tbuckley/cabot-search huggingface dataset:
Functional Roles of Multiple Feedback Loops in Extracellular Signal-Regulated Kinase and Wnt Signaling Pathways That Regulate Epithelial-Mesenchymal Transition
Authors: Sung-Young Shin, Oliver Rath, Armin Zebisch, Sang-Mok Choo, Walter Kolch, Kwang-Hyun Cho
Journal: Cancer Research (2010)

Epithelial-mesenchymal transition (EMT) is a key event in the generation of invasive tumor cells. A hallmark of EMT is the repression of E-cadherin expression, which is regulated by various signal transduction pathways including extracellular signal-regulated kinase (ERK) and Wnt. These pathways are highly interconnected via multiple coupled feedback loops (CFL). As the function of such coupled feedback regulations is difficult to analyze experimentally, we used a systems biology approach where computational models were designed to predict biological effects that result from the complex interplay of CFLs. Using epidermal growth factor (EGF) and Wnt as input and E-cadherin transcriptional regulation as output, we established an ordinary differential equation model of the ERK and Wnt signaling network containing six feedback links and used extensive computer simulations to analyze the effects of these feedback links in isolation and different combinations. The results show that the feedbacks can generate a rich dynamic behavior leading to various dose-response patterns and have a decisive role in determining network responses to EGF and Wnt. In particular, we made two important findings: first, that coupled positive feedback loops composed of phosphorylation of Raf kinase inhibitor RKIP by ERK and transcriptional repression of RKIP by Snail have an essential role in causing a switch-like behavior of E-cadherin expression; and second, that RKIP expression inhibits EMT progression by preventing E-cadherin suppression. Taken together, our findings provide us with a system-level understanding of how RKIP can regulate EMT progression and may explain why RKIP is downregulated in so many metastatic cancer cells.
Effectiveness of agricultural interventions that aim to improve nutritional status of children: systematic review
Authors: E. Masset, L. Haddad, A. Cornelius, J. Isaza-Castro
Journal: BMJ (2012)

Anticipatory load forces for dexterous object manipulation in humans are modulated based on visual object property cues, sensorimotor memories of previous experiences with the object, and, when digit positioning varies from trial to trial, the integrating of this sensed variability with force modulation. Studies of the neural representations encoding these anticipatory mechanisms have not considered these mechanisms separately from each other or from feedback mechanisms emerging after lift onset. Here, representational similarity analyses of fMRI data were used to identify neural representations of sensorimotor memories and the sensing and integration of digit position. Cortical activity and movement kinematics were measured as 20 human subjects (11 women) minimized tilt of a symmetrically shaped object with a concealed asymmetric center of mass (CoM, left and right sided). This task required generating compensatory torques in opposite directions, which, without helpful visual CoM cues, relied primarily on sensorimotor memories of the same object and CoM. Digit position was constrained or unconstrained, the latter of which required modulating forces beyond what can be recalled from sensorimotor memories to compensate for digit position variability. Ventral premotor (PMv), somatosensory, and cerebellar lobule regions (CrusII, VIIIa) were sensitive to anticipatory behaviors that reflect sensorimotor memory content, as shown by larger voxel pattern differences for unmatched than matched CoM conditions. Cerebellar lobule I–IV, Broca area 44, and PMv showed greater voxel pattern differences for unconstrained than constrained grasping, which suggests their sensitivity to monitor the online coincidence of planned and actual digit positions and correct for a mismatch by force modulation. <b>SIGNIFICANCE STATEMENT</b> To pick up a water glass without slipping, tipping, or spilling requires anticipatory planning of fingertip load forces before the lift commences. This anticipation relies on object visual properties (e.g., mass/mass distribution), sensorimotor memories built from previous experiences (especially when object properties cannot be inferred visually), and online sensing of where the digits are positioned. There is limited understanding of how the brain represents each of these anticipatory mechanisms. We used fMRI measures of regional brain patterns and digit position kinematics before lift onset of an object with nonsalient visual cues specifically to isolate sensorimotor memories and integration of sensed digit position with force modulation. In doing so, we localized neural representations encoding these anticipatory mechanisms for dexterous object manipulation.
Prolonged pregnancy: the management debate
Authors: K J. Dennis
Journal: BMJ (1986)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Prolonged pregnancy: the management debate Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Automating curation using a natural language processing pipeline
Authors: Beatrice Alex, Claire Grover, Barry Haddow, Mijail Kabadjov, Ewan Klein, Michael Matthews, Richard Tobin, Xinglong Wang
Journal: Genome biology (2008)

