tbuckley/cabot-search huggingface dataset:
The Effect of Multifunctionality on the Rate of Evolution in Yeast
Authors: M. Salathe
Journal: Molecular Biology and Evolution (2005)

Multifunctional genes are expected to evolve at lower rates because mutations in such genes that improve one function might often have deleterious effects on other functions. Here we tested for an association between multifunctionality and evolutionary rates in genes of Saccharomyces cerevisiae, and we find a highly significant negative correlation between the number of biological processes in which a gene is involved in and its rate of evolution. However, the magnitude of this effect is small, and the results do not support the notion that multifunctionality limits a gene's rate of evolution.
Overweight - a risk factor of overuse injuries in children? the childhood health, activity and motor performance school study - a 3-year controlled intervention study
Authors: H Klakk, E Jespersen, N Wedderkopp
Journal: British Journal of Sports Medicine (2011)

Background Increased adiposity is a well-recognised risk factor for tendon injuries in adults. The mechanisms could be excess biomechanical load and/or the low inflammatory condition caused by excess body fat. The issue has not been investigated in children. Objective To investigate if children (aged 8–12) with elevated body mass index (BMI) or total body fat% (TBF%) and/or abdominal fat% (AF%) experience more overuse injuries than ‘normal’ children, taking into account sport participation and physical activity. Design A whole body DEXA scan was used to measure TBF% and AF% in 614 schoolchildren (aged 8–12). Standard anthropometric methods were used to measure waist circumference, weight and height. Physical activity was measured using the MTI accelerometer GT3. Complaints, injuries and sport participation were reported by answering text messages on a weekly basis (SMS-track). If an injury was reported, the child was seen and evaluated by a clinician (physiotherapist, chiropractor or orthopaedic surgeon), and clinical evaluation using ultrasound or MRI was performed when necessary, only diagnosed injuries were included. Main outcome measurements The primary outcome measures are the number and duration of diagnosed overuse injuries and the impact of BMI, TBF%/AF% will be analysed using cox regression for recurrent events as described by Wei, L. J., D. Y. Lin, and L. Weissfeld. 1989. The analyses will be adjusted for age, sport participation and objectively measured physical activity. Results and Conclusion Results and conclusion from 2 years follow-up will be reported at the conference.
Combined use of vasopressin and synthetic hypothalamic releasing factors as a new test of anterior pituitary function.
Authors: L M Sandler, J M Burrin, G F Joplin, S R Bloom
Journal: BMJ (1986)

Nine normal volunteers and 15 patients with pituitary disorders were given a combined test of anterior pituitary function using four hypothalamic releasing factors and arginine vasopressin. Rapid sequential intravenous infusions of human corticotrophin releasing factor 100 micrograms, growth hormone releasing factor 100 micrograms, luteinising hormone releasing hormone 100 micrograms, and thyrotrophin releasing hormone 200 micrograms were administered. Arginine vasopressin (10 pressor units) was given intramuscularly at the same time. Plasma or serum samples were assayed for concentrations of cortisol, growth hormone, luteinising hormone, follicle stimulating hormone, prolactin, and thyroid stimulating hormone at multiple times for 120 minutes. No troublesome side effects occurred. The results of the releasing factor combined test with arginine vasopressin were compared in the same subjects with a conventional combined test using insulin together with thyrotrophin releasing hormone and luteinising hormone releasing hormone. No difference was observed in the basal and peak concentrations of luteinising hormone, follicle stimulating hormone, thyroid stimulating hormone, and prolactin. Both cortisol and growth hormone responses to the releasing factors with arginine vasopressin were much greater than those seen with insulin induced hypoglycaemia or the combined releasing factors without arginine vasopressin. Patients with pituitary hypo-function were similarly recognised in both studies. There was a rapid increase in all hormone values with a peak usually by 60 minutes. In most people adequate assessment of individual hormone reserves may be achieved using basal, 30 minute, and 60 minute samples. This new combined releasing factor test appears to be a safe, rapid, and useful test of anterior pituitary function.
Regulation of hippocampal progenitor cell survival, proliferation and dendritic development by BDNF
Authors: Se Hoon Choi, Yun Li, Luis F Parada, Sangram S Sisodia
Journal: Molecular Neurodegeneration (2009)

