tbuckley/cabot-search huggingface dataset:
On the Origins of Mendelian Disease Genes in Man: The Impact of Gene Duplication
Authors: J. E. Dickerson, D. L. Robertson
Journal: Molecular Biology and Evolution (2011)

Over 3,000 human diseases are known to be linked to heritable genetic variation, mapping to over 1,700 unique genes. Dating of the evolutionary age of these disease-associated genes has suggested that they have a tendency to be ancient, specifically coming into existence with early metazoa. The approach taken by past studies, however, assumes that the age of a disease is the same as the age of its common ancestor, ignoring the fundamental contribution of duplication events in the evolution of new genes and function. Here, we date both the common ancestor and the duplication history of known human disease-associated genes. We find that the majority of disease genes (80%) are genes that have been duplicated in their evolutionary history. Periods for which there are more disease-associated genes, for example, at the origins of bony vertebrates, are explained by the emergence of more genes at that time, and the majority of these are duplicates inferred to have arisen by whole-genome duplication. These relationships are similar for different disease types and the disease-associated gene's cellular function. This indicates that the emergence of duplication-associated diseases has been ongoing and approximately constant (relative to the retention of duplicate genes) throughout the evolution of life. This continued until approximately 390 Ma from which time relatively fewer novel genes came into existence on the human lineage, let alone disease genes. For single-copy genes associated with disease, we find that the numbers of disease genes decreases with recency. For the majority of duplicates, the disease-associated mutation is associated with just one of the duplicate copies. A universal explanation for heritable disease is, thus, that it is merely a by-product of the evolutionary process; the evolution of new genes (de novo or by duplication) results in the potential for new diseases to emerge.
Hyperparathyroidism and Anemia in Uremic Subjects
Authors: Diego Brancaccio, Mario Cozzolino, Maurizio Gallieni
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Several factors are involved in conditioning renal anemia, and a critical role is attributed to parathyroid hormone (PTH) oversecretion, which has some direct effects on endogenous erythropoietin (EPO) synthesis, bone marrow erythroid progenitors, and red cell survival. Indirect effects are mainly based on the induction of bone marrow fibrosis. Indirect evidence of the role of PTH is based on the observation that parathyroidectomy, when performed in uremic patients, is often followed by restoration of the hematocrit. The interpretations of such positive results are based on the observation of the restored bone marrow space after operation and also in a rise of immunoreactive EPO serum concentrations observed in the first weeks after gland removal. Another field of clinical interest is the possible beneficial effects of vitamin D therapy in controlling PTH secretion, which in turn determines an improvement of anemia of uremic subjects. Several uncontrolled studies confirmed this possibility, indicating that patients who respond to calcitriol or its analogs also show an increase of their hemoglobin levels. Thus, a combined therapeutic approach to PTH oversecretion and anemia is possible by intravenous calcitriol or parathyroidectomy pointing to the possible reversibility of bone marrow fibrosis, which is a common feature of secondary hyperparathyroidism. The increased sensitivity to EPO therapy can also induce a successful reduction of its dosage, thus allowing an interesting reduction of costs.
Thrombolytic treatment of pulmonary embolism with APSAC
Authors: J Vander Sande, L Bossaert, M Brochier, B Charbonnier, A Serradigmini, A Elias, H Pintens, MC Lauwers
Journal: European Respiratory Journal (1988)

BRL 26921 (Eminase registered trade mark in Belgium, Germany and The Netherlands) is the p-anisoyl derivative of the primary (human) lys plasminogen-streptokinase activator complex (APSAC). The acyl-enzyme has the theoretical advantage of causing fibrinolysis in situ in the presence of fibrin clotbound plasminogen. It was administered to 34 patients with severe pulmonary embolism (PE) in an open multicentre study. PE was suspected on clinical, blood gas, ECG, and radiographic data. Pulmonary angiograms performed pre- and post-treatment confirmed the diagnosis and were assessed using the Miller Index (MI). Fibrinogen, plasminogen, alpha-2-antiplasmin, fibrinogen degradation products (FDP), activated partial thromboplastin time (APTT), partial thromboplastin time (PTT) were closely monitored before and after each administration of APSAC. Median angiographic improvement was 50% (range 0-94%). The following adverse events were reported: bleeding at puncture sites (n = 12), haematuria (n = 1), epistaxis (n = 3), fever (n = 2). A blood transfusion was given in one patient with an inguinal haematoma. Systemic fibrinogenolysis occurred in 20/28 patients.
Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension
Authors: Elisabeth Marcos, Elie Fadel, Olivier Sanchez, Marc Humbert, Philippe Dartevelle, Gerald Simonneau, Michel Hamon, Serge Adnot, Saadia Eddahibi
Journal: Circulation Research (2004)

Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of pulmonary hypertension (PH). Serotonin (5-HT) is involved in the hyperplasia through its interactions with specific receptors and internalization by a specific plasma membrane transporter. We investigated the expression and role of the 5-HT transporter (5-HTT) and 5-HT1B, 5-HT2A, and 5-HT2B receptors in lungs and isolated PA-SMCs from patients with primary PH (n=14), pulmonary veno-occlusive disease (n=4), or secondary PH (SPH, n=8) and nonpulmonary hypertensive control subjects. Whereas strong immunostaining for the three receptor types and 5-HTT was seen in remodeled pulmonary vessels from patients in all PH categories, only 5-HTT expression was increased in lungs and cultured PA-SMCs from patients versus controls. The increased growth response of PA-SMCs from patients with primary PH, pulmonary veno-occlusive disease, or SPH to 5-HT or serum was entirely attributable to 5-HTT overexpression, because 5-HTT inhibitors but not 5-HT receptor antagonists abolished 5-HT mitogenic activity and reduced the serum-induced growth response to similar levels in patients as in controls. The L-allelic variant of the 5-HTT gene promoter, which is associated with 5-HTT overexpression, was present homozygously in 14 of 25 (56%) lung transplantation patients with SPH but in only 27% of controls. Polymorphism of the 5-HTT gene promoter was only partly responsible for the increased 5-HTT expression in PH, because PA-SMCs from patients exhibited higher 5-HTT levels than same-genotype cells from controls and no additional promoter sequence alterations were found. We conclude that 5-HTT overexpression is a common pathogenic mechanism in various forms of PH.
The Use of Control Systems Analysis in the Neurophysiology of Eye Movements
Authors: D A Robinson
Journal: Annual Review of Neuroscience (1981)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Identification of Novel and Widely Expressed Cancer/Testis Gene Isoforms That Elicit Spontaneous Cytotoxic T-Lymphocyte Reactivity to Melanoma
Authors: Kevin T. Hogan, Michael A. Coppola, Christine L. Gatlin, Lee W. Thompson, Jeffrey Shabanowitz, Donald F. Hunt, Victor H. Engelhard, Mark M. Ross, Craig L. Slingluff
Journal: Cancer Research (2004)

Abstract Multiple isoforms (TAG-1, TAG-2a, TAG-2b, and TAG-2c) of a novel cancer/testis antigen gene have been identified and are expressed in 84–88% of melanoma cell lines tested. The tumor antigen (TAG) genes are also expressed in K562, a myelogenous leukemia cell line, and they have homology to two chronic myelogenous leukemia-derived clones and a hepatocellular carcinoma clone in the human expressed sequence tags (EST) database, thus indicating that their expression is not restricted to melanomas. In contrast to the fact that many cancer/testis antigens are poorly immunogenic, the TAG-derived peptide, RLSNRLLLR, is recognized by HLA-A3-restricted, melanoma-specific CTLs that were obtained from a melanoma patient with spontaneous reactivity to the peptide. Unlike most cancer/testis antigen genes which are located on the X chromosome, the TAG genes are located on chromosome 5. The genes have the additional unusual features of being coded for in an open reading frame that is initiated by one of three nonstandard initiation codons, and the sequence coding the RLSNRLLLR peptide crosses an exon-exon boundary. The properties of the TAG antigens indicate that they are excellent vaccine candidates for the treatment of melanoma and perhaps other cancers.
Toxic bile acids in gastro-oesophageal reflux disease: influence of gastric acidity
Authors: D Nehra, P Howell, C P Williams, J K Pye, J Beynon
Journal: Gut (1999)