The tasks in BioCreative II were designed to approximate some of the laborious work involved in curating biomedical research papers. The approach to these tasks taken by the University of Edinburgh team was to adapt and extend the existing natural language processing (NLP) system that we have developed as part of a commercial curation assistant. Although this paper concentrates on using NLP to assist with curation, the system can be equally employed to extract types of information from the literature that is immediately relevant to biologists in general. Our system was among the highest performing on the interaction subtasks, and competitive performance on the gene mention task was achieved with minimal development effort. For the gene normalization task, a string matching technique that can be quickly applied to new domains was shown to perform close to average. The technologies being developed were shown to be readily adapted to the BioCreative II tasks. Although high performance may be obtained on individual tasks such as gene mention recognition and normalization, and document classification, tasks in which a number of components must be combined, such as detection and normalization of interacting protein pairs, are still challenging for NLP systems.
Derivation and Validation of a New Cardiovascular Risk Score for People With Type 2 Diabetes
Authors: C. Raina Elley, Elizabeth Robinson, Tim Kenealy, Dale Bramley, Paul L. Drury
Journal: Diabetes Care (2010)

To derive a 5-year cardiovascular disease (CVD) risk equation from usual-care data that is appropriate for people with type 2 diabetes from a wide range of ethnic groups, variable glycemic control, and high rates of albuminuria in New Zealand.This prospective open-cohort study used primary-care data from 36,127 people with type 2 diabetes without previous CVD to derive a CVD equation using Cox proportional hazards regression models. Data from 12,626 people from a geographically different area were used for validation. Outcome measure was time to first fatal or nonfatal cardiovascular event, derived from national hospitalization and mortality records. Risk factors were age at diagnosis, diabetes duration, sex, systolic blood pressure, smoking status, total cholesterol-to-HDL ratio, ethnicity, glycated hemoglobin (A1C), and urine albumin-to-creatinine ratio.Baseline median age was 59 years, 51% were women, 55% were of non-European ethnicity, and 33% had micro- or macroalbuminuria. Median follow-up was 3.9 years (141,169 person-years), including 10,030 individuals followed for at least 5 years. At total of 6,479 first cardiovascular events occurred during follow-up. The 5-year observed risk was 20.8% (95% CI 20.3-21.3). Risk increased with each 1% A1C (adjusted hazard ratio 1.06 [95% CI 1.05-1.08]), when macroalbuminuria was present (2.04 [1.89-2.21]), and in Indo-Asians (1.29 [1.14-1.46]) and Maori (1.23 [1.14-1.32]) compared with Europeans. The derived risk equations performed well on the validation cohort compared with other risk equations.Renal function, ethnicity, and glycemic control contribute significantly to cardiovascular risk prediction. Population-appropriate risk equations can be derived from routinely collected data.
Risk Factors for Classical Kaposi's Sarcoma
Authors: J. J. Goedert
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Classical Kaposi's sarcoma (KS) is a malignancy of lymphatic endothelial skin cells. Although all forms of KS are associated with the KS-associated herpesvirus (KSHV), classical KS occurs in a small fraction of KSHV-infected people. We sought to identify risk factors for classical KS in KSHV-infected individuals. Methods: Lifestyle and medical history data from case patients with biopsy-proven non-AIDS (non-acquired immunodeficiency syndrome) KS in Italy were compared by logistic regression analysis with data from population-based KSHV-seropositive control subjects of comparable age and sex. After KSHV immunofluorescence testing, randomly selected patients on the rosters of local physicians were identified as control subjects. Risk of KS was estimated by odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: From April 13, 1998, through October 8, 2001, we enrolled 141 classical KS case patients and 192 KSHV-seropositive control subjects of similar age (mean = 72 years for case patients and 73 years for control subjects) and sex (30% female case patients and 35% female control subjects). The strongest association was a reduced risk of KS with cigarette smoking (OR = 0.25, 95% CI = 0.14 to 0.45). Cigarette smoking intensity and duration could be evaluated for men, among whom the risk for KS was inversely related to the amount of cumulative smoking (Ptrend<.001). KS risk decreased approximately 20% (OR = 0.81, 95% CI = 0.74 to 0.89) for each 10 pack-years reported, and it was decreased sevenfold (OR = 0.14, 95% CI = 0.07 to 0.30) with more than 40 pack-years. In multivariable analysis, a decreased KS risk was associated with smoking (OR = 0.23, 95% CI = 0.12 to 0.44); but an increased KS risk was associated with topical corticosteroid use (OR = 2.73, 95% CI = 1.35 to 5.51), infrequent bathing (OR = 1.85, 95% CI = 1.04 to 3.33), and a history of asthma (OR = 2.18, 95% CI = 0.95 to 4.97) or of allergy among men (OR = 2.59, 95% CI = 1.15 to 5.83) but not among women (OR = 0.09, 95% CI = 0.003 to 2.76). KS was not related to other exposures or illnesses examined. Conclusion: Risk for classical KS was approximately fourfold lower in cigarette smokers, a result that requires confirmation by other studies. Identification of how smoking affects KS risk may lead to a better understanding of the pathogenesis of this malignancy and interventions for its prevention.
Somatoform Disorders: Time for a New Approach in DSM-V
Authors: Richard Mayou, Laurence J. Kirmayer, Greg Simon, Kurt Kroenke, Michael Sharpe
Journal: American Journal of Psychiatry (2005)

