bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional Profiling of the Immune Response to Marburg Virus Infection
Authors: Connor John H. , Yen Judy , Caballero Ignacio S. , Garamszegi Sara , Malhotra Shikha , Lin Kenny , Hensley Lisa , Goff Arthur J. 
Published: July 2015

ABSTRACT
Marburg virus is a genetically simple RNA virus that causes a severe hemorrhagic fever in humans and nonhuman primates. The mechanism of pathogenesis of the infection is not well understood, but it is well accepted that pathogenesis is appreciably driven by a hyperactive immune response. To better understand the overall response to Marburg virus challenge, we undertook a transcriptomic analysis of immune cells circulating in the blood following aerosol exposure of rhesus macaques to a lethal dose of Marburg virus. Using two-color microarrays, we analyzed the transcriptomes of peripheral blood mononuclear cells that were collected throughout the course of infection from 1 to 9 days postexposure, representing the full course of the infection. The response followed a 3-stage induction (early infection, 1 to 3 days postexposure; midinfection, 5 days postexposure; late infection, 7 to 9 days postexposure) that was led by a robust innate immune response. The host response to aerosolized Marburg virus was evident at 1 day postexposure. Analysis of cytokine transcripts that were overexpressed during infection indicated that previously unanalyzed cytokines are likely induced in response to exposure to Marburg virus and further suggested that the early immune response is skewed toward a Th2 response that would hamper the development of an effective antiviral immune response early in disease. Late infection events included the upregulation of coagulation-associated factors. These findings demonstrate very early host responses to Marburg virus infection and provide a rich data set for identification of factors expressed throughout the course of infection that can be investigated as markers of infection and targets for therapy.

IMPORTANCE
Marburg virus causes a severe infection that is associated with high mortality and hemorrhage. The disease is associated with an immune response that contributes to the lethality of the disease. In this study, we investigated how the immune cells circulating in the blood of infected primates respond following exposure to Marburg virus. Our results show that there are three discernible stages of response to infection that correlate with presymptomatic, early, and late symptomatic stages of infection, a response format similar to that seen following challenge with other hemorrhagic fever viruses. In contrast to the ability of the virus to block innate immune signaling
in vitro
, the earliest and most sustained response is an interferon-like response. Our analysis also identifies a number of cytokines that are transcriptionally upregulated during late stages of infection and suggest that there is a Th2-skewed response to infection. When correlated with companion data describing the animal model from which our samples were collected, our results suggest that the innate immune response may contribute to overall pathogenesis.
Temporal Characterization of Marburg Virus Angola Infection following Aerosol Challenge in Rhesus Macaques
Authors: Lin Kenny L. , Twenhafel Nancy A. , Connor John H. , Cashman Kathleen A. , Shamblin Joshua D. , Donnelly Ginger C. , Esham Heather L. , Wlazlowski Carly B. , Johnson Joshua C. , Honko Anna N. , Botto Miriam A. , Yen Judy , Hensley Lisa E. , Goff Arthur J. 
Published: July 2015

ABSTRACT

Marburg virus (MARV) infection is a lethal hemorrhagic fever for which no licensed vaccines or therapeutics are available. Development of appropriate medical countermeasures requires a thorough understanding of the interaction between the host and the pathogen and the resulting disease course. In this study, 15 rhesus macaques were sequentially sacrificed following aerosol exposure to the MARV variant Angola, with longitudinal changes in physiology, immunology, and histopathology used to assess disease progression. Immunohistochemical evidence of infection and resulting histopathological changes were identified as early as day 3 postexposure (p.e.). The appearance of fever in infected animals coincided with the detection of serum viremia and plasma viral genomes on day 4 p.e. High (>10
7
PFU/ml) viral loads were detected in all major organs (lung, liver, spleen, kidney, brain, etc.) beginning day 6 p.e. Clinical pathology findings included coagulopathy, leukocytosis, and profound liver destruction as indicated by elevated liver transaminases, azotemia, and hypoalbuminemia. Altered cytokine expression in response to infection included early increases in Th2 cytokines such as interleukin 10 (IL-10) and IL-5 and late-stage increases in Th1 cytokines such as IL-2, IL-15, and granulocyte-macrophage colony-stimulating factor (GM-CSF). This study provides a longitudinal examination of clinical disease of aerosol MARV Angola infection in the rhesus macaque model.