Abstract Background Environmental enrichment (EE) is known to enhance BDNF levels and neurogenesis in the adult hippocampus. To examine the role of BDNF in modulating EE-mediated adult hippocampal neurogenesis, we conditionally ablated BDNF expression in the hippocampus (cKO mice) and have assessed proliferation, survival, differentiation and dendritic development of hippocampal progenitors. Results We show that while the extent of cell proliferation and neuronal fate differentiation in the hippocampus of cKO mice is not different from wild-type (WT) littermates maintained in either standard or enriched conditions, reduced BDNF levels significantly impaired the survival of newborn cells in both housing conditions. In addition, while highly active enriched WT mice exhibited a robust increase in progenitor cell proliferation, highly active cKO mice showed a modest increase in cell proliferation compared to standard housed or underactive cKO mice. Conclusions There results argue that while BDNF plays a role in exercise-induced cell proliferation, other factors must contribute to this phenomenon. We also show that dendritic development was impaired in cKO mice maintained in standard housing conditions, and that EE rescued this phenotype.
The role of organic osmolytes in the cerebral cell volume regulatory response to acute and chronic renal failure.
Authors: H Trachtman, S Futterweit, W Tonidandel, S R Gullans
Journal: Journal of the American Society of Nephrology (1993)

Brain cells respond to increased osmolality of the extracellular fluid by accumulating inorganic electrolytes and nonperturbing organic osmolytes to limit the extent of brain cell shrinkage. It is unclear whether urea is an effective osmole that triggers this adaptive response. Therefore, the amount of brain water and the cerebral content of organic osmolytes in rats with acute renal failure induced by bilateral ureteral ligation and in animals with chronic renal failure for 6 weeks created by a 75% reduction in renal mass were measured. Eight hours after the onset of acute renal failure, the BUN concentration and serum osmolality were 61 +/- 4 mg/dL and 314 +/- 2 mosmol/kg, respectively, compared with 13 +/- 1 mg/dL and 288 +/- 1 mosmol/kg, respectively, in sham-operated rats. This hyperosmolal state reduced brain water from 79.7 +/- 0.1% in controls to 79.2 +/- 0.1% in uremic animals (P < 0.01). During acute renal failure lasting 48 h, the BUN concentration and serum osmolality rose to 251 +/- 10 mg/dL and 370 +/- 4 mosmol/kg versus 18 +/- 1 mg/dL and 286 +/- 4 mosmol/kg, respectively, in sham-operated control rats. The percentage of brain water content was unchanged in rats with azotemia for 48 h--79.6 +/- 0.1 compared with 79.5 +/- 0.2% in controls. Stabilization of brain volume was associated with a 19% increment in total organic osmolyte content in brain cells from 123 +/- 6 to 146 +/- 2 mmol/kg dry wt (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Dendritic cell subsets: the ultimate T cell differentiation decision makers?
Authors: J L VINEY
Journal: Gut (1999)

It is not known whether subsets of dendritic cells provide diVerent cytokine microenvironments that determine the diVerentiation of either type-1 T helper (TH1) or TH2 cells.Human monocyte (pDC1)-derived dendritic cells (DC1) were found to induce TH1 diVerentiation, whereas dendritic cells (DC2) derived from CD4+CD3-CD11c-plasmacytoid cells (pDC2) induced TH2 diVerentiation by use of a mechanism unaVected by interleukin-4 (IL-4) or IL-12.The TH2 cytokine IL-4 enhanced DC1 maturation and killed pDC2, an eVect potentiated by IL-10 but blocked by CD40 ligand and interferon-gamma.Thus, a negative feedback loop from the mature T helper cells may selectively inhibit prolonged TH1 or TH2 responses by regulating survival of the appropriate dendritic cell subset.
Novel and Emerging Therapies for Pulmonary Hypertension
Authors: Soni Savai Pullamsetti, Ralph Schermuly, Ardeschir Ghofrani, Norbert Weissmann, Friedrich Grimminger, Werner Seeger
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Section:ChooseTop of pageAbstract <<Regulation of VasomotionVascular Reverse Remodeli...ConclusionsReferencesCITING ARTICLES
Adult Medulloblastoma Comprises Three Major Molecular Variants
Authors: Marc Remke, Thomas Hielscher, Paul A. Northcott, Hendrik Witt, Marina Ryzhova, Andrea Wittmann, Axel Benner, Andreas von Deimling, Wolfram Scheurlen, Arie Perry, Sidney Croul, Andreas E. Kulozik, Peter Lichter, Michael D. Taylor, Stefan M. Pfister, Andrey Korshunov
Journal: Journal of Clinical Oncology (2011)

