tbuckley/cabot-search huggingface dataset:
Contribution of the epigenetic mark H3K27me3 to functional divergence after whole genome duplication in Arabidopsis
Authors: Lidija Berke, Gabino F Sanchez-Perez, Berend Snel
Journal: Genome biology (2012)

Abstract Background Following gene duplication, retained paralogs undergo functional divergence, which is reflected in changes in DNA sequence and expression patterns. The extent of divergence is influenced by several factors, including protein function. We examine whether an epigenetic modification, trimethylation of histone H3 at lysine 27 (H3K27me3), could be a factor in the evolution of expression patterns after gene duplication. Whereas in animals this repressive mark for transcription is deposited on long regions of DNA, in plants its localization is gene-specific. Because of this and a well-annotated recent whole-genome duplication, Arabidopsis thaliana is uniquely suited for studying the potential association of H3K27me3 with the evolutionary fate of genes. Results Paralogous pairs with H3K27me3 show the highest coding sequence divergence, which can be explained by their low expression levels. Interestingly, they also show the highest similarity in expression patterns and upstream regulatory regions, while paralogous pairs where only one gene is an H3K27me3 target show the highest divergence in expression patterns and upstream regulatory sequence. These trends in divergence of expression and upstream regions are especially pronounced for transcription factors. Conclusions After duplication, a histone modification can be associated with a particular fate of paralogs: H3K27me3 is linked to lower expression divergence yet higher coding sequence divergence. Our results show that H3K27me3 constrains expression divergence after duplication. Moreover, its association with higher conservation of upstream regions provides a potential mechanism for the conserved H3K27me3 targeting of the paralogs.
Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation
Authors: F Baron, M Labopin, D Niederwieser, S Vigouroux, J J Cornelissen, C Malm, L L Vindelov, D Blaise, J J W M Janssen, E Petersen, G Socié, A Nagler, V Rocha, M Mohty
Journal: Leukemia (2012)
Hematopoietic stem cell quiescence and function are controlled by the CYLD–TRAF2–p38MAPK pathway
Authors: Melania Tesio, Yilang Tang, Katja Müdder, Massimo Saini, Lisa von Paleske, Elizabeth Macintyre, Manolis Pasparakis, Ari Waisman, Andreas Trumpp
Journal: The Journal of Experimental Medicine (2015)

The status of long-term quiescence and dormancy guarantees the integrity of hematopoietic stem cells (HSCs) during adult homeostasis. However the molecular mechanisms regulating HSC dormancy remain poorly understood. Here we show that cylindromatosis (CYLD), a tumor suppressor gene and negative regulator of NF-κB signaling with deubiquitinase activity, is highly expressed in label-retaining dormant HSCs (dHSCs). Moreover, Cre-mediated conditional elimination of the catalytic domain of CYLD induced dHSCs to exit quiescence and abrogated their repopulation and self-renewal potential. This phenotype is dependent on the interactions between CYLD and its substrate TRAF2 (tumor necrosis factor–associated factor 2). HSCs expressing a mutant CYLD with an intact catalytic domain, but unable to bind TRAF2, showed the same HSC phenotype. Unexpectedly, the robust cycling of HSCs lacking functional CYLD–TRAF2 interactions was not elicited by increased NF-κB signaling, but instead by increased activation of the p38MAPK pathway. Pharmacological inhibition of p38MAPK rescued the phenotype of CYLD loss, identifying the CYLD–TRAF2–p38MAPK pathway as a novel important regulator of HSC function restricting HSC cycling and promoting dormancy.
Physician Visits and 30-Day Hospital Readmissions in Patients Receiving Hemodialysis
Authors: Kevin F. Erickson, Wolfgang C. Winkelmayer, Glenn M. Chertow, Jay Bhattacharya
Journal: Journal of the American Society of Nephrology (2014)

