tbuckley/cabot-search huggingface dataset:
Functionally important segments in proteins dissected using Gene Ontology and geometric clustering of peptide fragments
Authors: Karuppasamy Manikandan, Debnath Pal, Suryanarayanarao Ramakumar, Nathan E Brener, Sitharama S Iyengar, Guna Seetharaman
Journal: Genome biology (2008)

We have developed a geometric clustering algorithm using backbone φ,ψ angles to group conformationally similar peptide fragments of any length. By labeling each fragment in the cluster with the level-specific Gene Ontology 'molecular function' term of its protein, we are able to compute statistics for molecular function-propensity and p-value of individual fragments in the cluster. Clustering-cum-statistical analysis for peptide fragments 8 residues in length and with only trans peptide bonds shows that molecular function propensities ≥20 and p-values ≤0.05 can dissect fragments within a protein linked to the molecular function.
Use of Insulin Glargine During Pregnancy in Seven Type 1 Diabetic Women
Authors: Jorien M. Woolderink, Aren J. van Loon, Fred Storms, Loek de Heide, Klaas Hoogenberg
Journal: Diabetes Care (2005)

Insulin glargine is a human insulin analog with an activity that results in a relatively constant concentration/time profile over 24 h with no pronounced peak. It is increasingly recognized to provide good glycemic control and to reduce the risk of hypoglycemia in type 1 diabetes (1). There may be a place for insulin glargine in diabetic pregnancies in which strict glycemic control and prevention of hypoglycemia reduce the higher adverse outcome risk. Despite animal studies showing the safety and efficacy of insulin glargine during pregnancy (2), its use in human pregnancies is currently not recommended. There are two case reports on the occasional use of insulin glargine during pregnancy (3, 4) and a notification of its safety in five patients during the first weeks of pregnancy (5). To …
Evidence for sequential signals in the induction of the arachidonic acid cascade in macrophages.
Authors: A A Aderem, W A Scott, Z A Cohn
Journal: The Journal of Experimental Medicine (1986)

We have examined the requirement for Na+, Ca2+, and protein synthesis in the induction of the arachidonic acid (20:4) cascade in cultured murine peritoneal macrophages. Replacement of extracellular Na+ with choline or with K+ inhibited receptor-mediated 20:4 release by 60-90%, but did not inhibit release stimulated by the soluble triggers PMA and A23187. Cells that had preingested zymosan particles in a K+ medium could be induced to secrete 20:4 metabolites merely by changing the medium to one containing Na+. The Ca2+ ionophore A23187 caused cells in Na+-free medium to release and metabolize 20:4 to prostacyclin, PGE2, leukotriene C, and hydroxyeicosatetraenoic acids, suggesting that the phospholipase(s), cyclooxygenase, and lipoxygenase enzymes do not have a requirement for extracellular Na+. These data suggest that receptor-mediated 20:4 secretion has a requirement for extracellular Na+, while 20:4 release triggered by soluble stimuli do not. Immune complex- and A23187-induced 20:4 release was absolutely dependent on extracellular Ca2+. PMA-triggered 20:4 secretion was inhibited 50% in Ca2+-free medium, but could be inhibited completely by preloading the cells with the Ca2+ antagonist quinine. Protein and RNA synthesis was required for 20:4 release induced by zymosan, immune complex, and PMA, but not by A23187. Cycloheximide and emetine were effective within 15 min of addition, while actinomycin D was an effective inhibitor within 45 min. We suggest that receptor-mediated signal response coupling in the 20:4 cascade in macrophages comprises a sequential series of signals that includes an Na+ influx, synthesis of a rapid turnover-protein, and finally an increase in intracellular Ca2+.
Cancer in the Elderly Population: The Protection Racket
Authors: Derek Raghavan, Theodore Suh
Journal: Journal of Clinical Oncology (2006)