Bile acid toxicity has been shown in the gastric, colonic, and hepatic tissues; the effect on oesophageal mucosa is less well known.To determine the spectrum of bile acids refluxing in patients with gastro-oesophageal reflux disease and its relation to oesophageal pH using a new technique of combined oesophageal aspiration and pH monitoring.Ten asymptomatic subjects and 30 patients with symptoms of gastro-oesophageal reflux disease (minimal mucosal injury, erosive oesophagitis (grade 2 or 3 Savary-Miller), Barrett's oesophagus/stricture; n=10 in each group) underwent 15 hour continuous oesophageal aspiration with simultaneous pH monitoring. Bile acid assay of the oesophageal samples was performed using modified high performance liquid chromatography.The peak bile acid concentration and DeMeester acid scores were significantly higher in the patients with oesophagitis (median bile acid concentration 124 micromol/l; acid score 20.2) and Barrett's oesophagus/stricture (181 micromol/l; 43. 3) than patients with minimal injury (14 micromol/l; 12.5) or controls (0 micromol/l; 11.1). The predominant bile acids detected were cholic, taurocholic, and glycocholic acids but there was a significantly greater proportion of secondary bile acids, deoxycholic and taurodeoxycholic acids, in patients with erosive oesophagitis and Barrett's oesophagus/stricture. Although bile acid reflux episodes occurred at variable pH, a temporal relation existed between reflux of taurine conjugates and oesophageal acid exposure (r=0.58, p=0.009).Toxic secondary bile acid fractions have been detected in patients with extensive mucosal damage. Mixed reflux is more harmful than acid reflux alone with possible toxic synergism existing between the taurine conjugates and acid.
RAG-induced DNA double-strand breaks signal through Pim2 to promote pre–B cell survival and limit proliferation
Authors: Jeffrey J. Bednarski, Andrew Nickless, Deepta Bhattacharya, Rupesh H. Amin, Mark S. Schlissel, Barry P. Sleckman
Journal: The Journal of Experimental Medicine (2011)

Interleukin 7 (IL-7) promotes pre–B cell survival and proliferation by activating the Pim1 and Akt kinases. These signals must be attenuated to induce G1 cell cycle arrest and expression of the RAG endonuclease, which are both required for IgL chain gene rearrangement. As lost IL-7 signals would limit pre–B cell survival, how cells survive during IgL chain gene rearrangement remains unclear. We show that RAG-induced DNA double-strand breaks (DSBs) generated during IgL chain gene assembly paradoxically promote pre–B cell survival. This occurs through the ATM-dependent induction of Pim2 kinase expression. Similar to Pim1, Pim2 phosphorylates BAD, which antagonizes the pro-apoptotic function of BAX. However, unlike IL-7 induction of Pim1, RAG DSB-mediated induction of Pim2 does not drive proliferation. Rather, Pim2 has antiproliferative functions that prevent the transit of pre–B cells harboring RAG DSBs from G1 into S phase, where these DNA breaks could be aberrantly repaired. Thus, signals from IL-7 and RAG DSBs activate distinct Pim kinase family members that have context-dependent activities in regulating pre–B cell proliferation and survival.
Method of delivery and pregnancy outcomes in Asia: the WHO global survey on maternal and perinatal health 2007–08
Authors: Pisake Lumbiganon, Malinee Laopaiboon, A Metin Gülmezoglu, João Paulo Souza, Surasak Taneepanichskul, Pang Ruyan, Deepika Eranjanie Attygalle, Naveen Shrestha, Rintaro Mori, Nguyen Duc Hinh, Hoang Thi Bang, Tung Rathavy, Kang Chuyun, Kannitha Cheang, Mario Festin, Venus Udomprasertgul, Maria Julieta V Germar, Gao Yanqiu, Malabika Roy, Guillermo Carroli, Katherine Ba-Thike, Ekaterina Filatova, José Villar
Journal: The Lancet (2010)
Dynamic Adipocyte Phosphoproteome Reveals that Akt Directly Regulates mTORC2
Authors: Sean J. Humphrey, Guang Yang, Pengyi Yang, Daniel J. Fazakerley, Jacqueline Stöckli, Jean Y. Yang, David E. James
Journal: Cell Metabolism (2013)

A major challenge of the post-genomics era is to define the connectivity of protein phosphorylation networks. Here, we quantitatively delineate the insulin signaling network in adipocytes by high-resolution mass spectrometry-based proteomics. These data reveal the complexity of intracellular protein phosphorylation. We identified 37,248 phosphorylation sites on 5,705 proteins in this single-cell type, with approximately 15% responding to insulin. We integrated these large-scale phosphoproteomics data using a machine learning approach to predict physiological substrates of several diverse insulin-regulated kinases. This led to the identification of an Akt substrate, SIN1, a core component of the mTORC2 complex. The phosphorylation of SIN1 by Akt was found to regulate mTORC2 activity in response to growth factors, revealing topological insights into the Akt/mTOR signaling network. The dynamic phosphoproteome described here contains numerous phosphorylation sites on proteins involved in diverse molecular functions and should serve as a useful functional resource for cell biologists.
What you don't know can hurt you; early asymptomatic lung disease in cystic fibrosis
Authors: Steve Cunningham
Journal: Thorax (2012)

Clinicians caring for children with cystic fibrosis (CF) should now take note; despite your best clinical care, lung disease in CF infants develops surreptitiously and ill-defined by early symptoms. By the time lung disease has symptomatically declared itself, it's probably structurally established and too late to reverse. What you don't know can hurt you.