A focus of health care reform has been on reducing 30-day hospital readmissions. Patients with ESRD are at high risk for hospital readmission. It is unknown whether more monitoring by outpatient providers can reduce hospital readmissions in patients receiving hemodialysis. In nationally representative cohorts of patients in the United States receiving in-center hemodialysis between 2004 and 2009, we used a quasi-experimental (instrumental variable) approach to assess the relationship between frequency of visits to patients receiving hemodialysis following hospital discharge and the probability of rehospitalization. We then used a multivariable regression model and published hospitalization data to estimate the cost savings and number of hospitalizations that could be prevented annually with additional provider visits to patients in the month following hospitalization. In the main cohort (n=26,613), one additional provider visit in the month following hospital discharge was estimated to reduce the absolute probability of 30-day hospital readmission by 3.5% (95% confidence interval, 1.6% to 5.3%). The reduction in 30-day hospital readmission ranged from 0.5% to 4.9% in an additional four cohorts tested, depending on population density around facilities, facility profit status, and patient Medicaid eligibility. At current Medicare reimbursement rates, the effort to visit patients one additional time in the month following hospital discharge could lead to 31,370 fewer hospitalizations per year, and $240 million per year saved. In conclusion, more frequent physician visits following hospital discharge are estimated to reduce rehospitalizations in patients undergoing hemodialysis. Incentives for closer outpatient monitoring following hospital discharge could lead to substantial cost savings.
CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development
Authors: Ganeshwaran H Mochida, Vijay S Ganesh, Maria I de Michelena, Hugo Dias, Kutay D Atabay, Katie L Kathrein, Hsuan-Ting Huang, R Sean Hill, Jillian M Felie, Daniel Rakiec, Danielle Gleason, Anthony D Hill, Athar N Malik, Brenda J Barry, Jennifer N Partlow, Wen-Hann Tan, Laurie J Glader, A James Barkovich, William B Dobyns, Leonard I Zon, Christopher A Walsh
Journal: Nature Genetics (2012)
Sodium accumulation during ischemia induces mitochondrial damage in perfused rat hearts
Authors: Takeshi Iwai, Kouichi Tanonaka, Rie Inoue, Sayaka Kasahara, Kanataka Motegi, Shotaro Nagaya, Satoshi Takeo
Journal: Cardiovascular Research (2002)

The present study aimed to elucidate the involvement of sodium overload and following damage to mitochondria during ischemia in the genesis of ischemia/reperfusion injury of perfused rat hearts.Isolated, perfused hearts were exposed to different durations (15-35 min) of ischemia followed by 60-min reperfusion. At the end of ischemia or reperfusion, myocardial sodium and calcium contents and myocardial high-energy phosphates were determined. The cardiac mitochondrial ability to produce ATP was measured using saponin-skinned bundles. The effects of sodium on the mitochondrial membrane potential and the oxidative phosphorylation rate were examined using isolated mitochondria from normal hearts.Post-ischemic recovery of left ventricular developed pressure decreased in an ischemic duration-dependent manner. Ischemia induced an increase in myocardial sodium, but not calcium. This increase was dependent on the duration of ischemia. The oxygen consumption rate of skinned bundles from the ischemic heart decreased at the end of ischemia. Incubation of mitochondria with various concentrations of sodium chloride or sodium lactate in vitro resulted in a depolarization of mitochondrial membrane potential and a decrease in ATP-generating activity. This decrease was not restored after elimination of sodium compounds.The present findings suggest that ischemia induces an increase in sodium influx from the extracellular space and that accumulated sodium may induce irreversible damage to mitochondria during ischemia. This mitochondrial dysfunction may be one of the most important determinants for the genesis of ischemia/reperfusion injury in perfused rat hearts.
Efficacy of topical recombinant human platelet-derived growth factor for treatment of diabetic lower-extremity ulcers: Systematic review and meta-analysis
Authors: Xiao-hong Zhao, Hai-feng Gu, Zhe-rong Xu, Qin Zhang, Xue-ying Lv, Xiao-jun Zheng, Yun-mei Yang
Journal: Metabolism (2014)
Survival in IPF acute exacerbations: The non-steroid approach
Authors: Spyros Papiris, Konstantinos Kagouridis, Likurgos Kolilekas, Aneza Roussou, Christina Triantafillidou, Katerina Baou, Anastasia Papaporfyriou, Georgia Papadaki, Kostas Vougas, Katerina Malagari, Stelios Loukides, Anastasia Kotanidou, Anna Karakatsani, Effrosyni Manali
Journal: European Respiratory Journal (2013)