Medulloblastoma is a rare primary brain tumor in adults, whereas it constitutes the most common malignant brain tumor in children. Integrated genomics approaches revealed at least four distinct disease variants in children. The aim of this study was to investigate molecular subtypes and their prognostic implication in a large cohort of adult medulloblastomas as the biology in this age group remains poorly understood.We combined transcriptome and DNA copy number analyses for 28 adult medulloblastomas. Statistical and bioinformatic tools were applied to discover distinct molecular variants. Clinical and molecular characteristics of each biologic subtype were validated using immunohistochemistry on a tissue microarray derived from an independent patient cohort of adult medulloblastomas (n = 103).Gene expression profiles revealed three distinct molecular variants with stable subtype separation using the 300 most varying transcripts. Distinct demographics, genetics, transcriptome, and prognosis were noted for each subtype of adult medulloblastoma. Immunohistochemistry revealed aberrant activation of the sonic hedgehog (SHH) pathway in over half of adult medulloblastomas constituting a promising molecular therapeutic target. In contrast, subtype C tumors, which comprise a robust subtype in childhood medulloblastoma are only exceptionally seen in adult cohorts. Notably, adult subtype D and Wnt/wingless tumors were associated with worse prognosis than pediatric cohorts, whereas survival for SHH tumors was similar for both age groups.The transcriptome of adult medulloblastomas differs considerably from pediatric counterparts, both in terms of tumor biology and prognostic impact. Therefore, age-specific classification is required and must be adapted for use in clinical trials of adult medulloblastoma.
A Serum MicroRNA Signature Predicts Tumor Relapse and Survival in Triple-Negative Breast Cancer Patients
Authors: Kristine Kleivi Sahlberg, Giulia Bottai, Bjørn Naume, Barbara Burwinkel, George A. Calin, Anne-Lise Børresen-Dale, Libero Santarpia
Journal: Clinical Cancer Research (2014)

Triple-negative breast cancers (TNBC) are associated with high risk of early tumor recurrence and poor outcome. Common prognostic biomarkers give very restricted predictive information of tumor recurrences in TNBC. Human serum contains stably expressed microRNAs (miRNAs), which have been discovered to predict prognosis in patients with cancer. The purpose of this study was to identify circulating biomarkers able to predict clinical outcome in TNBC.We performed genome-wide serum miRNA expression and real-time PCR analyses to investigate the ability of miRNAs in predicting tumor relapse in serum samples from 60 primary TNBC. Patients were divided into training and testing cohorts.By Cox regression analysis, we identified a four-miRNA signature (miR-18b, miR-103, miR-107, and miR-652) that predicted tumor relapse and overall survival. This miRNA signature was further validated in an independent cohort of 70 TNBC. A high-risk signature score was developed and significantly associated with tumor recurrence and reduced survival. Multivariate Cox regression models indicated that the risk score based on the four-miRNA signature was an independent prognostic classifier of patients with TNBC.This signature may serve as a minimally invasive predictor of tumor relapse and overall survival for patients with TNBC. This prediction model may ultimately lead to better treatment options for patients with TNBC.
Targeted Radiotherapy for Prostate Cancer with an Oncolytic Adenovirus Coding for Human Sodium Iodide Symporter
Authors: Tanja Hakkarainen, Maria Rajecki, Mirkka Sarparanta, Mikko Tenhunen, Anu J. Airaksinen, Renée A. Desmond, Kalevi Kairemo, Akseli Hemminki
Journal: Clinical Cancer Research (2009)

Oncolytic adenoviruses are promising tools for cancer therapy. Although several clinical reports have indicated both safety and promising antitumor capabilities for these viruses, there are only a few examples of complete tumor eradication. Thus, the antitumor efficacy of oncolytic adenoviruses needs to be improved. One potentially useful approach is combination with radiotherapy.To target systemically administered radioiodide to tumors, we created Ad5/3-Delta24-human sodium iodide symporter (hNIS), a Rb-p16 pathway selective infectivity enhanced oncolytic adenovirus encoding hNIS.Ad5/3-Delta24-hNIS replication effectively killed prostate cancer cells in vitro and in vivo. Also, the virus-mediated radioiodide uptake into prostate cancer cells in vitro and into tumors in vivo. Furthermore, Ad5/3-Delta24-hNIS with radioiodide was significantly more effective than virus alone in mice with prostate cancer xenografts.These results suggest that oncolytic adenovirus-mediated targeted radiotherapy might be a potentially useful option for enhancing the efficacy or adenoviral virotherapy.
ON CROSS REACTIONS OF IMMUNE SERA TO AZOPROTEINS
Authors: K. Landsteiner, J. van der Scheer
Journal: The Journal of Experimental Medicine (1936)

