bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tacaribe Virus Causes Fatal Infection of An Ostensible Reservoir Host, the Jamaican Fruit Bat
Authors: Cogswell-Hawkinson Ann , Bowen Richard , James Stephanie , Gardiner David , Calisher Charles H. , Adams Rick , Schountz Tony 
Published: March 2012

ABSTRACT

Tacaribe virus (TCRV) was first isolated from 11
Artibeus
species bats captured in Trinidad in the 1950s during a rabies virus surveillance program. Despite significant effort, no evidence of infection of other mammals, mostly rodents, was found, suggesting that no other vertebrates harbored TCRV. For this reason, it was hypothesized that TCRV was naturally hosted by artibeus bats. This is in stark contrast to other arenaviruses with known hosts, all of which are rodents. To examine this hypothesis, we conducted experimental infections of Jamaican fruit bats (
Artibeus jamaicensis
) to determine whether they could be persistently infected without substantial pathology. We subcutaneously or intranasally infected bats with TCRV strain TRVL-11573, the only remaining strain of TCRV, and found that low-dose (10
4
50% tissue culture infective dose [TCID
50
]) inoculations resulted in asymptomatic and apathogenic infection and virus clearance, while high-dose (10
6
TCID
50
) inoculations caused substantial morbidity and mortality as early as 10 days postinfection. Uninoculated cage mates failed to seroconvert, and viral RNA was not detected in their tissues, suggesting that transmission did not occur. Together, these data suggest that
A. jamaicensis
bats may not be a reservoir host for TCRV.
Protective Role of Interferon Regulatory Factor 3-Mediated Signaling against Prion Infection
Authors: Ishibashi Daisuke , Atarashi Ryuichiro , Fuse Takayuki , Nakagaki Takehiro , Yamaguchi Naohiro , Satoh Katsuya , Honda Kenya , Nishida Noriyuki 
Published: March 2012

ABSTRACTAbnormal prion protein (PrPSc) generated from the cellular isoform of PrP (PrPC) is assumed to be the main or sole component of the pathogen, called prion, of transmissible spongiform encephalopathies (TSE). Because PrP is a host-encoded protein, acquired immune responses are not induced in TSE. Meanwhile, activation of the innate immune system has been suggested to partially block the progression of TSE; however, the mechanism is not well understood. To further elucidate the role of the innate immune system in prion infection, we investigated the function of interferon regulatory factor 3 (IRF3), a key transcription factor of the MyD88-independent type I interferon (IFN) production pathway. We found that IRF3-deficient mice exhibited significantly earlier onset with three murine TSE strains, namely, 22L, FK-1, and murine bovine spongiform encephalopathy (mBSE), following intraperitoneal transmission, than with wild-type controls. Moreover, overexpression of IRF3 attenuated prion infection in the cell culture system, while PrPScwas increased in prion-infected cells treated with small interfering RNAs (siRNAs) against IRF3, suggesting that IRF3 negatively regulates PrPScformation. Our findings provide new insight into the role of the host innate immune system in the pathogenesis of prion diseases.
Decreased Neuraminidase Activity Is Important for the Adaptation of H5N1 Influenza Virus to Human Airway Epithelium
Authors: Ilyushina Natalia A. , Bovin Nicolai V. , Webster Robert G. 
Published: March 2012

ABSTRACT
Highly pathogenic avian H5N1 influenza viruses remain a pandemic threat. Antiviral drugs such as neuraminidase (NA) inhibitors will be crucial for disease control in the event of a pandemic. Should drug-resistant H5N1 viruses develop, all defense strategies will be compromised. To determine the likelihood and mechanisms of emergence of NA inhibitor-resistant H5N1 variants in humans, we serially passaged two H5N1 viruses, A/Hong Kong/213/03 and A/Turkey/65-1242/06, in normal human bronchial epithelial (NHBE) cells in the presence of oseltamivir, zanamivir, or peramivir. To monitor the emergence of changes associated with the adaptation of H5N1 viruses to humans, we passaged the strains in the absence of drugs. Under pressure of each NA inhibitor, A/Turkey/65-1242/06 developed mutations in the hemagglutinin (HA) (H28R and P194L/T215I) and NA (E119A) proteins that reduced virus binding to α2,3-sialyl receptor and NA activity. Oseltamivir pressure selected a variant of A/Hong Kong/213/03 virus with HA P194S mutation that decreased viral binding to α2,6 receptor. Under peramivir pressure, A/Hong Kong/213/03 virus developed a novel NA mutation, R156K, that reduced binding to all three drugs, caused about 90% loss of NA activity, and compromised replication in NHBE cells. Both strains were eliminated in NHBE cells when they were cultivated in the absence of drugs. Here, we show for the first time that decreased NA activity mediated through NA inhibitors is essential for the adaptation of pandemic H5N1 influenza virus to humans. This ability of decreased NA activity to promote H5N1 infection underlines the necessity to optimize management strategies for a plausible H5N1 pandemic.
Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Replication by Targeting the Interaction between Vif and ElonginC
Authors: Zuo Tao , Liu Donglai , Lv Wei , Wang Xiaodan , Wang Jiawen , Lv Mingyu , Huang Wenlin , Wu Jiaxin , Zhang Haihong , Jin Hongwei , Zhang Liangren , Kong Wei , Yu Xianghui 
Published: March 2012

