tbuckley/cabot-search huggingface dataset:
Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion
Authors: Toshio Miyata, Reiko Inagi, Masaomi Nangaku, Toshiyuki Imasawa, Masahiro Sato, Yuko Izuhara, Daisuke Suzuki, Atsusi Yoshino, Hiroshi Onogi, Minoru Kimura, Satoshi Sugiyama, Kiyoshi Kurokawa
Journal: Journal of Clinical Investigation (2002)

Mesangial cells maintain normal glomerular function by mediating ECM remodeling and immune complex disposal. We have recently identified megsin, a novel member of the serine protease inhibitor (serpin) superfamily predominantly expressed in the mesangium. While our previous studies suggested a role for megsin in the pathogenesis of human glomerular diseases, its exact biological significance remained unknown. Here we produced two lines of megsin transgenic mice. Overexpression of megsin led to progressive mesangial matrix expansion and an increase in the number of mesangial cells. These glomerular lesions were accompanied by an augmented immune complex deposition, together with Ig's and complement. Binding and functional assays in vitro identified plasmin as one biological substrate of megsin and confirmed its activity as a proteinase inhibitor. Transgenic animals exhibiting nephritis as a result of treatment with anti–glomerular basement membrane antiserum showed significantly more persistent expansion of the mesangial ECM than was seen in parental mice. Megsin therefore exerts a biologically relevant influence on mesangial function, and on the mesangial microenvironment, such that simple overexpression of this endogenous serpin engenders elementary mesangial lesions.
Early Tissue Distribution of Bone Marrow Mononuclear Cells After Intra-Arterial Delivery in a Patient With Chronic Stroke
Authors: Lea Mirian Barbosa da Fonseca, Valeria Battistella, Gabriel Rodriguez de Freitas, Bianca Gutfilen, Regina Coeli dos Santos Goldenberg, Angelo Maiolino, Eduardo Wajnberg, Paulo Henrique Rosado de Castro, Rosalia Mendez-Otero, Charles Andre
Journal: Circulation (2009)
Molecular Mechanisms of Extensive Mitochondrial Gene Rearrangement in Plethodontid Salamanders
Authors: Rachel Lockridge Mueller, Jeffrey L. Boore
Journal: Molecular Biology and Evolution (2005)

Extensive gene rearrangement is reported in the mitochondrial genomes of lungless salamanders (Plethodontidae). In each genome with a novel gene order, there is evidence that the rearrangement was mediated by duplication of part of the mitochondrial genome, including the presence of both pseudogenes and additional, presumably functional, copies of duplicated genes. All rearrangement-mediating duplications include either the origin of light-strand replication and the nearby tRNA genes or the regions flanking the origin of heavy-strand replication. The latter regions comprise nad6, trnE, cob, trnT, an intergenic spacer between trnT and trnP and, in some genomes, trnP, the control region, trnF, rrnS, trnV, rrnL, trnL1, and nad1. In some cases, two copies of duplicated genes, presumptive regulatory regions, and/or sequences with no assignable function have been retained in the genome following the initial duplication; in other genomes, only one of the duplicated copies has been retained. Both tandem and nontandem duplications are present in these genomes, suggesting different duplication mechanisms. In some of these mitochondrial DNAs, up to 25% of the total length is composed of tandem duplications of noncoding sequence that includes putative regulatory regions and/or pseudogenes of tRNAs and protein-coding genes along with the otherwise unassignable sequences. These data indicate that imprecise initiation and termination of replication, slipped-strand mispairing, and intramolecular recombination may all have played a role in generating repeats during the evolutionary history of plethodontid mitochondrial genomes.
N-<i>myc</i> Is an Essential Downstream Effector of Shh Signaling during both Normal and Neoplastic Cerebellar Growth
Authors: Beryl A. Hatton, Paul S. Knoepfler, Anna Marie Kenney, David H. Rowitch, Ignacio Moreno de Alborán, James M. Olson, Robert N. Eisenman
Journal: Cancer Research (2006)