The phenomena observed on absorption of immune sera to azoproteins with heterologous azoantigens lead to the conclusion that in general the sera do not contain a single antibody but antibody fractions somewhat different in their reactivity for heterologous antigens. From the constitution of the azocomponent it follows that these fractions cannot be specific for distinct chemical groups in the molecule. In fact, inhibition experiments showed that in the cases examined the various antibodies are all specifically directed towards the whole molecule of the homologous hapten.
The RB-E2F1 Pathway Regulates Autophagy
Authors: Hong Jiang, Vanesa Martin, Candelaria Gomez-Manzano, David G. Johnson, Marta Alonso, Erin White, Jing Xu, Timothy J. McDonnell, Naoki Shinojima, Juan Fueyo
Journal: Cancer Research (2010)

Autophagy is a protective mechanism that renders cells viable in stressful conditions. Emerging evidence suggests that this cellular process is also a tumor suppressor pathway. Previous studies showed that cyclin-dependent kinase inhibitors (CDKI) induce autophagy. Whether retinoblastoma protein (RB), a key tumor suppressor and downstream target of CDKIs, induces autophagy is not clear. Here, we show that RB triggers autophagy and that the RB activators p16INK4a and p27/kip1 induce autophagy in an RB-dependent manner. RB binding to E2 transcription factor (E2F) is required for autophagy induction and E2F1 antagonizes RB-induced autophagy, leading to apoptosis. Downregulation of E2F1 in cells results in high levels of autophagy. Our findings indicate that RB induces autophagy by repressing E2F1 activity. We speculate that this newly discovered aspect of RB function is relevant to cancer development and therapy.
Variable window binding for mutually exclusive alternative splicing.
Authors: Dimitris Anastassiou, Hairuo Liu, Vinay Varadan
Journal: Genome biology (2006)

Genes of advanced organisms undergo alternative splicing, which can be mutually exclusive, in the sense that only one exon is included in the mature mRNA out of a cluster of alternative choices, often arranged in a tandem array. In many cases, however, the details of the underlying biologic mechanisms are unknown.We describe 'variable window binding'--a mechanism used for mutually exclusive alternative splicing by which a segment ('window') of a conserved nucleotide 'anchor' sequence upstream of the exon 6 cluster in the pre-mRNA of the fruitfly Dscam gene binds to one of the introns, thereby activating selection of the exon directly downstream from the binding site. This mechanism is supported by the fact that the anchor sequence can be inferred solely from a comparison of the intron sequences using a genetic algorithm. Because the window location varies for each exon choice, regulation can be achieved by obstructing part of that sequence. We also describe a related mechanism based on competing pre-mRNA stem-loop structures that could explain the mutually exclusive choice of exon 17 of the Dscam gene.On the basis of comparative sequence analysis, we propose efficient biologic mechanisms of alternative splicing of the Drosophila Dscam gene that rely on the inherent structure of the pre-mRNA. Related mechanisms employing 'locus control regions' could be involved on other occasions of mutually exclusive choices of exons or genes.
Comparative Effects of Irbesartan on Ambulatory and Office Blood Pressure
Authors: Kasper Rossing, Per K. Christensen, Steen Andersen, Peter Hovind, Henrik Post Hansen, Hans-Henrik Parving
Journal: Diabetes Care (2003)