Hoo and colleagues in this issue provide evidence of early lung disease in patients with CF diagnosed by newborn screening.1 At a mean 3 months of age, 34% of CF patients had abnormalities of pulmonary function (including lung clearance index (LCI) and/or forced expiratory volume in 0.5 second (FEV0.5)) when compared with healthy controls. The presence of symptoms, sometimes aggressively treated, did not reliably identify those with abnormal pulmonary function. This study, by the London CF Collaborative, used contemporaneous healthy controls and adhered to treatment protocols from diagnosis. The research examines with great clarity the vital question of how early lung disease starts in those born with CF. The children studied were provided with every opportunity for optimal health, by the use of newborn screening, regular chest physiotherapy and prophylactic oral flucloxacillin. Disappointingly, our current best care is not good enough to prevent lung disease. Of even greater disappointment is that those with lung disease do not stand out from the crowd.

This is not isolated data. Studies over the past decade have shown that lung disease is established very early in life with bronchiectasis and ventilation inhomogeneity preceding both symptoms and a notable decline in FEV1. Children …
Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression.
Authors: R de Waal Malefyt, J Haanen, H Spits, M G Roncarolo, A te Velde, C Figdor, K Johnson, R Kastelein, H Yssel, J E de Vries
Journal: The Journal of Experimental Medicine (1991)

Interleukin 10 (IL-10) and viral IL-10 (v-IL-10) strongly reduced antigen-specific proliferation of human T cells and CD4+ T cell clones when monocytes were used as antigen-presenting cells. In contrast, IL-10 and v-IL-10 did not affect the proliferative responses to antigens presented by autologous Epstein-Barr virus-lymphoblastoid cell line (EBV-LCL). Inhibition of antigen-specific T cell responses was associated with downregulation of constitutive, as well as interferon gamma- or IL-4-induced, class II MHC expression on monocytes by IL-10 and v-IL-10, resulting in the reduction in antigen-presenting capacity of these cells. In contrast, IL-10 and v-IL-10 had no effect on class II major histocompatibility complex (MHC) expression on EBV-LCL. The reduced antigen-presenting capacity of monocytes correlated with a decreased capacity to mobilize intracellular Ca2+ in the responder T cell clones. The diminished antigen-presenting capacities of monocytes were not due to inhibitory effects of IL-10 and v-IL-10 on antigen processing, since the proliferative T cell responses to antigenic peptides, which did not require processing, were equally well inhibited. Furthermore, the inhibitory effects of IL-10 and v-IL-10 on antigen-specific proliferative T cell responses could not be neutralized by exogenous IL-2 or IL-4. Although IL-10 and v-IL-10 suppressed IL-1 alpha, IL-1 beta, tumor necrosis factor alpha (TNF-alpha), and IL-6 production by monocytes, it was excluded that these cytokines played a role in antigen-specific T cell proliferation, since normal antigen-specific responses were observed in the presence of neutralizing anti-IL-1, -IL-6, and -TNF-alpha mAbs. Furthermore, addition of saturating concentrations of IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha to the cultures had no effect on the reduced proliferative T cell responses in the presence of IL-10, or v-IL-10. Collectively, our data indicate that IL-10 and v-IL-10 can completely prevent antigen-specific T cell proliferation by inhibition of the antigen-presenting capacity of monocytes through downregulation of class II MHC antigens on monocytes.
A new method for studying gut transit times using radioopaque markers
Authors: J. M. Hinton, J. E. Lennard-Jones, A. C. Young
Journal: Gut (1969)

A simple technique for measuring gastrointestinal transit times using radioopaque pellets of barium-impregnated polythene has been developed and validated. A normal range has been established by studying 25 normal subjects; all passed the first marker within three days and most passed 80% of the markers within five days.
Oxidized Lipoproteins Degrade the Endothelial Surface Layer
Authors: Hans Vink, Alina A. Constantinescu, Jos A. E. Spaan
Journal: Circulation (2000)

