, Yang Lu, Jianwei Xing, Yanjuan Xu, Stuart C. Ray, Adrian M. Di Bisceglie
Journal: Hepatology (2009)

Differential response patterns to optimal antiviral therapy, peginterferon alpha plus ribavirin, are well documented in patients with chronic hepatitis C virus (HCV) infection. Among many factors that may affect therapeutic efficiency, HCV quasispecies (QS) characteristics have been a major focus of previous studies, yielding conflicting results. To obtain a comprehensive understanding of the role of HCV QS in antiviral therapy, we performed the largest-ever HCV QS analysis in 153 patients infected with HCV genotype 1 strains. A total of 4,314 viral clones spanning hypervarible region 1 were produced from these patients during the first 12 weeks of therapy, followed by detailed genetic analyses. Our data show an exponential distribution pattern of intrapatient QS diversity in this study population in which most patients (63%) had small QS diversity with genetic distance (d) less than 0.2. The group of patients with genetic distance located in the decay region (d>0.53) had a significantly higher early virologic response (EVR) rate (89.5%), which contributed substantially to the overall association between EVR and increased baseline QS diversity. In addition, EVR was linked to a clustered evolutionary pattern in terms of QS dynamic changes. Conclusion: EVR is associated with elevated HCV QS diversity and complexity, especially in patients with significantly higher HCV genetic heterogeneity.(HEPATOLOGY 2009;50:1765–1772.)
Gankyrin Activates IL-8 to Promote Hepatic Metastasis of Colorectal Cancer
Authors: Zhaofang Bai, Yanhong Tai, Weihua Li, Cheng Zhen, Weiting Gu, Zhao Jian, Qianyi Wang, Jieru E. Lin, Qing Zhao, Weili Gong, Bing Liang, Chenguang Wang, Tao Zhou
Journal: Cancer Research (2013)

Hepatic metastasis is responsible for the majority of colorectal cancer (CRC)-related mortalities. Although Gankyrin (PSMD10) has been implicated in cancer metastasis, its exact role and underlying mechanisms of CRC hepatic metastasis remain largely unknown. Herein, we showed that the expression of Gankyrin was higher in primary CRC with hepatic metastasis compared with CRC without metastasis. RNAi-mediated silencing of Gankyrin expression in highly metastatic human CRC cells impaired their migratory and metastatic capacity in vivo. Genome-wide transcriptome profiling revealed activation of the interleukin (IL)-8 signaling pathway by Gankyrin. Protein levels of IL-8 and cyclin D1 (CCND1), the two important molecules in the IL-8 pathway, were positively correlated with Gankyrin expression in human CRC specimens. Furthermore, genetic deletion of cyclin D1 showed its requirement in Gankyrin-mediated cell migration. Finally, administration of recombinant IL-8 rescued the migratory defect of CRC cells where Gankyrin expression was silenced. Together, our findings highlight the importance of Gankyrin in hepatic metastasis of CRC and point out its candidature as a potential prognostic marker and therapeutic target to improve the clinical management of metastatic CRC.
Arf6 and Phosphoinositol-4-Phosphate-5-Kinase Activities Permit Bypass of the Rac1 Requirement for β1 Integrin–mediated Bacterial Uptake
Authors: Ka-Wing Wong, Ralph R. Isberg
Journal: The Journal of Experimental Medicine (2003)

Efficient entry of the bacterium Yersinia pseudotuberculosis into mammalian cells requires the binding of the bacterial invasin protein to β1 integrin receptors and the activation of the small GTPase Rac1. We report here that this Rac1-dependent pathway involves recruitment of phosphoinositol-4-phosphate-5-kinase (PIP5K) to form phosphoinositol-4,5-bisphosphate (PIP2) at the phagocytic cup. Reducing the concentration of PIP2 in the target cell by using a membrane-targeted PIP2-specific phosphatase lowered bacterial uptake proportionately. PIP2 formation is regulated by Arf6. An Arf6 derivative defective for nucleotide binding (Arf6N122I) interfered with uptake and decreased the level of PIP2 around extracellular bacteria bound to host cells. This reduction in PIP2 occurred in spite of fact that PIP5K appeared to be recruited efficiently to the site of bacterial binding, indicating a role for Arf6 in activation of the kinase. The elimination of the Rac1-GTP–bound form from the cell by the introduction of the Y. pseudotuberculosis YopE RhoGAP protein could be bypassed by the overproduction of either PIP5K or Arf6, although the degree of bypass was greater for Arf6 transfectants. These results indicate that both Arf6 and PIP5K are involved in integrin-dependent uptake, and that Arf6 participates in both activation of PIP5K as well as in other events associated with bacterial uptake.
Genome-wide comparative analysis of the Brassica rapa gene space reveals genome shrinkage and differential loss of duplicated genes after whole genome triplication
Authors: Jeong-Hwan Mun, Soo-Jin Kwon, Tae-Jin Yang, Young-Joo Seol, Mina Jin, Jin-A Kim, Myung-Ho Lim, Jung Sun Kim, Seunghoon Baek, Beom-Soon Choi, Hee-Ju Yu, Dae-Soo Kim, Namshin Kim, Ki-Byung Lim, Soo-In Lee, Jang-Ho Hahn, Yong Pyo Lim, Ian Bancroft, Beom-Seok Park
Journal: Genome biology (2009)