OBJECTIVE—Irbesartan was renoprotective independently of its blood pressure-lowering effect in the Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA2) study. However, blood pressure was evaluated by trough office blood pressure (OBP), which may underestimate reductions in 24-h ambulatory blood pressure (ABP). In the present study, we evaluated 24-h blood pressure patterns in a subpopulation of the IRMA2 trial. RESEARCH DESIGN AND METHODS—Type 2 diabetic patients (n = 43) with persistent microalbuminuria (as determined by repeated overnight measurements of urinary albumin excretion [UAE]) and hypertension who were included in the IRMA2 study at the Steno Diabetes Center were subjected to 24-h ABP (Takeda, TM2420) measurements before and 2 years after randomization to placebo (n = 15), irbesartan 150 mg daily (Irb150; n = 13), or irbesartan 300 mg daily (Irb300; n = 15). RESULTS—At baseline, the placebo, Irb150, and Irb300 groups were comparable: OBP: 157 ± 15/89 ± 7, 156 ±15/91 ± 11, and 159 ± 16/90 ± 9 mmHg (NS); 24-h ABP: 148 ± 13/83 ± 11, 148 ± 16/82 ± 7 and 147 ± 16/81 ± 10 mmHg (NS); and UAE (geometric mean with 95% CI): 43 (32–57), 46 (30–70), and 59 (42–85) μg/min (NS), respectively. We found that 2 years after randomization, OBP was significantly reduced in all three groups (by 11/7, 13/8, and 13/8 mmHg in the placebo, Irb150, and Irb300 groups, respectively), but that there were no significant differences among groups. Reductions in 24-h ABP were similar in the three groups (11/10, 5/7, and 7/8 mmHg, respectively; NS), as were reductions in day ABP (11/9, 7/7, and 8/9 mmHg, respectively; NS) and night ABP (4/11, 7/7, and 3/3 mmHg, respectively; NS). The reduction in UAE at the end of the study was 0% (−86 to 42), 38% (−14 to 66), and 73% (59 to 82), respectively (overall, P &amp;lt; 0.01). CONCLUSION—Irbesartan is renoprotective independently of its beneficial effect in lowering 24-h blood pressure in patients with type 2 diabetes and persistent microalbuminuria.
Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock.
Authors: C Natanson, R L Danner, R J Elin, J M Hosseini, K W Peart, S M Banks, T J MacVittie, R I Walker, J E Parrillo
Journal: Journal of Clinical Investigation (1989)

Using different types of bacteria and a canine model simulating human septic shock, we investigated the role of endotoxin in cardiovascular dysfunction and mortality. Either Escherichia coli (a microorganism with endotoxin) or Staphylococcus aureus (a microorganism without endotoxin) were placed in an intraperitoneal clot in doses of viable or formalin-killed bacteria. Cardiovascular function of conscious animals was studied using simultaneous radionuclide heart scans and thermodilution cardiac outputs. Serial plasma endotoxin levels were measured. S. aureus produced a pattern of reversible cardiovascular dysfunction over 7-10 d that was concordant (P less than 0.01) with that of E. coli. Although this cardiovascular pattern was not altered by formalin killing (S. aureus and E. coli), formalin-killed organisms produced a lower mortality and less myocardial depression (P less than 0.01). S. aureus, compared to E. coli, produced higher postmortem concentrations of microorganisms and higher mortality (P less than 0.025). E. coli produced significant endotoxemia (P less than 0.01), though viable organisms (versus nonviable) resulted in higher endotoxin blood concentrations (P less than 0.05). Significant endotoxemia did not occur with S. aureus. Thus, in the absence of endotoxemia, S. aureus induced the same cardiovascular abnormalities of septic shock as E. coli. These findings indicate that structurally and functionally distinct microorganisms, with or without endotoxin, can activate a common pathway resulting in similar cardiovascular injury and mortality.
Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy
Authors: Nelson Jumbe, Arnold Louie, Robert Leary, Weiguo Liu, Mark R. Deziel, Vincent H. Tam, Reetu Bachhawat, Christopher Freeman, James B. Kahn, Karen Bush, Michael N. Dudley, Michael H. Miller, George L. Drusano
Journal: Journal of Clinical Investigation (2003)

The worldwide increase in the prevalence of multi-antibiotic–resistant bacteria has threatened the physician's ability to provide appropriate therapy for infections. The relationship between antimicrobial drug concentration and infecting pathogen population reduction is of primary interest. Using data derived from mice infected with the bacterium Pseudomonas aeruginosa and treated with a fluoroquinolone antibiotic, a mathematical model was developed that described relationships between antimicrobial drug exposures and changes in drug-susceptible and -resistant bacterial subpopulations at an infection site. Dosing regimens and consequent drug exposures that amplify or suppress the emergence of resistant bacterial subpopulations were identified and prospectively validated. Resistant clones selected in vivo by suboptimal regimens were characterized. No mutations were identified in the quinolone resistance–determining regions of gyrA/B or parC/E. However, all resistant clones demonstrated efflux pump overexpression. At base line, MexAB-OprM, MexCD-OprJ, and MexEF-OprN were represented in the drug-resistant population. After 28 hours of therapy, MexCD-OprJ became the predominant pump expressed in the resistant clones. The likelihood of achieving resistance-suppression exposure in humans with a clinically prescribed antibiotic dose was determined. The methods developed in this study provide insight regarding how mathematical models can be used to identify rational dosing regimens that suppress the amplification of the resistant mutant population.