Background  IPF acute exacerbations (IPF-AE) have no proven etiology and although they represent the development of diffuse alveolar damage upon usual interstitial pneumonia, international guidelines recommend high dose steroids. However, the prognosis remains unacceptably dismal.  Aims and objectives  Assuming that IPF-AE is an ARDS of unknown cause we tested the hypothesis whether ARDS treatment and withdrawing or withholding immunosuppression plus broad spectrum antibiotics influence survival (Papiris et al AJRCCM 2012;185:587-8)  Methods  We studied patients hospitalized in our clinic from 2007 to 2012 with IPF deterioration. Our protocol consists of immediate cessation of immunosuppression (if any), best supportive care, broad spectrum antibiotics and thorough evaluation to detect reversible causes of respiratory deterioration. All patients were followed up for survival; after discharge none received immunosuppression. We analyzed our data using logistic regression analysis.  Results  Out of 77 admissions, after excluding other causes of deterioration such as respiratory infection, heart failure, sepsis, pulmonary embolism, pneumothorax, disease progression or progression to the final end, 22 (29%) fulfilled IPF-AE criteria. Among them 50% survived; 3 out of 11 (27%) survived in the group previously receiving immunosuppression whereas 8 out of 11 (73%) in the group not receiving immunosuppression (p=0.033). The median survival of IPF-AE survivors was 11.5 months.  Conclusions  Survival of patients treated with the non-steroid approach is better than published data. Previous treatment with immunosuppression is related with increased mortality. No administration of immunosuppression post-discharge is related with prolonged survival.
Heterogeneity of helper/inducer T lymphocytes. I. Lymphokine production and lymphokine responsiveness.
Authors: E A Kurt-Jones, S Hamberg, J Ohara, W E Paul, A K Abbas
Journal: The Journal of Experimental Medicine (1987)

Antigen-specific, Ia-restricted helper/inducer T lymphocytes consist of subsets that can be distinguished by lymphokine secretion. One, called Th1, secretes IL-2 and the other, termed Th2, produces BSF-1/IL-4 in response to stimulation by lectin or antigen receptor signals, and each uses the respective lymphokine as its autocrine growth factor. Cloned lines representing Th2 cells proliferate in response to both IL-2 and their autocrine lymphokine, BSF-1/IL-4, but this proliferation is dependent on the synergistic costimulator activity of the monokine, IL-1. In contrast, Th1 clones proliferate only in response to IL-2, are unresponsive to BSF-1/IL-4, and their growth is unaffected by IL-1. These response patterns are not attributable to variations in culture conditions but apparently reflect intrinsic properties of the two T cell subsets. Moreover, the unresponsiveness of Th1 cells to BSF-1/IL-4 may be related to lower levels of expression of surface receptors for this lymphokine. These results may explain the observed heterogeneity among bulk populations of T cells in terms of lymphokine responsiveness and requirement for accessory factors (costimulators). In addition, our findings suggest that IL-2, unlike BSF-1/IL-4, is a fully competent growth factor that is potentially involved in antigen-independent expansion of bystander T cells present at sites of immune stimulation.
Cytokine-induced neutrophil chemoattractant mediates neutrophil influx in immune complex glomerulonephritis in rat.
Authors: X Wu, A J Wittwer, L S Carr, B A Crippes, J E DeLarco, J B Lefkowith
Journal: Journal of Clinical Investigation (1994)