DSM-III introduced somatoform disorders as a speculative diagnostic category for somatic symptoms "not explained by a general medical condition." Although retained and enlarged in DSM-IV, somatoform disorders have been the subject of continuing criticism by both professionals and patients. The extended period of preparation for DSM-V offers an important opportunity to reconsider the category of somatoform disorders.Exploration of the diverse aims of a diagnostic classification indicates that the authors must not only address the conceptual and practical problems associated with this category but also reconcile it with the parallel medical descriptive classification of functional symptoms and syndromes.The existing somatoform disorders categories require modification. The authors favor the radical option of the abolition of the categories. Diagnoses currently within somatoform disorders could be redistributed into other groupings, and the disorders currently defined solely by somatic symptoms could be placed on axis III as "functional somatic symptoms and syndromes." Greater use could be made of "psychological factors affecting medical condition" on axis I. The authors suggest supplementing the diagnosis of functional somatic symptoms with a multiaxial formulation.The authors promote a classification of somatic symptoms in DSM-V that is compatible with that used in general medicine and offers new opportunities both for research into the etiology and treatment of symptoms and for the greater integration of psychiatry into general medical practice.
Current trends in the structure—activity relationship studies of the endogenous agouti‐related protein (AGRP) melanocortin receptor antagonist
Authors: Andrzej M. Wilczynski, Christine G. Joseph, Carrie Haskell‐Luevano
Journal: Medicinal Research Reviews (2005)

Abstract Agouti‐related protein (AGRP) is an endogenous antagonist of the melanocortin‐3 and ‐4 (MC3R and MC4) G‐protein coupled receptors. The 87–132 amino acid C‐terminal domain of hAGRP possesses five disulfide bridges and a well‐defined three‐dimensional structure that displays full biological activity as compared to the full‐length protein. Based on the NMR structure of the C‐terminal AGRP(87–132), a novel mini‐protein, referred to as “Mini‐AGRP” was designed that exhibited receptor binding affinity and antagonism similar to that of the parent hAGRP(87–132) protein. It was demonstrated that this new‐engineered protein autonomously folds to the inhibitor cystine knot (ICK) motif. As this AGRP is a novel mammalian protein involved in energy homeostasis and possibly other physiological functions remaining to be identified, structure‐function studies are starting to emerge toward the understanding of how this unique protein putatively interacts with the melanocortin receptors with the objective of designing potential therapeutic agents for in vivo physiological studies. This article summarizes the progress to date of AGRP‐based structure–activity relationships and putative ligand–receptor interactions. © 2005 Wiley Periodicals, Inc.
Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155
Authors: Suhwan Chang, Rui-Hong Wang, Keiko Akagi, Kyung-Ae Kim, Betty K Martin, Luca Cavallone, Diana C Haines, Mark Basik, Phuong Mai, Elizabeth Poggi, Claudine Isaacs, Lai M Looi, Kein S Mun, Mark H Greene, Stephen W Byers, Soo H Teo, Chu-Xia Deng, Shyam K Sharan
Journal: Nature Medicine (2011)
Do Interventions to Reduce Coronary Heart Disease Reduce the Incidence of Type 2 Diabetes? A Possible Role for Inflammatory Factors
Authors: Steven M. Haffner
Journal: Circulation (2001)