IMPORTANCE
In this study, we carefully analyzed the timeline of Marburg virus infection in nonhuman primates in order to provide a well-characterized model of disease progression following aerosol exposure.
Protection from Severe Influenza Virus Infections in Mice Carrying theMx1Influenza Virus Resistance Gene Strongly Depends on Genetic Background
Authors: Shin Dai-Lun , Hatesuer Bastian , Bergmann Silke , Nedelko Tatiana , Schughart Klaus 
Published: July 2015

ABSTRACTInfluenza virus infections represent a serious threat to human health. Both extrinsic and intrinsic factors determine the severity of influenza. The MX dynamin-like GTPase 1 (Mx1) gene has been shown to confer strong resistance to influenza A virus infections in mice. Most laboratory mouse strains, including C57BL/6J, carry nonsense or deletion mutations inMx1and thus a nonfunctional allele, whereas wild-derived mouse strains carry a wild-typeMx1allele. Congenic C57BL/6J (B6-Mx1r/r) mice expressing a wild-type allele from the A2G mouse strain are highly resistant to influenza A virus infections, to both mono- and polybasic subtypes. Furthermore, in genetic mapping studies,Mx1was identified as the major locus of resistance to influenza virus infections. Here, we investigated whether theMx1protective function is influenced by the genetic background. For this, we generated a congenic mouse strain carrying the A2G wild-typeMx1resistance allele on a DBA/2J background (D2-Mx1r/r). Most remarkably, congenic D2-Mx1r/rmice expressing a functionalMx1wild-type allele are still highly susceptible to H1N1 virus. However, pretreatment of D2-Mx1r/rmice with alpha interferon protected them from lethal infections. Our results showed, for the first time, that the presence of anMx1wild-type allele from A2G as such does not fully protect mice from lethal influenza A virus infections. These observations are also highly relevant for susceptibility to influenza virus infections in humans.IMPORTANCEInfluenza A virus represents a major health threat to humans. Seasonal influenza epidemics cause high economic loss, morbidity, and deaths each year. Genetic factors of the host strongly influence susceptibility and resistance to virus infections. TheMx1(MX dynamin-like GTPase 1) gene has been described as a major resistance gene in mice and humans. Most inbred laboratory mouse strains are deficient inMx1, but congenic B6-Mx1r/rmice that carry the wild-typeMx1gene from the A2G mouse strain are highly resistant. Here, we show that, very unexpectedly, congenic D2-Mx1r/rmice carrying the wild-typeMx1gene from the A2G strain are not fully protected against lethal influenza virus infections. These observations demonstrate that the genetic background is very important for the protective function of theMx1resistance gene. Our results are also highly relevant for understanding genetic susceptibility to influenza virus infections in humans.
The Cellular Factor NXP2/MORC3 Is a Positive Regulator of Influenza Virus Multiplication
Authors: Ver Lorena S. , Marcos-Villar Laura , Landeras-Bueno Sara , Nieto Amelia , Ortín Juan 
Published: July 2015

ABSTRACT

Transcription and replication of influenza A virus are carried out in the nuclei of infected cells in the context of viral ribonucleoproteins (RNPs). The viral polymerase responsible for these processes is a protein complex composed of the PB1, PB2, and PA proteins. We previously identified a set of polymerase-associated cellular proteins by proteomic analysis of polymerase-containing intracellular complexes expressed and purified from human cells. Here we characterize the role of NXP2/MORC3 in the infection cycle. NXP2/MORC3 is a member of the Microrchidia (MORC) family that is associated with the nuclear matrix and has RNA-binding activity. Influenza virus infection led to a slight increase in NXP2/MORC3 expression and its partial relocalization to the cytoplasm. Coimmunoprecipitation and immunofluorescence experiments indicated an association of NXP2/MORC3 with the viral polymerase and RNPs during infection. Downregulation of NXP2/MORC3 by use of two independent short hairpin RNAs (shRNAs) reduced virus titers in low-multiplicity infections. Consistent with these findings, analysis of virus-specific RNA in high-multiplicity infections indicated a reduction of viral RNA (vRNA) and mRNA after NXP2/MORC3 downregulation. Silencing of NXP2/MORC3 in a recombinant minireplicon system in which virus transcription and replication are uncoupled showed reductions in
cat
mRNA and chloramphenicol acetyltransferase (CAT) protein accumulation but no alterations in
cat
vRNA levels, suggesting that NXP2/MORC3 is important for influenza virus transcription.