Chemokines are a family of cytokines whose participation in inflammation in vivo remains to be established. Using the rat model of anti-glomerular basement membrane (GBM) nephritis, we found that mRNA for the chemokine CINC (cytokine-induced neutrophil chemoattractant) was induced in the kidney, and the corresponding protein was elaborated by isolated inflamed glomeruli. Production of CINC by glomeruli was unaffected by complement- or leukocyte-depletion prior to disease induction. Cytokines which induce CINC expression in renal cells (TNF-alpha and IL-1 beta) were also expressed in the kidney during glomerular inflammation. TNF-alpha production, unlike CINC, was complement and leukocyte dependent. In vivo administration of anti-CINC, but not anti-human IL-8, IgG selectively attenuated the influx of PMNs into the glomerulus and commensurately diminished proteinuria. The participation of CINC was not tissue-specific: anti-CINC IgG also diminished the influx of PMNs in dermal immune complex inflammation. In sum, we propose that glomerular immune complex deposition/complement activation leads to cytokine production which results in CINC expression by endogenous glomerular cells. The CINC produced plays a contributory role in the influx of PMNs into the glomerulus in the context of the activation of other inflammatory mediators. These results suggest a potential role for CINC homologues, IL-8 and the GRO family of chemokines, in human immune complex-mediated disease.
Role of Dok-1 and Dok-2 in Leukemia Suppression
Authors: Masaru Niki, Antonio Di Cristofano, Mingming Zhao, Hiroaki Honda, Hisamaru Hirai, Linda Van Aelst, Carlos Cordon-Cardo, Pier Paolo Pandolfi
Journal: The Journal of Experimental Medicine (2004)

Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr/abl oncoprotein that shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although several p210bcr/abl substrates have been identified, their relevance in the pathogenesis of the disease is unclear. We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells. Members of this family such as p62dok(Dok-1) and p56dok-2(Dok-2) associate with the p120 rasGTPase-activating protein (rasGAP) upon phosphorylation by p210bcr/abl as well as receptor and nonreceptor tyrosine kinases. Here, we report the generation and characterization of single and double Dok-1 or Dok-2 knockout (KO) mutants. Single KO mice displayed normal steady-state hematopoiesis. By contrast, concomitant Dok-1 and Dok-2 inactivation resulted in aberrant hemopoiesis and Ras/MAP kinase activation. Strikingly, all Dok-1/Dok-2 double KO mutants spontaneously developed transplantable CML-like myeloproliferative disease due to increased cellular proliferation and reduced apoptosis. Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p210bcr/abl transgenic mice known to develop, after long latency, a myeloproliferative disorder resembling human CML. These findings unravel the critical and unexpected role of Dok-1 and Dok-2 in tumor suppression and control of the hematopoietic compartment homeostasis.
Inhibition of Diabetic Nephropathy in Rats by an Oral Antidiabetic Material Extracted from Yeast
Authors: Farid Nakhoul, Zaid Abassi, Michal Morgan, Sharbel Sussan, Nitza Mirsky
Journal: Journal of the American Society of Nephrology (2006)

Diabetic nephropathy is one of the major complications of diabetes. The glucose tolerance factor (GTF) is a dietary agent extracted from several natural sources; the richest among them is brewer’s yeast. Extraction and purification of an active and stable GTF preparation from brewer’s yeast previously was successful, and a remarkable decrease in plasma glucose and lipids from administration of GTF to animals with type 1 diabetes was demonstrated. The purpose of the present study was to examine whether GTF affects nephropathy in diabetic rats. The average urinary volume and protein excretion throughout the collection period in diabetic rats was 56.95 ± 2.2 ml/d and 5.42 ± 0.95 mg/d, respectively. These values were significantly (P < 0.001 versus baseline values) higher compared with healthy controls (average urine volume 15.12 ± 0.5 ml/d; average protein excretion 0.15 ± 0.08 mg/d). Treatment with GTF reduced average urine volume and protein excretion to 29.1 ± 1.94 ml/d (P < 0.01) and 1.55 ± 1.17 mg/d (P < 0.05), respectively. Kidney weight, which was elevated in diabetic rats, slightly decreased in diabetic animals that were treated with GTF, in association with reduction of lipid peroxidation levels in the renal cortex and the heart. Endothelial nitric oxide immunoreactivity in the renal cortex of both healthy and diabetic rats that were treated with GTF was remarkably lower than that found in renal cortex of untreated diabetic animals. This study demonstrates that yeast-derived material, GTF, can inhibit the development of nephropathy that is induced by diabetes.
Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 KATP channels
Authors: William A. Chutkow, Jielin Pu, Matthew T. Wheeler, Tomoyuki Wada, Jonathan C. Makielski, Charles F. Burant, Elizabeth M. McNally
Journal: Journal of Clinical Investigation (2002)