ype 2 diabetes is as a major cause of coronary heart disease (CHD).In some studies, the rate of CHD in type 2 diabetic subjects approaches that observed in some subjects with prevalent CHD. 1 Additionally, the case fatality rate of CHD is increased in type 2 diabetics. 2In one Finnish study, 50% of diabetic men who had a first coronary heart event died within a year of their initial presentation; 50% of these fatal cases died before they reached the hospital ("sudden death").These subjects, by definition, could not benefit from a secondary prevention program. 2 Clearly, preventing type 2 diabetes would be important in the reduction of CHD.The Diabetes Prevention Program 3 is a large National Institutes of Health-funded trial to prevent diabetes in subjects with impaired glucose tolerance.The interventions being tested are metformin and intensive lifestyle changes.Recently, the Finnish Diabetes Prevention Program reported a 58% reduction in the incidence of type 2 diabetes in 523 subjects with impaired glucose tolerance (American Diabetes Association, personal communication, June 2000).
Increased Superoxide and Vascular Dysfunction in CuZnSOD-Deficient Mice
Authors: Sean P. Didion, Michael J. Ryan, Lisa A. Didion, Pamela E. Fegan, Curt D. Sigmund, Frank M. Faraci
Journal: Circulation Research (2002)

Increased superoxide is thought to play a major role in vascular dysfunction in a variety of disease states. Superoxide dismutase (SOD) limits increases in superoxide; however, the functional significance of selected isoforms of SOD within the vessel wall are unknown. We tested the hypothesis that selective loss of CuZnSOD results in increased superoxide and altered vascular responsiveness in CuZnSOD-deficient (CuZnSOD(-/-)) mice compared with wild-type (CuZnSOD(+/+)) littermates. Total SOD activity was reduced (P<0.05) by approximately 60% and CuZnSOD protein was absent in aorta from CuZnSOD(-/-) as compared with wild-type mice. Vascular superoxide levels, measured using lucigenin (5 micro mol/L)-enhanced chemiluminescence and hydroethidine (2 micro mol/L)-based confocal microscopy, were increased (approximately 2-fold; P<0.05) in CuZnSOD(-/-) mice as compared with wild-type mice. Relaxation of the carotid artery in response to acetylcholine and authentic nitric oxide was impaired (P<0.05) in CuZnSOD(-/-) mice. For example, maximal relaxation to acetylcholine (100 micro mol/L) was 50+/-6% and 69+/-5% in CuZnSOD(-/-) and wild-type mice, respectively. Contractile responses of the carotid artery were enhanced (P<0.05) in CuZnSOD(-/-) mice in response to phenylephrine and serotonin, but not to potassium chloride or U46619. In vivo, dilatation of cerebral arterioles (baseline diameter=31+/-1 micro m) to acetylcholine was reduced by approximately 50% in CuZnSOD(-/-) mice as compared with wild-type mice (P<0.05). These findings provide the first direct insight into the functional importance of CuZnSOD in blood vessels and indicate that this specific isoform of SOD limits increases in superoxide under basal conditions. CuZnSOD-deficiency results in altered responsiveness in both large arteries and microvessels.
Germ cell-induced immune suppression in mice. Effect of inoculation of syngeneic spermatozoa on cell-mediated immune responses.
Authors: U Hurtenbach, G M Shearer
Journal: The Journal of Experimental Medicine (1982)