Abstract We examined the genetic requirements for the Myc family of oncogenes in normal Sonic hedgehog (Shh)–mediated cerebellar granule neuronal precursor (GNP) expansion and in Shh pathway–induced medulloblastoma formation. In GNP-enriched cultures derived from N-mycFl/Fl and c-mycFl/Fl mice, disruption of N-myc, but not c-myc, inhibited the proliferative response to Shh. Conditional deletion of c-myc revealed that, although it is necessary for the general regulation of brain growth, it is less important for cerebellar development and GNP expansion than N-myc. In vivo analysis of compound mutants carrying the conditional N-myc null and the activated Smoothened (ND2:SmoA1) alleles showed, that although granule cells expressing the ND2:SmoA1 transgene are present in the N-myc null cerebellum, no hyperproliferation or tumor formation was detected. Taken together, these findings provide in vivo evidence that N-myc acts downstream of Shh/Smo signaling during GNP proliferation and that N-myc is required for medulloblastoma genesis even in the presence of constitutively active signaling from the Shh pathway. (Cancer Res 2006; 66(17): 8655-61)
KRASD13 Promotes Apoptosis of Human Colorectal Tumor Cells by ReovirusT3D and Oxaliplatin but not by Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand
Authors: Niels Smakman, Diana J.M. van den Wollenberg, Sjoerd G. Elias, Takehiko Sasazuki, Senji Shirasawa, Rob C. Hoeben, Inne H.M. Borel Rinkes, Onno Kranenburg
Journal: Cancer Research (2006)

Colorectal tumors frequently contain activating mutations in KRAS. ReovirusT3D is an oncolytic virus that preferentially kills tumor cells with an activated Ras pathway. Here we have assessed the contribution of endogenous mutant KRAS in human colorectal cancer cell lines to ReovirusT3D replication and to tumor cell oncolysis. In addition, treatment combinations involving ReovirusT3D, oxaliplatin, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were tested for their efficacy in tumor cell killing. The mutation status of KRAS did not predict the sensitivity of a panel of human colorectal cancer cell lines to ReovirusT3D. Virus replication was observed in all cell lines tested regardless of KRAS status and was not affected by deletion of endogenous mutant KRAS(D13). However, deletion of KRAS(D13) or p53 did reduce apoptosis induction by ReovirusT3D whereas deletion of beta-catenin(DeltaS45) had no effect. Likewise, KRAS(D13)- or p53-deficient cells display reduced sensitivity to oxaliplatin but not to death receptor activation by TRAIL. Finally, the treatment of colorectal cancer cells with ReovirusT3D combined with either oxaliplatin or TRAIL resulted in a nonsynergistic increase in tumor cell killing. We conclude that oncolysis of human tumor cells by ReovirusT3D is not determined by the extent of virus replication but by their sensitivity to apoptosis induction. Oncogenic KRAS(D13) increases tumor cell sensitivity to activation of the cell-intrinsic apoptosis pathway without affecting ReovirusT3D replication.
Identification and Linkage Analyses of a Gene, &lt;italic&gt;Rcs-1&lt;/italic&gt;, Suppressing Spontaneous SJL/J Lymphoma Expression&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J E Bubbers
Journal: JNCI Journal of the National Cancer Institute (1984)

Populations of SJL/J (SJL), A.SW/SnJ (A.SW), F1, and backcross mice were followed over 2 years for the spontaneous development of reticulum cell sarcoma (RCS). A.SW, F1, and SJL mice demonstrated cumulative RCS incidences of 0, 9, and greater than 95%, respectively. The incidence of RCS in SJL × (SJL × A.SW), SJL × (A.SW × SJL), and (SJL × A.SW) × SJL backcross mice was 58%, a rate consistent (P<.001) with a single dominant A.SW gene, termed “Rcs-1,” suppressing disease. Rcs-1 is not an H-2 gene nor is it on the X- or Y-chromosome. Rcs-1 abrogates tumor initiation relatively early rather than later by affecting tumor growth; its effect is not transmitted by (SJL × A.SW)F1 females to their offspring by non-Medelian maternal factors. No linkage was detected between Rcs-1 and the marker genes lgh-1 (chromosome 12), Pgm-1 (chromosome 5), Hbb (chromosome 7), ldh-1 (chromosome 1), or Gr-1 (chromosome 8). Thus Rcs-1 is different from three genes linked to these markers and known to influence murine leukemia virus, Fv-4 (chromosome 12), Cv (chromosome 5), and Fgv-1 (chromosome 7).
Continuously Recorded Changes of Thoracic Aortic Blood Flow in Man in Response to Leg Exercise in Supine Position
Authors: RALPH S. ZITNIK, FILMORE S. RODICH, HIRAM W. MARSHALL, EARL H. WOOD
Journal: Circulation Research (1965)