KATP channels couple the intracellular energy state to membrane excitability and regulate a wide array of biologic activities. KATP channels contain a pore-forming inwardly rectifying potassium channel and a sulfonylurea receptor regulatory subunit (SUR1 or SUR2). To clarify the role of KATP channels in vascular smooth muscle, we studied Sur2 gene-targeted mice (Sur2–/–) and found significantly elevated resting blood pressures and sudden death. Using in vivo monitoring, we detected transient, repeated episodes of coronary artery vasospasm in Sur2–/– mice. Focal narrowings in the coronary arteries were present in Sur2–/– mice consistent with vascular spasm. We treated Sur2–/– mice with a calcium channel antagonist and successfully reduced vasospastic episodes.
Surgical closure of the back lesion in open neural tube defects.
Authors: A. N. Guthkelch
Journal: BMJ (1988)

It is strange that Dr Forsvthe should ask why it takes the secretary of state a vear to determine an appeal under section 190 when the issues are so much weightier.)isciplinary pro- ceedings may arise from a clash of personalities.-Whatever the result of the current deliberations between the DHSS and the Joint Consultants Committee, the lMN6I )112 or similar procedure would lose some of its unf:airness if regional health authorities were stripped of their responsibilitics.if onlv becausc thcv do not tollow the fundamental principles of natural justice in which the accused consultant is told who his accuser is.
In vivo sequestration of Plasmodium falciparum-infected human erythrocytes: a severe combined immunodeficiency mouse model for cerebral malaria.
Authors: K Willimann, H Matile, N A Weiss, B A Imhof
Journal: The Journal of Experimental Medicine (1995)

Cerebral malaria is a fatal complication of infection by Plasmodium falciparum in man. The neurological symptoms that characterize this form of malarial disease are accompanied by the adhesion of infected erythrocytes to the vasculature of the brain. To study this phenomenon in vivo, an acute phase severe combined immunodeficiency (SCID) mouse model was developed in which sequestration of P. falciparum-infected human erythrocytes took place. During acute cerebral malaria in humans, the expression of intercellular adhesion molecule-1 (ICAM-1) is induced in vascular endothelium by inflammatory reactions. Acute phase ICAM-1 expression can also be obtained in SCID mice. The endothelium of the midbrain region was the most responsive to such inflammatory stimulus. It is noteworthy that the reticular formation in the midbrain controls the level of consciousness, and loss of consciousness is a symptom of cerebral malaria. We found that infected human erythrocytes were retained 24 times more than normal erythrocytes in ICAM-1-positive mouse brain. Sequestration to the brain was reduced by anti-ICAM-1 antibodies. These in vivo results were confirmed by the binding of P. falciparum-infected erythrocytes to the ICAM-1-positive endothelium in tissue sections of mouse brain. We conclude that the SCID mouse serves as a versatile in vivo model that allows the study of P. falciparum-infected erythrocyte adhesion as it occurs in human cerebral malaria. Upregulation of ICAM-1 expression in the region of the midbrain correlates with increased retention of malaria-infected erythrocytes and with the symptoms of cerebral malaria.
Revisiting Notch in remyelination of multiple sclerosis lesions
Authors: Celia F. Brosnan, Gareth R. John
Journal: Journal of Clinical Investigation (2008)

MS results from destruction of the protective myelin sheath surrounding axons, which prevents the transmission of nerve impulses. Precursors of oligodendrocytes, the cells capable of myelinating axons, are preserved in demyelinating lesions; however, why these precursors do not differentiate into mature oligodendrocytes and remyelinate axons is unknown. Contactin is a noncanonical Notch receptor ligand that mediates oligodendrocyte differentiation. In this issue of the JCI, Nakahara et al. show that Contactin is abundantly expressed on demyelinated axons in human chronic MS lesions and that Notch1 is activated in oligodendrocyte precursor cells (see the related article beginning on page 169). However, Notch1 intracellular domain coassociates with the nuclear transporter Importin beta but fails to show evidence of nuclear translocation. These cytoplasmic aggregates also contain TAT-interacting protein 30 kDa (TIP30), a proapoptotic factor, which inhibits nuclear transport and, consequently, Notch1-mediated oligodendrocyte differentiation and remyelination. These data target TIP30 as a new pathogenic factor in MS.