For the past century, patients of older age have constituted one of the substantially underserved populations in cancer care, 1 a puzzling dichotomy when one considers that cancer is classically a disease of the older population and that the proportion of these patients in the community is increasing. 2 The reasons for this imbalance are protean— older patients are traditionally conservative, have a somewhat nihilistic view of cancer treatment, and often have fewer resources needed to gain optimal care. The situation has been compounded by the medical protectionism that has been fostered by the government—in the past, studies of the National Cancer Institute (Bethesda, MD) have excluded patients over the age of 65 or 70 years, few provisions have been made for the additional requirements for participation in clinical trials by older patients, and government agencies have interfered with the implementation of studies focused on them by limiting the aggression of proposed treatment protocols in favor of more conservative, gentler regimens. In addition, physicians have been notoriously reluctant to refer older patients for clinical trials, and as a result of governmental disincentives, have avoided designing trials specifically for older patients. It is clear that the use of optimal treatment for curable cancers in elders is ultimately much less morbid than the implementation of attenuated strategies that sacrifice the chance of cure in exchange for reduced acute toxicity. Although this is particularly important in the management of localized disease, our studies from more than 15 years ago showed quite clearly that chemotherapy can be very useful in curing or palliating elderly populations with advanced cancer. 3,4 The choice of treatment must be predicated on consideration of the untreated natural history of the disease, the efficacy and toxicity of the proposed treatment, and the active life expectancy and comorbidities of the patient— essentially a costbenefit analysis. In the setting of advanced disease, the efficacy and toxicity of treatment are influenced by several factors, including age, comorbidity and organ function, other medications, and adherence to medication schedules. Unfortunately, this information is not available for many of the drugs available for cancer treatment in very elderly populations, largely because the acquisition of these data requires time and commitment on the part of investigators and patients. The investigators of Cancer and Leukemia Group B are to be complimented for their creativity in modifying pharmacologic sampling schedules, and thus in completing this important study that shows the variability of pharmacokinetics of paclitaxel in older patients, with the general reduction of clearance of this agent with increasing age. 5 However, there was no attempt at direct comparison
Excessive Sarcoplasmic/Endoplasmic Reticulum Ca <sup>2+</sup> -ATPase Expression Causes Increased Sarcoplasmic Reticulum Ca <sup>2+</sup> Uptake but Decreases Myocyte Shortening
Authors: Nils Teucher, Juergen Prestle, Tim Seidler, Susan Currie, Elspeth B. Elliott, Deborah F. Reynolds, Peter Schott, Stefan Wagner, Harald Kogler, Giuseppe Inesi, Donald M. Bers, Gerd Hasenfuss, Godfrey L. Smith
Journal: Circulation (2004)

Increasing sarcoplasmic/endoplasmic reticulum (SR) Ca2+-ATPase (SERCA) uptake activity is a promising therapeutic approach for heart failure. We investigated the effects of different levels of SERCA1a expression on contractility and Ca2+ cycling. We tested whether increased SERCA1a expression levels enhance myocyte contractility in a gene-dose-dependent manner.Rabbit isolated cardiomyocytes were transfected at different multiplicities of infection (MOIs) with adenoviruses encoding SERCA1a (or beta-galactosidase as control). Myocyte relaxation half-time was decreased by 10% (P=0.052) at SERCA1a MOI 10 and by 28% at MOI 50 (P<0.05). Myocyte fractional shortening was increased by 12% at MOI 10 (P<0.05) but surprisingly decreased at MOI 50 (-22%, P<0.05) versus control. SR Ca2+ uptake (in permeabilized myocytes) demonstrated a gene-dose-dependent decrease in K(m) by 29% and 46% and an increase in Vmax by 37% and 72% at MOI 10 and MOI 50, respectively (all P<0.05 versus control). Ca2+ transient amplitude was increased in Ad-SERCA1a-infected myocytes at MOI 10 (by 121%, P<0.05), but at MOI 50, the Ca2+ transient amplitude was not significantly changed. Caffeine-induced Ca2+ transients indicated significantly increased SR Ca2+ content in Ad-SERCA1a-infected cells, by 72% at MOI 10 and by 87% at MOI 50. Mathematical simulations demonstrate that the functional increase in SR Ca2+-ATPase uptake activity at MOI 50 (and increased cytosolic Ca2+ buffering) is sufficient to curtail the Ca2+ transient amplitude and explain the reduced contraction.Moderate SERCA1a gene transfer and expression improve contractility and Ca(2+) cycling. However, higher SERCA1a expression levels can impair myocyte shortening because of higher SERCA activity and Ca2+ buffering.
Benefits of lifestyle modification in NAFLD
Authors: S. A Harrison, C. P. Day
Journal: Gut (2007)