ABSTRACT
The HIV-1 viral infectivity factor (Vif) protein is essential for viral replication. Vif recruits cellular ElonginB/C-Cullin5 E3 ubiquitin ligase to target the host antiviral protein APOBEC3G (A3G) for proteasomal degradation. In the absence of Vif, A3G is packaged into budding HIV-1 virions and introduces multiple mutations in the newly synthesized minus-strand viral DNA to restrict virus replication. Thus, the A3G-Vif-E3 complex represents an attractive target for development of novel anti-HIV drugs. In this study, we identified a potent small molecular compound (VEC-5) by virtual screening and validated its anti-Vif activity through biochemical analysis. We show that VEC-5 inhibits virus replication only in A3G-positive cells. Treatment with VEC-5 increased cellular A3G levels when Vif was coexpressed and enhanced A3G incorporation into HIV-1 virions to reduce viral infectivity. Coimmunoprecipitation and computational analysis further attributed the anti-Vif activity of VEC-5 to the inhibition of Vif from direct binding to the ElonginC protein. These findings support the notion that suppressing Vif function can liberate A3G to carry out its antiviral activity and demonstrate that regulation of the Vif-ElonginC interaction is a novel target for small-molecule inhibitors of HIV-1.
Influenza Virus H1N1pdm09 Infections in the Young and Old: Evidence of Greater Antibody Diversity and Affinity for the Hemagglutinin Globular Head Domain (HA1 Domain) in the Elderly than in Young Adults and Children
Authors: Verma Nitin , Dimitrova Milena , Carter Donald M. , Crevar Corey J. , Ross Ted M. , Golding Hana , Khurana Surender 
Published: March 2012

ABSTRACT
The H1N1 2009 influenza virus (H1N1pdm09) pandemic had several unexpected features, including low morbidity and mortality in older populations. We performed in-depth evaluation of antibody responses generated following H1N1pdm09 infection of naïve ferrets and of 130 humans ranging from the very young (0 to 9 years old) to the very old (70 to 89 years old). In addition to hemagglutination inhibition (HI) titers, we used H1N1pdm09 whole-genome-fragment phage display libraries (GFPDL) to evaluate the antibody repertoires against internal genes, hemagglutinin (HA), and neuraminidase (NA) and also measured antibody affinity for antigenic domains within HA. GFPDL analyses of H1N1pdm09-infected ferrets demonstrated gradual development of antibody repertoires with a focus on M1 and HA1 by day 21 postinfection. In humans, H1N1pdm09 infection in the elderly (>70 years old) induced antibodies with broader epitope recognition in both the internal genes and the HA1 receptor binding domain (RBD) than for the younger age groups (0 to 69 years). Importantly, post-H1N1 infection serum antibodies from the elderly demonstrated substantially higher avidity for recombinant HA1 (rHA1) (but not HA2) than those from younger subjects (50% versus <22% 7 M urea resistance, respectively) and lower antibody dissociation rates using surface plasmon resonance. This is the first study in humans that provides evidence for a qualitatively superior antibody response in the elderly following H1N1pdm09 infection, indicative of recall of long-term memory B cells or long-lived plasma cells. These findings may help explain the age-related morbidity and mortality pattern observed during the H1N1pdm09 pandemic.
Myocardial infarction with normal coronaries: an autopsy perspective
Authors: Silvanto Anna , de Noronha Sofia Victoria , Sheppard Mary N 
Published: March 2012