The constant-rate-injection, indicator-dilution technic was used to determine thoracic aortic blood flow before, during, and after five minutes of single-leg exercise (bicycle ergometer) in five healthy male subjects in the supine position. Resistance to blood flow in the lower body and mean aortic pressure decreased immediately at the onset of exercise, at the same time that thoracic aortic blood flow and heart rate increased. There was a further slow rise of heart rate, mean aortic pressure, and thoracic aortic blood flow along with a decrease of lower body resistance until fairly stable levels were reached after five minutes of exercise. After five and ten minutes' rest all values tended to return toward those observed in the control state. These data are consistent with the concept that baroreceptor activity may play an important part in the early cardiovascular responses to exercise in man. Most of the cardiovascular response to this exercise occurred in the first 30 seconds.
THE ECONOMIES OF THE HEREFORD COUNTY COUNCIL
Authors: J. E. O'Connor
Journal: BMJ (1908)

The use of genomic information to better understand and prevent common complex diseases has been an ongoing goal of genetic research. Over the past few years, research in this area has proliferated with several proposed methods of generating polygenic scores. This has been driven by the availability of larger data sets, primarily from genome-wide association studies and concomitant developments in statistical methodologies. Here we provide an overview of the methodological aspects of polygenic model construction. In addition, we consider the state of the field and implications for potential applications of polygenic scores for risk estimation within healthcare.
Independent Domestication of Asian Rice Followed by Gene Flow from japonica to indica
Authors: C.-c. Yang, Y. Kawahara, H. Mizuno, J. Wu, T. Matsumoto, T. Itoh
Journal: Molecular Biology and Evolution (2011)

Results from studies on the domestication process of Asian rice Oryza sativa have been controversial because of its complicated evolutionary history. Previous studies have yielded two alternative hypotheses about the origin(s) of the two major groups of O. sativa: japonica and indica. One study proposes a single common wild ancestor, whereas the other suggests that there were multiple domestication events of different types of wild rice. Here, we provide clear evidence of the independent domestication of japonica and indica obtained via high-throughput sequencing and a large-scale comparative analysis of two wild rice accessions (W1943 and W0106) and two cultivars (a japonica cultivar called "Nipponbare" and an indica cultivar called "Guangluai-4"). The different domestication processes of the two cultivar groups appear to have led to distinct patterns of molecular evolution in protein-coding regions. The intensity of purifying selection was relaxed only in the japonica group, possibly because of a bottleneck effect. Moreover, a genome-wide comparison between Nipponbare, Guangluai-4, and another indica cultivar (93-11) suggests multiple hybridization events between japonica and indica, both before and after the divergence of the indica cultivars. We found that a large amount of genomic DNA, including domestication-related genes, was transferred from japonica to indica, which might have been important in the development of modern rice. Our study provides an overview of the dynamic process of Asian rice domestication, including independent domestication events and subsequent gene flow.
Unidentified Inert Ingredients in Pesticides: Implications for Human and Environmental Health
Authors: Caroline Cox, Michael Surgan
Journal: Environmental Health Perspectives (2006)

By statute or regulation in the United States and elsewhere, pesticide ingredients are divided into two categories: active and inert (sometimes referred to as other ingredients, adjuvants, or coformulants). Despite their name, inert ingredients may be biologically or chemically active and are labeled inert only because of their function in the formulated product. Most of the tests required to register a pesticide are performed with the active ingredient alone, not the full pesticide formulation. Inert ingredients are generally not identified on product labels and are often claimed to be confidential business information.In this commentary, we describe the shortcomings of the current procedures for assessing the hazards of pesticide formulations and demonstrate that inert ingredients can increase the toxicity of and potential exposure to pesticide formulations.Inert ingredients can increase the ability of pesticide formulations to affect significant toxicologic end points, including developmental neurotoxicity, genotoxicity, and disruption of hormone function. They can also increase exposure by increasing dermal absorption, decreasing the efficacy of protective clothing, and increasing environmental mobility and persistence. Inert ingredients can increase the phytotoxicity of pesticide formulations as well as the toxicity to fish, amphibians, and microorganisms.Pesticide registration should require full assessment of formulations. Evaluations of pesticides under the National Environmental Policy Act, the Endangered Species Act, and similar statutes should include impact assessment of formulations. Environmental monitoring for pesticides should include inert ingredients. To enable independent research and risk assessment, inert ingredients should be identified on product labels.
Three Epigenetic Biomarkers, <i>GDF15</i>, <i>TMEFF2</i>, and <i>VIM</i>, Accurately Predict Bladder Cancer from DNA-Based Analyses of Urine Samples
Authors: Vera L. Costa, Rui Henrique, Stine A. Danielsen, Sara Duarte-Pereira, Mette Eknaes, Rolf I. Skotheim, Ângelo Rodrigues, José S. Magalhães, Jorge Oliveira, Ragnhild A. Lothe, Manuel R. Teixeira, Carmen Jerónimo, Guro E. Lind
Journal: Clinical Cancer Research (2010)