Abstract Background Brassica rapa is one of the most economically important vegetable crops worldwide. Owing to its agronomic importance and phylogenetic position, B. rapa provides a crucial reference to understand polyploidy-related crop genome evolution. The high degree of sequence identity and remarkably conserved genome structure between Arabidopsis and Brassica genomes enables comparative tiling sequencing using Arabidopsis sequences as references to select the counterpart regions in B. rapa , which is a strong challenge of structural and comparative crop genomics. Results We assembled 65.8 megabase-pairs of non-redundant euchromatic sequence of B. rapa and compared this sequence to the Arabidopsis genome to investigate chromosomal relationships, macrosynteny blocks, and microsynteny within blocks. The triplicated B. rapa genome contains only approximately twice the number of genes as in Arabidopsis because of genome shrinkage. Genome comparisons suggest that B. rapa has a distinct organization of ancestral genome blocks as a result of recent whole genome triplication followed by a unique diploidization process. A lack of the most recent whole genome duplication (3R) event in the B. rapa genome, atypical of other Brassica genomes, may account for the emergence of B. rapa from the Brassica progenitor around 8 million years ago. Conclusions This work demonstrates the potential of using comparative tiling sequencing for genome analysis of crop species. Based on a comparative analysis of the B. rapa sequences and the Arabidopsis genome, it appears that polyploidy and chromosomal diploidization are ongoing processes that collectively stabilize the B. rapa genome and facilitate its evolution.
Heterogeneous Selection on LEGCYC Paralogs in Relation to Flower Morphology and the Phylogeny of Lupinus (Leguminosae)
Authors: Richard H Ree, Hélène L Citerne, Matt Lavin, Quentin C B Cronk
Journal: Molecular Biology and Evolution (2003)

An analysis of the molecular evolution of two LEGCYC paralogs in Lupinus (Genisteae: Leguminosae) reveals a varied history of site-specific and lineage-specific evolutionary rates and selection both within and between loci. LEGCYC genes are homologous to regulatory loci known to control floral symmetry and adaxial flower organ identity in Antirrhinum and its relatives. Within Lupinus, L. densiflorus is unusual in having flowers with a proportionally smaller standard (upright adaxial petals) and larger wings (lateral petals) than other lupin species. Phylogenetic estimates of the nonsynonymous/synonymous substitution rate ratio, omega, suggest that along the L. densiflorus lineage, positive selection (omega > 1) acted at some codon sites of one paralog, LEGCYC1B, and greater purifying selection (omega < 1) acted at some sites of the other paralog, LEGCYC1A. Overall, LEGCYC1A appears to be evolving faster than LEGCYC1B, and both paralogs are evolving faster than the internal transcribed spacer (ITS) region of nr DNA. The predominant historical pattern inferred is a highly heterogeneous "selectional mosaic" which we suggest may be typical of the teosinte branched 1-cycloidea-PCF (TCP) class of transcriptional activators, and possibly other genes. Codon models that do not account for both site-specific and lineage-specific variation in omega do not detect positive selection at these loci. We suggest a modification of existing branch-site models involving an additional omega parameter along the foreground branch, to account for the effects of both greater positive selection and greater purifying selection at different codon sites along a particular branch. The higher rates of evolution and congruent phylogenetic signal of both LEGCYC paralogs show promise for the use of these genes as markers for phylogeny reconstruction at low taxonomic levels in Genisteae [corrected]
Oral desensitization to rifampin and ethambutol in mycobacterial disease.
Authors: J Matz, L C Borish, J M Routes, L J Rosenwasser
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

The incidence of disease caused by Mycobacterium tuberculosis (including drug-resistant strains) and M. avium complex (MAC) is increasing. Hypersensitivity reactions to antimycobacterial agents are relatively uncommon, but when they occur they may result in cessation of therapeutic medications. We report our experience with rapid oral desensitization to ethambutol and rifampin in a group of 10 patients with mycobacterial disease who had experienced cutaneous hypersensitivity reactions to these drugs. An adaptation of the rapid oral desensitization protocol for penicillin was used, with the dosing intervals increased to account for the different kinetics of these drugs. Adverse reactions were few and easily treated without necessitating cessation of therapy. We conclude that oral desensitization to rifampin and ethambutol by our protocol is safe and effective, allowing these patients to proceed with an optimal antimycobacterial regimen.
Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension
Authors: Vasilios Papademetriou, Csaba Farsang, Dag Elmfeldt, Albert Hofman, Hans Lithell, Bertil Olofsson, Ingmar Skoog, Peter Trenkwalder, Alberto Zanchetti
Journal: Journal of the American College of Cardiology (2004)
Turning Telomerase into a Jekyll and Hyde Case?
Authors: Raymund J. Wellinger
Journal: Cancer Discovery (2015)

Abstract Summary: It may be possible to coerce telomerase to incorporate modified guanine nucleotides into telomeric repeat DNA, thereby seriously compromising the functionality of the telomeres. Thus, a guanine analogue such as 6-thio-dG could turn active telomerase into a chromosome de-protecting enzyme, the opposite of what it is normally, namely a chromosome-protecting enzyme. Cancer Discov; 5(1); 19–21. ©2015 AACR. See related article by Mender et al., p. 82