ompared with our ancestors, Western societies today lead a lifestyle that is much more sedentary, probably as a result of cultural changes stemming from modern socio-economic morays.Taking into account differences in body size, our energy expenditure per kilogram of body weight has been estimated to be ,40% of that of our prehistoric ancestors. 1 Current estimates suggest that 7 out of 10 adults are inactive or lack adequate conditioning, 2 and this lack of adequate exercise, combined with dietary indiscretion, has contributed to the worldwide epidemic of obesity and non-alcoholic fatty liver disease (NAFLD).Within the USA, data suggest that 64.5% of the adult population is now overweight or obese, with a worldwide prevalence of 40-60%. 3-5Obesity, combined with host factors such as diet, sedentary lifestyle and genetic predisposition, has been directly associated with increases in the prevalence of insulin resistance, diabetes mellitus and the metabolic syndrome.The hepatic manifestation of the metabolic syndrome, NAFLD, has also increased in prevalence, now considered to be around 20-30% in Western countries.Among morbidly obese patients undergoing bariatric surgery, approximately 90% have NAFLD and 36-37% have the more aggressive form of fatty liver, non-alcoholic steatohepatitis (NASH). 6 7In patients with NAFLD, advancing age, increasing weight, the number of features of the metabolic syndrome and the degree of insulin resistance have all been independently associated with NASH severity. 8Evidence-based treatment options for NAFLD are currently lacking.Recent data suggest that the thiazolidinedione class of insulin sensitisers may be efficacious, but widespread utilisation of these agents awaits further investigation. 9Evidence also supports a role for weight loss, achieved through diet and exercise.The purpose of this review is to describe the currently accepted pathophysiology of NAFLD, to highlight the known dietary and exercise habits of patients with NAFLD, and to detail the benefits of lifestyle modification with diet and/or exercise on parameters of metabolic syndrome, including insulin resistance and NAFLD.The effects on liver histopathology, where available, will also be detailed.
Climate change: The impact of different pollen burden on hay fever peculiarities
Authors: Rafail Rozenson, Saule Zhumambayeva
Journal: European Respiratory Journal (2012)

The aim of the study: To compare hay fever peculiarities and clinical duration in children and adolescents of the same region in the conditions of different pollen burden.  Material and methods: the study conducted in seasons of 2010 and 2011. The special allergological questionnaires were completed. Pollen burden count was assessed by the standard method. Correlation between intensity of clinical manifestations and meteorological factors like average temperature, atmospheric moisture capacity and precipitations were determined. Meteorological data were obtained in the Civil Aviation Meteorological Station of Astana airport.  Results: We compared two different pollen loads in two consequent pollination seasons of 2010 and 2011. Due to unusually warm April of 2011 with average temperature more than 17oC, a great shift in pollination duration and intensity ascertained. The total pollen load in August 2010 was from 14 to 37 pollen grains per one air liter3, whereas in the same period in August 2011 it varied from 31 to 64 pollen grains per one air liter3. Totally 467 patients with hay fever were examined. In comparison to 2010, the season of 2011 showed high incidence of firstly diagnosed hay fever cases (36.4% instead of 17.3%, P  Conclusions: Climate change has a great influence on hay fever clinical peculiarities in children and adolescents.
Both Cell Fusion and Transdifferentiation Account for the Transformation of Human Peripheral Blood CD34-Positive Cells Into Cardiomyocytes In Vivo
Authors: Sui Zhang, Dachun Wang, Zeev Estrov, Sean Raj, James T. Willerson, Edward T.H. Yeh
Journal: Circulation (2004)