Spleen cells from mice injected intravenously with syngeneic male germ cells exhibited reduced immune functions as determined by natural killer cell activity, mixed lymphocyte reactivity and cytotoxic lymphocyte (CTL) function. The decrease in CTL responses to trinitrophenyl-modified self (TNP-self) was detected as early as 4 d after sperm injection and was observed to H-2 alloantigens 3 wk after injection. Radiosensitive suppressor T cells were found to suppress the CTL response to TNP-self. Suppression lasted for a period of at least 7 wk after a single inoculation of the germ cells. Some variability in immune suppression capability was observed using different preparations of germ cells which are not yet completely understood. Sperm were more effective in inducing suppression than testicular cells derived from the seminiferous tubules. Furthermore, sperm from older animals were more effective than those from younger mice. These findings are discussed with respect to possible regulatory influences of germ cells on the immune system when the blood-testes barrier is broken.
A Trip Through my Life With an Immunological Theme
Authors: Charles A. Janeway
Journal: Annual Review of Immunology (2002)

In this essay, I make four points about the operation of the immune system. First, thanks to the innate immune system's regulation of the main costimulatory molecules CD80 and CD86, the immune system rarely mistakes a pathogen for a self-antigen. Second, the adaptive immune system consisting of T lymphocytes and B lymphocytes can mistake self for non-self because adaptive immunity is selected in single somatic cells. Third, the adaptive immune system of T lymphocytes and B lymphocytes is always referential to self, as it is selected on self-ligands; it persists in the periphery on self-ligands; and at least for T cells, it is dependent on self-ligands to be able to mount a response. Fourth, it is becoming clear that regulatory or suppressor T cells are our main defense against autoimmunity, as my first boss, Richard Gershon, had predicted. These cells recognize antigen as do all T cells, but they secrete the immunoregulatory cytokines IL-10 and TGFβ.
Adiponectin Is Associated With Vascular Function Independent of Insulin Sensitivity
Authors: José-Manuel Fernández-Real, Antoni Castro, Gabriel Vázquez, Roser Casamitjana, Abel López-Bermejo, Georgina Peñarroja, Wifredo Ricart
Journal: Diabetes Care (2004)

OBJECTIVE—Adiponectin has been proposed to play important roles in the regulation of energy homeostasis and insulin sensitivity. In experimental studies, adiponectin has also been found to inhibit vascular smooth muscle cell proliferation. Decreased adiponectin levels have been described in patients with coronary artery disease, and circulating adiponectin predicts cardiovascular death in patients with renal failure. Because adiponectin appears to influence both insulin sensitivity and vessel wall physiology, we examined insulin sensitivity and vascular function in relation with circulating adiponectin. RESEARCH DESIGN AND METHODS—We studied brachial artery vascular reactivity (high-resolution external ultrasound) and insulin sensitivity (minimal model) in 68 healthy subjects. Brachial artery vascular reactivity was also determined in 52 patients with altered glucose tolerance: 30 subjects with impaired fasting glucose (IFG) or glucose intolerance (GIT) and 22 patients with type 2 diabetes. RESULTS—Circulating adiponectin concentration was significantly associated with insulin sensitivity (r = 0.29, P = 0.02) and with fasting serum triglycerides (r = −0.29, P = 0.02) in healthy subjects. In the latter, adiponectin levels were positively associated with arterial vasodilation in response to nitroglycerin (endothelium-independent vasodilation [EIVD], r = 0.41, P = 0.002) but not with flux-induced, endothelium-dependent vasodilation (EDVD) (r = 0.007, P = NS). In contrast, EIVD was not significantly associated with adiponectin in subjects with IFG, GIT, or type 2 diabetes (r ≤ 0.10, P = NS). In a multiple linear regression analysis to predict EIVD in healthy subjects, age (P = 0.012), sex (P = 0.042), and adiponectin concentration (P = 0.045), but not BMI, insulin sensitivity, or fasting triglycerides, contributed to 39% of EIVD variance. CONCLUSIONS—Serum adiponectin concentration appears to be significantly associated with vascular function in apparently healthy humans. This association seems to be independent of its link with insulin sensitivity.