IMPORTANCE
Influenza virus infections appear as yearly epidemics and occasional pandemics of respiratory disease, with high morbidity and occasional mortality. Influenza viruses are intracellular parasites that replicate and transcribe their genomic ribonucleoproteins in the nuclei of infected cells, in a complex interplay with host cell factors. Here we characterized the role of the human NXP2/MORC3 protein, a member of the Microrchidia family that is associated with the nuclear matrix, during virus infection. NXP2/MORC3 associates with the viral ribonucleoproteins in infected cells. Downregulation of NXP2/MORC3 reduced virus titers and accumulations of viral genomic RNA and mRNAs. Silencing of NXP2/MORC3 in an influenza virus CAT minireplicon system diminished CAT protein and
cat
mRNA levels but not genomic RNA levels. We propose that NXP2/MORC3 plays a role in influenza virus transcription.
Determinants of Human CD134 Essential for Entry of Human Herpesvirus 6B
Authors: Tang Huamin , Mori Yasuko 
Published: July 2015

ABSTRACT
We identified two key amino acid residues within human CD134 (hCD134) that are required for its interaction with human herpesvirus 6B (HHV-6B) and for HHV-6B entry into cells. One of the residues (K79) allows access of the HHV-6B ligand to hCD134. Murine CD134 (mCD134) functioned as an HHV-6B receptor when these two amino acid residues were replaced with homologous human residues. This study identifies both the HHV-6B receptor-ligand interaction and the species-specific determinants of hCD134 essential for HHV-6B entry.
Clinical characteristics, complications, comorbidities and treatment patterns among patients with type 2 diabetes mellitus in a large integrated health system
Authors: Pantalone Kevin M , Hobbs Todd M , Wells Brian J , Kong Sheldon X , Kattan Michael W , Bouchard Jonathan , Yu Changhong , Sakurada Brian , Milinovich Alex , Weng Wayne , Bauman Janine M , Zimmerman Robert S 
Published: July 2015

PurposeTo compare the prevalence of diabetes-related complications and comorbidities, clinical characteristics, glycemic control, and treatment patterns in patients with type 2 diabetes (T2D) within a large integrated healthcare system in 2008 vs 2013.MethodsAn electronic health record system was used to create a cross-sectional summary of all patients with T2D as on 1 July 2008 and 1 July 2013. Differences between the two data sets were assessed after adjusting for age, gender, race, and household income.ResultsIn 2008 and 2013, 24 493 and 41 582 patients with T2D were identified, respectively, of which the majority were male (52.3% and 50.1%) and Caucasian (79% and 75.2%). The mean ages (years) were 64.8 and 64.3. The percentages of patients across the defined A1C categories were 64.3 and 66.7 for <7%, 21.1 and 18.8 for 7–7.9%, 7.8 and 7.5 for 8–8.9%, and 6.8 and 7.0 for ≥9% in 2008 and 2013, respectively. The most prevalent T2D-related comorbidities were hypertension (82.5% and 87.2%) and cardiovascular disease (26.9% and 22.3%) in 2008 and 2013, respectively. Thiazolidinedione and sulfonylurea use decreased, whereas metformin and dipeptidyl peptidase-4 inhibitor use increased in the 5-year period.ConclusionsPatients with T2D are characterized by a high number of comorbidities. Over 85% of the patients had an A1C<8% within our integrated health delivery system in 2008 and 2013. In 2008 and 2013, metformin therapy was the most commonly utilized antidiabetic agent, and sulfonylureas were the most commonly utilized oral antidiabetic agent in combination with metformin. As integrated health systems assume greater shared financial risk in newer payment models, achieving glycemic targets (A1C) and the management of comorbidities will become ever-more important, for preventing diabetes-related complications, as well as to ensure reimbursement for the medical care that is rendered to patients with diabetes.
Farm environment during infancy and lung function at the age of 31: a prospective birth cohort study in Finland
Authors: Lampi Jussi , Koskela Heikki , Hartikainen Anna-Liisa , Ramasamy Adaikalavan , Couto Alves Alexessander , Järvelin Marjo-Riitta , Pekkanen Juha 
Published: July 2015