Background —Flowing erythrocytes and platelets are separated from the luminal endothelial cell (EC) surface by a 0.5-μm-wide space named the endothelial surface layer. We hypothesized that the disruption of the endothelial surface layer by oxidized low-density lipoproteins (Ox-LDL) contributes to atherogenic increases in vascular wall adhesiveness. Methods and Results —The hamster cremaster muscle preparation was used for intravital microscopic observation of the distance between erythrocytes and the capillary EC surface. Moderate Ox-LDL was prepared by exposing native LDL to CuSO 4 for 6 hours. The dimension of the EC surface layer averaged 0.6±0.1 μm during control situations, but a bolus intravenous injection of Ox-LDL (0.4 mg/100 g of body weight) transiently diminished the EC surface layer by 60% within 25 minutes, which correlated with a transient increase in the number of platelet-EC adhesions. Combined administration of superoxide dismutase and catalase completely blocked the effect of Ox-LDL on the dimension of the EC surface layer and inhibited platelet-EC adhesion. Conclusions —Oxygen-derived free radicals mediate the disruption of the EC surface layer and increase vascular wall adhesiveness by Ox-LDL.
Tuberous sclerosis
Authors: F. J K O'Callaghan
Journal: BMJ (1999)

Tuberous sclerosis is a dominantly inherited syndrome of high penetrance characterised pathologically by the presence of hamartomas in multiple organ systems. The clinical features of epilepsy, learning difficulties, and skin signs are well known, but recent epidemiological and genetic research has begun to reveal the complexity of the condition.

Compared with many other genetic diseases tuberous sclerosis is common. The two most recent and highest estimates of its prevalence in the United Kingdom have been 3.7 per 100 000 population in the west of Scotland and 3.8 per 100 000 population in Wessex. 1 2 A recent capture-recapture analysis of the Wessex data suggests that this survey failed to identify about half the prevalent cases. The total population prevalence may therefore be as high as 8-9 per 100 000, which means that many people with tuberous sclerosis are receiving neither specialist medical supervision nor genetic counselling.3

We know now that over half the affected individuals have normal intelligence and a quarter do not …
Relationship Between Gastric Emptying and an α-Glucosidase Inhibitor Effect on Postprandial Hyperglycemia in NIDDM Patients
Authors: Takahiko Kawagishi, Yoshiki Nishizawa, Hiromichi Taniwaki, Shinji Tanaka, Yasuhisa Okuno, Masaaki Inaba, Eiji Ishimura, Masanori Emoto, Hirotoshi Morii
Journal: Diabetes Care (1997)

OBJECTIVE The purpose of the study was to examine the relationship between gastric emptying and the efficacy of an α-glucosidase inhibitor in NIDDM patients. RESEARCH DESIGN AND METHODS Sixteen NIDDM patients (4 patients treated with diet therapy alone and 12 receiving a sulfonylurea) were given 0.6 mg of voglibose daily for 4 weeks. The efficacy of voglibose was assessed by measurement of HbA1c, fasting plasma glucose, and 45- and 120-min postprandial plasma glucose (PPG) and serum insulin concentrations before and after the 4 weeks of voglibose therapy. Gastric emptying was evaluated using the proportional cumulative area under the absorption curve (% AUC) of plasma acetaminophen concentration at 60 min after ingestion of a liquid test meal containing 20 mg/kg of acetaminophen. These measurements were also taken before and after the therapy. RESULTS The change in the 45-min PPG levels from the fasting state correlated significantly with the % AUC of the plasma acetaminophen concentrations (r = 0.625, P = 0.0096) before the voglibose administrations. The mean 45-min and 2-h PPG levels were reduced significantly after 4 weeks of voglibose (P &amp;lt; 0.05 and P &amp;lt; 0.01, respectively). Two-hour postprandial serum insulin concentrations were also significantly reduced at the end of the treatment period (P &amp;lt; 0.05). The changes in the PPG levels between pre- and posttreatment periods correlated significantly with the % AUC of the plasma acetaminophen concentrations before the treatment period (r = 0.499, P = 0.0490; r = 0.713, P = 0.0019, respectively). There was no significant difference in the plasma acetaminophen concentrations between pre- and posttreatment periods. CONCLUSIONS The rate of gastric emptying affects the efficacy of voglibose therapy in NIDDM patients. Voglibose did not however alter the rate of gastric emptying.
Liposomal daunorubicin in the treatment of relapsed or refractory non-Hodgkin’s lymphoma
Authors: A. Tulpule, M.U. Rarick, J. Kolitz, J. Bernstein, A. Myers, L.A. Buchanan, B.M. Espina, A. Traynor, J. Letzer, G.R. Justice, D. McDonald, L. Roberts, W. Boswell, B. Nathwani, A.M. Levine
Journal: Annals of Oncology (2001)