To identify a panel of epigenetic biomarkers for accurate bladder cancer (BlCa) detection in urine sediments.Gene expression microarray analysis of BlCa cell lines treated with 5-aza-2'-deoxycytidine and trichostatin A as well as 26 tissue samples was used to identify a list of novel methylation candidates for BlCa. Methylation levels of candidate genes were quantified in 4 BlCa cell lines, 50 BlCa tissues, 20 normal bladder mucosas (NBM), and urine sediments from 51 BlCa patients and 20 healthy donors, 19 renal cancer patients, and 20 prostate cancer patients. Receiver operator characteristic curve analysis was used to assess the diagnostic performance of the gene panel.GDF15, HSPA2, TMEFF2, and VIM were identified as epigenetic biomarkers for BlCa. The methylation levels were significantly higher in BlCa tissues than in NBM (P < 0.001) and the cancer specificity was retained in urine sediments (P < 0.001). A methylation panel comprising GDF15, TMEFF2, and VIM correctly identified BlCa tissues with 100% sensitivity and specificity. In urine samples, the panel achieved a sensitivity of 94% and specificity of 100% and an area under the curve of 0.975. The gene panel could discriminate BlCa from both healthy individuals and renal or prostate cancer patients (sensitivity, 94%; specificity, 90%).By using a genome-wide approach, we have identified a biomarker panel that allows for early and accurate noninvasive detection of BlCa using urine samples.
Effect of POL6014, a protein epitope mimetic (PEM) neutrophil elastase inhibitor, in a model of monocrotaline (MCT)-induced pulmonary arterial hypertension in rats
Authors: Odile Sellier-Kessler, Eric Chevalier
Journal: European Respiratory Journal (2013)

Rationale : Neutrophil elastase (NE) contributes to the development of pulmonary arterial hypertension (PAH) by enhancing pulmonary arterial smooth muscle cell proliferation which thickens the vessel wall and reduces the lumen.   Objective : Evaluate the effect of a NE inhibitor, POL6014, after repeated direct administration in the lungs in a rat PAH model.   Methods : After a single injection of MCT Sprague Dawley rats were treated daily with POL6014 at two doses, 0.3 and 3 mg/kg, or its vehicle PBS, and with a reference compound, Tadalafil at 10mg/kg or its vehicle respitose for 21 days. All treatments were given intratracheally (IT). On Day 21 hemodynamic parameters were recorded and right ventricular hypertrophy was assessed by the calculated mass ratio RV/LV+S (right ventricle weight divided by left ventricle and septum weight).   Results : POL6014 at both doses induced a statistically significant reduction in mean right ventricular pressure (RVP) when compared to the PBS group (PBS: 50.01±2.35 mmHg  vs  POL6014, 0.3 mg/kg: 36.52±2.56 mmHg, p vs  POL6014, 3 mg/kg: 38.42±2.82 mmHg, p  Tadalafil at 10 mg/kg also reduced significantly mean RVP in comparison to respitose (respitose: 49.43±3.15 mmHg  vs  Tadalafil: 36.68±1.79 mmHg, p  Moreover POL6014 and Tadalafil significantly decreased the ratio RV/LV+S.   Conclusion : POL6014 significantly improves RVP and attenuates right ventricular hypertrophy in a rat MCT-induced PAH model after chronic IT administration. POL6014 at 0.3 mg/kg is as efficient as Tadalafil at 10 mg/kg. The PEM NE inhibitor POL6014 may thus provide another therapeutic treatment option for PAH.
Viral-induced wheezing during early childhood is associated with abnormal spirometry at age 5
Authors: L.E. Pleiss, M.D. Evans, E.L. Anderson, D.F.G. DaSilva, R. Kelly, T.E. Pappas, K.A. Roberg, K.T. Sullivan Dillie, C.J. Tisler, M.E. Krawiec, R.E. Gangnon, J.E. Gern, R.F. Lemanske
Journal: Journal of Allergy and Clinical Immunology (2005)
Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364–1379
Authors: SE Inzucchi, RM Bergenstal, JB Buse, M Diamant, E Ferrannini, M Nauck, AL Peters, A Tsapas, R Wender, DR Matthews
Journal: Diabetes Care (2013)

In Table 1 "Properties of currently available glucose-lowering agents that may guide treatment choice in individual patients with type 2 diabetes mellitus" vildagliptin was incorrectly assigned footnote "a" (Limited use in the U.S./Europe) instead of footnote "b" (Not licensed in the U.S.).The online version reflects these changes.
Medical bioremediation: Prospects for the application of microbial catabolic diversity to aging and several major age-related diseases
Authors: Aubrey D.N.J. de Grey, Pedro J.J. Alvarez, Roscoe O. Brady, Ana Maria Cuervo, W. Gray Jerome, Perry L. McCarty, Ralph A. Nixon, Bruce E. Rittmann, Janet R. Sparrow
Journal: Ageing Research Reviews (2005)
Why hamstring eccentrics are hamstring essentials
Authors: Kristian Thorborg
Journal: British Journal of Sports Medicine (2012)

There is no dispute that acute hamstring injury is a major sports injury,1,–,6 particularly in football codes2 3 5 6 and other sports that demand high-speed running.1 The purpose of this editorial is to provide the reader with evidence-based tips for optimising hamstring injury prevention.