AimTo analyse postmortem cases of myocardial infarction (MI) with normal coronary arteries in terms of patient characteristics, features of the MI and risk factors.MethodsThis retrospective non-case controlled study was carried out at a specialist cardiac pathology department at a tertiary cardiac referral centre. Cases of histologically confirmed MI and normal coronary arteries during the period 1996–2010 were identified and analysed for the presence of risk factors.ResultsNineteen cases of histologically confirmed MI and normal coronary arteries were identified with a similar gender ratio 1:1.1 (male:female) and mean age of 33±12 years (range 14–58). All patients died suddenly. The location of the infarct was variable, with left anterior descending artery territory being the single most prevalent (47%). Risk factors were identified in the majority of cases (n=14), with some cases experiencing more than one association, including alcohol and/or predominately class A drug use (n=7), including cocaine, inflammation (n=2), hypercoagulable state (n=3) and exertion (n=2).ConclusionsCurrent data regarding prognosis in MI with normal coronary arteries suggests a favourable outcome in the context of major cardiovascular events. No large series of fatal cases have been reported. This study highlights that this entity can be fatal and its prognosis may be less favourable than currently considered. This autopsy series also demonstrates that the causation of MI with normal coronary arteries is complex and multifactorial, including a history of alcohol and/or drug use. It also highlights the importance of accurate epidemiological data from referring pathologists.
Palaeogeographic consequences of conservational models in the South Atlantic Ocean
Authors: Aslanian Daniel , Moulin Maryline 
Published: March 2012

Abstract
Conservational models, like simple shear, pure shear or polyphase models that exclude exchanges between the lower continental crust and upper mantle, are usually proposed to explain the lithospheric stretching and consequent crustal thinning of passive continental margins. These models need large amounts of horizontal movement, and have, therefore, important implications for plate kinematic reconstructions and intraplate deformation. In this paper we propose to show these implications in the Central Segment of the South Atlantic Ocean. In the Angola–Brazilian system, these models imply about 240 km of horizontal movement. This movement can be compensated by two end-member mechanisms: (1) an intraplate deformation located in Africa; and (2) an intraplate deformation located in South America. We detail for each solution the strong geological and geodynamical implications, and discuss the consequences for the genesis of passive continental margins.
Proinflammatory Characteristics of SMAC/DIABLO-Induced Cell Death in Antitumor Therapy
Authors: Emeagi Perpetua U. , Van Lint Sandra , Goyvaerts Cleo , Maenhout Sarah , Cauwels Anje , McNeish Iain A. , Bos Tomas , Heirman Carlo , Thielemans Kris , Aerts Joeri L. , Breckpot Karine 
Published: March 2012

Abstract
Molecular mimetics of the caspase activator second mitochondria-derived activator of caspase (SMAC) are being investigated for use in cancer therapy, but an understanding of in vivo effects remains incomplete. In this study, we offer evidence that SMAC mimetics elicit a proinflammatory cell death in cancer cells that engages an adaptive antitumor immune response. Cancer cells of different histologic origin underwent apoptosis when transduced with lentiviral vectors encoding a cytosolic form of the SMAC mimetic LV-tSMAC. Strikingly, treatment of tumor-bearing mice with LV-tSMAC resulted in the induction of apoptosis, activation of antitumor immunity, and enhanced survival. Antitumor immunity was accompanied by an increase of tumor-infiltrating lymphocytes displaying low PD-1 expression, high lytic capacity, and high levels of IFN-γ when stimulated. We also noted in vivo a decrease in regulatory T cells along with in vitro activation of tumor-specific CD8+ T cells by dendritic cells (DC) isolated from tumor draining lymph nodes. Last, tumor-specific cytotoxic T cells were also found to be activated in vivo. Mechanistic analyses showed that transduction of cancer cells with LV-tSMAC resulted in exposure of calreticulin but not release of HMGB1 or ATP. Nevertheless, DCs were activated upon engulfment of dying cancer cells. Further validation of these findings was obtained by their extension in a model of human melanoma using transcriptionally targeted LV-tSMAC. Together, our findings suggest that SMAC mimetics can elicit a proinflammatory cell death that is sufficient to activate adaptive antitumor immune responses in cancer. Cancer Res; 72(6); 1342–52. ©2012 AACR.
Adipose Tissue Inflammation and Adiponectin Resistance in Patients With Advanced Heart Failure
Authors: Khan Raffay S. , Kato Tomoko S. , Chokshi Aalap , Chew Michael , Yu Shuiqing , Wu Christina , Singh Parvati , Cheema Faisal H. , Takayama Hiroo , Harris Collette , Reyes-Soffer Gissette , Knöll Ralph , Milting Hendrik , Naka Yoshifumi , Mancini Donna , Schulze P. Christian 
Published: March 2012

Background—
Heart failure (HF) is characterized by inflammation, insulin resistance, and progressive catabolism. We hypothesized that patients with advanced HF also develop adipose tissue inflammation associated with impaired adipokine signaling and that hemodynamic correction through implantation of ventricular assist devices (VADs) would reverse adipocyte activation and correct adipokine signaling in advanced HF.