ObjectivesFarming as an occupation is considered a risk factor for asthma and reduced lung function. By contrast, living on a farm during infancy has been reported to be associated with lower risk of asthma in adulthood. However, little is known about the association between farming environment during infancy and lung function in adulthood. We aimed to study the prospective longitudinal association between farming environment during infancy and lung function in adulthood.DesignA prospective birth cohort study.SettingNorthern Finland.Participants5666 participants born in 1966 were followed up at the age of 31 years.Primary outcome measuresSpirometry at the age of 31 years.ResultsTo be born into a farmer’s family was associated with higher forced expiratory volume in 1 s (FEV1) (36 mL; 95% CI 6 to 67 mL) and forced vital capacity (FVC) (40 mL; 95% CI 5 to 75 mL) at the age of 31 years. Contact with farm animals during infancy was associated with higher FEV1. No associations were seen with FEV1/FVC (FEV1/FVC ratio). Having dogs in childhood revealed similar associations. There was a suggestive dose-dependent association with the number of animal species during childhood and higher FEV1 and FVC at adulthood, especially among women.ConclusionsFarming environment in early life may have a positive impact on lung function in adulthood.
‘You are just left to get on with it’: qualitative study of patient and carer experiences of the transition to secondary progressive multiple sclerosis
Authors: Davies F , Edwards A , Brain K , Edwards M , Jones R , Wallbank R , Robertson N P , Wood F 
Published: July 2015

ObjectivesAlthough the transition to secondary progressive multiple sclerosis (SPMS) is known to be a period of uncertainty for clinicians, who may find progressive disease challenging to objectively identify, little research has explored the experiences of patients and carers specifically during this transition period. Our objective was to explore what patients and their carers understand about their disease stage and describe their experiences and perspectives on the transition to SPMS.DesignSemistructured qualitative interviews and subsequent validation focus groups were analysed using inductive thematic analysis.SettingSouth East Wales, UK.Participants20 patients with MS and 13 carers were interviewed. Eight patients and two carers participated in focus groups.ResultsFour main themes around disease progression were identified. ‘Realisation’ describes how patients came to understand they had SPMS while ‘reaction’ describes their response to this realisation. The ‘realities’ of living with SPMS, including dealing with the healthcare system during this period, were described along with ‘future challenges’ envisaged by patients and carers.ConclusionsAwareness that the transition to SPMS has occurred, and subsequent emotional reactions and coping strategies, varied widely between patients and their carers. The process of diagnosing the transition was often not transparent and some individuals wanted information to help them understand what the transition to SPMS meant for them.
Exploring the impact of consultants’ experience on hospital mortality by day of the week: a retrospective analysis of hospital episode statistics
Authors: Ruiz Milagros , Bottle Alex , Aylin Paul P 
Published: July 2015