Adult human peripheral blood CD34-positive (CD34+) cells appear to transform into cardiomyocytes in the injured hearts of severe combined immunodeficient mice. It remains unclear, however, whether the apparent transformation is the result of transdifferentiation of the donor stem cells or of fusion of the donor cell with the cardiomyocyte of the recipients.We performed flow cytometry analyses of cells isolated from the hearts of mice that received human CD34+ cells. Human HLA-ABC antigen and cardiac troponin T or Nkx2.5 were used as markers for cardiomyocytes derived from human CD34+ cells, and HLA-ABC and VE-cadherin were used to identify the transformed endothelial cells. The double-positive cells were collected and interphase fluorescence in situ hybridization was used to detect the expression of human and mouse X chromosomes in these cells. We found that 73.3% of nuclei derived from HLA+ and troponin T+ or Nkx2.5+ cardiomyocytes contain both human and mouse X chromosomes and 23.7% contain only human X chromosome. In contrast, the nuclei of HLA-, troponin T+ cells contain only mouse X chromosomes. Furthermore, 97.3% of endothelial cells derived from CD34+ cells contained human X chromosome only.Thus, both cell fusion and transdifferentiation may account for the transformation of peripheral blood CD34+ cells into cardiomyocytes in vivo.
Afebrile meningoencephalitis with transient central facial paralysis due to Toscana virus infection, south-eastern France, 2014
Authors: M C Marlinge, L Crespy, C Zandotti, G Piorkowski, E Kaphan, R N Charrel, L Ninove
Journal: Eurosurveillance (2014)

We report a case of meningoencephalitis caused by Toscana virus (TOSV) with central facial paralysis lasting over two days acquired in south-eastern France. The patient was not febrile either before or during the course of the disease. The diagnosis was established by both real-time RT-PCR and virus isolation with complete genome sequencing. This case emphasises the need to consider TOSV in non-febrile neurological syndromes in people living in or having travelled to the Mediterranean area.
Lazarillo-related Lipocalins confer long-term protection against type I Spinocerebellar Ataxia degeneration contributing to optimize selective autophagy
Authors: Manuela del Caño-Espinel, Judith R Acebes, Diego Sanchez, Maria D Ganfornina
Journal: Molecular Neurodegeneration (2015)

A diverse set of neurodegenerative disorders are caused by abnormal extensions of polyglutamine (poly-Q) stretches in various, functionally unrelated proteins. A common feature of these diseases is altered proteostasis. Autophagy induction is part of the endogenous response to poly-Q protein expression. However, if autophagy is not resolved properly, clearance of toxic proteins or aggregates cannot occur effectively. Likewise, excessive autophagy induction can cause autophagic stress and neurodegeneration. The Lipocalins ApoD, Glial Lazarillo (GLaz) and Neural Lazarillo (NLaz) are neuroprotectors upon oxidative stress or aging. In this work we test whether these Lipocalins also protect against poly-Q-triggered deterioration of protein quality control systems.Using a Drosophila retinal degeneration model of Type-1 Spinocerebellar Ataxia (SCA1) combined with genetic manipulation of NLaz and GLaz expression, we demonstrate that both Lipocalins protect against SCA1 neurodegeneration. They are part of the endogenous transcriptional response to SCA1, and their effect is non-additive, suggesting participation in a similar mechanism. GLaz beneficial effects persist throughout aging, and appears when expressed by degenerating neurons or by retinal support and glial cells. GLaz gain-of-function reduces cell death and the extent of ubiquitinated proteins accumulation, and decreases the expression of Atg8a/LC3, p62 mRNA and protein levels, and GstS1 induction. Over-expression of GLaz is able to reduce p62 and ubiquitinated proteins levels when rapamycin-dependent and SCA1-dependent inductions of autophagy are combined. In the absence of neurodegeneration, GLaz loss-of-function increases Atg8a/LC3 mRNA and p62 protein levels without altering p62 mRNA levels. Knocking-down autophagy, by interfering with Atg8a or p62 expression or by expressing dominant-negative Atg1/ULK1 or Atg4a transgenes, rescues SCA1-dependent neurodegeneration in a similar extent to the protective effect of GLaz. Further GLaz-dependent improvement is concealed.This work shows for the first time that a Lipocalin rescues neurons from pathogenic SCA1 degeneration by optimizing clearance of aggregation-prone proteins. GLaz modulates key autophagy genes and lipid-peroxide clearance responsive genes. Down-regulation of selective autophagy causes similar and non-additive rescuing effects. These data suggest that SCA1 neurodegeneration concurs with autophagic stress, and places Lazarillo-related Lipocalins as valuable players in the endogenous protection against the two major contributors to aging and neurodegeneration: ROS-dependent damage and proteostasis deterioration.
Some clarification is necessary on the Oslo definitions for coeliac disease-related terms
Authors: Antonio Di Sabatino, Gino R Corazza
Journal: Gut (2012)