### Gambling early return against recurrence

Early return to sport (≤3 weeks) is often proposed for hamstring injuries,7 even though basic research clearly shows that ongoing muscle regeneration still occurs,8 and the risk of recurrence is dramatically increased at this point.7 Recurrence includes possible additional injury and non-optimal healing of the hamstring muscle-tendinous complex.9 Such an injury can cause an athlete severe hamstring problems up to a year.6 10

Therefore, to manage hamstring injuries properly, it is important to address one of the main problems – the extremely high recurrence rate5 6 7 – which includes everything from exacerbation to re-injury.11 The acute hamstring injury and its recovery can be difficult for most lay people (including athletes and coaches) to comprehend, as jogging and moderate-paced running is often possible early after the injury – suggesting that full recovery is close. However, because the eccentric capacity (the ability to dissipate forces through lengthening contractions) of the hamstring muscle-tendinous complex is not challenged until the introduction of high-paced running,12 13 full recovery can still be weeks/months away.

My own experience is that athletes, coaches and medical personnel are often overoptimistic in their evaluation of when the athlete should return after a hamstring injury. The classic example is the principle often applied in soccer, where a player is deemed ready to play if he can fully participate in the last training session the day or two before a game. This is not a good criterion for return to sport …
89 SEQUENTIAL ACTIVATION OF CXCR3 AND CCR6 MEDIATES RECRUITMENT AND POSITIONING OF INTERLEUKIN 17 PRODUCING T CELLS IN THE LIVER
Authors: V.M. Banz, Y.H. Oo, D. Kavanagh, D.R. Withers, E. Humphreys, L. Lee-Turner, G. Reynolds, S.G. Hubscher, B. Eksteen, D.H. Adams
Journal: Journal of Hepatology (2010)
Myocardin and Prx1 Contribute to Angiotensin II-Induced Expression of Smooth Muscle α-Actin
Authors: Tadashi Yoshida, Mark H. Hoofnagle, Gary K. Owens
Journal: Circulation Research (2004)

Previous studies demonstrated that angiotensin II (Ang II)-induced hypertrophy of smooth muscle cells (SMCs) was associated with increased transcription of SM alpha-actin gene. The aim of the present study was to determine whether myocardin, a SMC-selective cofactor of serum response factor (SRF), contributed to Ang II-induced increases in SM alpha-actin transcription. Results showed that Ang II increased myocardin mRNA expression as well as SM alpha-actin mRNA expression via the Ang II type 1 receptor in cultured rat aortic SMCs. Cotransfection studies revealed that CArG elements were required for Ang II-induced transcription of SM alpha-actin gene, and a dominant-negative form of myocardin or a short interfering RNA (siRNA) specific for myocardin decreased Ang II-induced SM alpha-actin transcription. Prx1, a homeodomain protein whose expression was increased by Ang II, also increased SM alpha-actin gene transcription in part via CArG elements, and siRNA specific for Prx1 markedly decreased basal and Ang II-induced SM alpha-actin transcription. Electrophoretic mobility shift assay showed that myocardin and Ang II, respectively, increased formation of a SMC-specific CArG-SRF-myocardin higher order complex. However, Ang II had no effect on binding between myocardin and SRF as determined by a mammalian two-hybrid assay, suggesting that Ang II-induced increases in formation of CArG-SRF-myocardin complex was the result of increased SRF binding to CArG elements and increased myocardin expression. Taken together, these results support a model in which Ang II-induced increases in expression of SM alpha-actin are mediated through Prx1-dependent increases in SRF binding to CArG elements and subsequent recruitment of myocardin.
Enhanced brain delivery of liposomal methylprednisolone improved therapeutic efficacy in a model of neuroinflammation
Authors: Pieter J. Gaillard, Chantal C.M. Appeldoorn, Jaap Rip, Rick Dorland, Susanne M.A. van der Pol, Gijs Kooij, Helga E. de Vries, Arie Reijerkerk
Journal: Journal of Controlled Release (2012)