ObjectiveTo examine the association of consultants’ experience with mortality by day of the week when elective surgery was performed.DesignRetrospective observational study using English hospital administrative data.SettingAll acute and specialist English National Health Service (NHS) hospitals carrying out elective surgery between financial years 2008–2009 and 2010–2011.ParticipantsPatients undergoing elective surgical procedures.Main outcome measuresDeath in or out of hospital within 30 days of the surgical procedure taking place.ResultsWe examined 3 922 091 (26 409 deaths) elective procedures with valid consultant information between 2008–2009 and 2010–2011 in English hospitals; there were 21 196 consultants in charge of these procedures, which took place in 163 NHS hospitals. Consultant seniority had no significant impact in predicting mortality (p=0.345). Patients undergoing elective surgery underjuniorconsultants had slightly lower odds of 30-day death when compared with patients under more experienced consultants (OR 0.95, 95% CI 0.91 to 0.99). We found significant mortality variation among consultants in charge of elective procedures within hospitals, with only moderate variation between hospitals. The adjusted odds of death remained higher for Friday (OR 1.48, 95% CI 1.42 to 1.54), Saturday (OR 1.97, 95% CI 1.83 to 2.12) and Sunday (OR 1.67, 95% CI 1.50 to 1.85) after adjusting for consultant seniority and patient characteristics. Consultant experience is significantly lower (p<0.0001) on a Friday (median (SD) was 7.9 years (4.4)) than the Monday to Thursday average (median (SD) was 8.5 years (4.3)).ConclusionsOur cohort of patients shows that consultant seniority is not a significant factor in predicting 30-day mortality following elective surgery by day of the week. The end-of-the-week effect remains significant after adjusting for patient, consultant and hospital effects, suggesting that other unobserved factors may be driving the higher mortality towards the end of the week. Consultant's years of experience are lowest on a Friday; however, we do not believe that this small variation has any impact on patient outcomes.
Warfarin Blocks Gas6-Mediated Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and Metastasis
Authors: Kirane Amanda , Ludwig Kathleen F. , Sorrelle Noah , Haaland Gry , Sandal Tone , Ranaweera Renate , Toombs Jason E. , Wang Miao , Dineen Sean P. , Micklem David , Dellinger Michael T. , Lorens James B. , Brekken Rolf A. 
Published: July 2015

Abstract
Repurposing “old” drugs can facilitate rapid clinical translation but necessitates novel mechanistic insight. Warfarin, a vitamin K “antagonist” used clinically for the prevention of thrombosis for more than 50 years, has been shown to have anticancer effects. We hypothesized that the molecular mechanism underlying its antitumor activity is unrelated to its effect on coagulation, but is due to inhibition of the Axl receptor tyrosine kinase on tumor cells. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here, we show that inhibiting Gas6-dependent Axl activation with low-dose warfarin, or with other tumor-specific Axl-targeting agents, blocks the progression and spread of pancreatic cancer. Warfarin also inhibited Axl-dependent tumor cell migration, invasiveness, and proliferation while increasing apoptosis and sensitivity to chemotherapy. We conclude that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low-dose warfarin or other Axl-targeting agents may improve outcome in patients with Axl-expressing tumors. Cancer Res; 75(18); 3699–705. ©2015 AACR.
Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth
Authors: Rigoni Alice , Bongiovanni Lucia , Burocchi Alessia , Sangaletti Sabina , Danelli Luca , Guarnotta Carla , Lewis Amy , Rizzo Aroldo , Silver Andrew R. , Tripodo Claudio , Colombo Mario P. 
Published: July 2015

Abstract
Mast cells (MC) are immune cells located next to the intestinal epithelium with regulatory function in maintaining the homeostasis of the mucosal barrier. We have investigated MC activities in colon inflammation and cancer in mice either wild-type (WT) or MC-deficient (KitW-sh) reconstituted or not with bone marrow-derived MCs. Colitis was chemically induced with dextran sodium sulfate (DSS). Tumors were induced by administering azoxymethane (AOM) intraperitoneally before DSS. Following DSS withdrawal, KitW-sh mice showed reduced weight gain and impaired tissue repair compared with their WT littermates or KitW-sh mice reconstituted with bone marrow-derived MCs. MCs were localized in areas of mucosal healing rather than damaged areas where they degraded IL33, an alarmin released by epithelial cells during tissue damage. KitW-sh mice reconstituted with MC deficient for mouse mast cell protease 4 did not restore normal mucosal healing or reduce efficiently inflammation after DSS withdrawal. In contrast with MCs recruited during inflammation-associated wound healing, MCs adjacent to transformed epithelial cells acquired a protumorigenic profile. In AOM- and DSS-treated WT mice, high MC density correlated with high-grade carcinomas. In similarly treated KitW-sh mice, tumors were less extended and displayed lower histologic grade. Our results indicate that the interaction of MCs with epithelial cells is dependent on the inflammatory stage, and on the activation of the tissue repair program. Selective targeting of MCs for prevention or treatment of inflammation-associated colon cancer should be timely pondered to allow tissue repair at premalignant stages or to reduce aggressiveness at the tumor stage. Cancer Res; 75(18); 3760–70. ©2015 AACR.