We read with much interest and welcome the Oslo definitions for coeliac disease (CD) drawn up by a multidisciplinary task force of 16 international experts,1 one of whom (FB) belongs to our group and shares our opinions on CD. However, the strength of each statement could have been graded according to an evidence-based consensus on the definition.2 The failure to do so is a pity, as the more convincing a statement is, the more it will be accepted and followed.

To give an example, while the reasons that led to rejecting terms such as ‘typical’ or ‘atypical’ seem very clear, those that led to preferring ‘asymptomatic’ (39 PubMed hits) to ‘silent’ (80 hits) are less …
Effect of Enhanced Contractility on the Left Ventricular Response to Vagus Nerve Stimulation in Dogs
Authors: MATTHEW N. LEVY, HARRISON ZIESKE
Journal: Circulation Research (1969)

In the canine isovolumetric left ventricle preparation, stimuli were applied to the efferent end of a transected cervical vagus nerve. The changes in left ventricular systolic pressure in response to vagal stimulation were compared under control conditions and when ventricular contractility was enhanced by various kinds of inotropic stimulation-left stellate ganglion stimulation, paired pacing, calcium chloride infusions, aminophylline infusions, and acetylstrophanthidin injections. Vagal stimulation under control conditions caused mean decreases in pressure in the various groups ranging from 13.2 to 16.2% of the control level. The depressant effect of vagal stimulation was potentiated during sympathetic stimulation, in confirmation of previous findings; the mean decrease in pressure produced by vagal stimulation during concurrent sympathetic stimulation varied from 20.1 to 20.8%. Calcium and aminophylline infusions had no significant effect on the ventricular response to vagal stimulation; the percent reductions in pressure caused by vagal stimulation were 18.1 and 15.5%, respectively. However, the response to vagal stimulation was markedly attenuated during paired pacing and after acetylstrophanthidin; the percent reductions in pressure caused by vagal stimulation were 5.0 and 9.4%, respectively. The potentiation of the response to vagal stimulation during increased cardiac sympathetic activity probably represents a specific adrenergic-cholinergic interaction.
STUDIES ON NATURAL IMMUNITY TO PNEUMOCOCCUS TYPE III
Authors: John F. Enders, Chao-Jen Wu, Morris F. Shaffer
Journal: The Journal of Experimental Medicine (1936)

Since there is no evidence for the occurrence of type specific antibody in the normal rabbit and since, as we have shown, the Pneumococcus Type III whether avirulent or virulent is not removed from the blood stream or destroyed when the capsule is intact, the following factors which have been revealed in the course of our work appear to represent certain essential components, if not the complete mechanism, upon which the natural immunity of the rabbit against this organism depends. (a) The elevation of the body temperature after intravenous infection to 41 degrees C. or thereabouts and its maintenance for varying periods. (b) The ability of the phagocytic cells, both fixed and mobile, to attack any cocci which have become vulnerable through the deterioration of capsular integrity. (c) The adjuvant effect of an antibody, reacting with the somatic C carbohydrate, which enhances the phagocytosis of such organisms as no longer possess a completely intact envelope. Conversely, the varying degrees of virulence for rabbits observed among Pneumococcus Type III strains are based upon: (a) differences in the ability of the organisms to multiply at the elevated temperatures encountered in the infected host. Strains markedly susceptible to the harmful influence of this factor fail to induce a generalized fatal infection. Not all "thermo-resistant" strains are highly virulent, however, and these may contrast sharply with regard to (b) size of the capsule and the ease with which it is impaired or completely lost. The capsules must be maintained intact for a sufficient time until multiplication of the organisms can proceed to such a degree that death of the host results. Avirulent strains even when capable of growth at 41 degrees C. appear to be unable to satisfy this requirement. The differences in virulence of various strains apparently conditioned by these factors are not limited solely to the case of the rabbit, since for at least two strains similar differences in virulence have been shown to exist when the intravenous route of infection is employed in mice.