Methods and Results—

Circulating insulin, adiponectin, leptin, and resistin levels were measured in 36 patients with advanced HF before and after VAD implantation and 10 healthy control subjects. Serum adiponectin was higher in HF patients before VAD implantation compared with control subjects (13.3±4.9 versus 6.4±2.1 μg/mL,
P
=0.02). VAD implantation (mean, 129±99 days) reduced serum adiponectin (7.4±3.4 μg/mL,
P
<0.05) and improved insulin resistance (Homeostasis Assessment Model of insulin resistance: 6.3±5.8–3.6±2.9;
P
<0.05). Adiponectin expression in adipose tissue decreased after VAD implantation (−65%;
P
<0.03). Adiponectin receptor expression was suppressed in the failing myocardium compared with control subjects and increased after mechanical unloading. Histomorphometric analysis of adipose tissue specimens revealed reduced adipocyte size in patients with advanced HF compared with control subjects (1999±24 μm
2
versus 5583±142 μm
2
in control subjects;
P
<0.05), which increased after VAD placement. Of note, macrophage infiltration in adipose tissue was higher in advanced HF patients compared with control subjects (+25%;
P
<0.01), which normalized after VAD implantation.

Conclusions—
Adipose tissue inflammation and adiponectin resistance develop in advanced HF. Mechanical unloading of the failing myocardium reverses adipose tissue macrophage infiltration, inflammation, and adiponectin resistance in patients with advanced HF.
Mortality Risk After Neonatal Seizures in Very Preterm Newborns
Authors: Pisani Francesco , Copioli Cristiana , Turco Emanuela Claudia , Sisti Lisa , Cossu Giuseppe , Seri Stefano 
Published: March 2012

We analyzed clinical and instrumental data of 403 consecutive newborns with gestational age from 24 to 32 weeks, admitted to the University-Hospital of Parma between January 2000 and December 2007, to evaluate the possible relationship between neonatal mortality and occurrence of neonatal seizures in very preterm newborns. Seventy-four subjects died during hospital stay. Seizures were present in 35 neonates, in whom the mortality rate was 37.1%. Multivariate analysis revealed that birth-weight <1000 g (odds ratio: 4.48; 95% confidence interval: 1.47-13.68; P < .01), cardiopulmonary resuscitation (odds ratio: 5.35; 95% confidence interval: 1.19-23.98; P = .02), and moderately and severely abnormal cerebral ultrasound scan findings (odds ratio: 2.48; 95% confidence interval: 1.02-6.05; P < .04; odds ratio: 9.56; 95% confidence interval: 3.45-26.51; P < .01, respectively) were related to the in-hospital mortality but not the presence of neonatal seizures. Our study suggests that neonatal seizures alone are not an independent risk factor for early death in very preterm newborns.
Global cardiovascular disease risk assessment in United States adults with diabetes
Authors: Wong Nathan D , Glovaci Diana , Wong Kalina , Malik Shaista , Franklin Stanley S , Wygant Gail , Iloeje Uchenna 
Published: March 2012

Background: Diabetes mellitus (DM) is often considered a risk equivalent for cardiovascular disease (CVD); however, the variation in CVD risk in adults with DM has not been described. Methods: We studied 1114 US adults aged ≥18 years with DM from national survey data and the proportion at low (<10%), intermediate (10–20%) and high (>20%) risk, or with CVD, by age, gender, ethnicity and diabetes type and treatment, and glycaemic and risk factor control by risk group. Results: Overall, 22.9% were low, 17.5% intermediate, 31.4% high risk and 28.2% had pre-existing CVD (total 59.6% high risk/CVD). More Hispanics (32.4%) and Blacks (30.6%) versus Whites (18.8%) were at lower risk ( p<0.0001). Among type 1 versus 2 DM, 35% vs. 65% ( p<0.0001) and among insulin users 68.1% were high risk or with CVD. However, among low-intermediate risk, >50% have metabolic syndrome and 7% chronic kidney disease, increasing the high risk/CVD group to 86.8%. Simultaneous achievement of HbA1c, blood pressure and low density lipoprotein-cholesterol goals was low (<15%) regardless of risk group. Conclusions: Many DM patients are not at high 10-year CVD risk, but metabolic factors may place them at greater long-term risk. Risk assessment could help target the intensity of treatment.
Effects of Platelet-Rich Plasma Composition on Anabolic and Catabolic Activities in Equine Cartilage and Meniscal Explants
Authors: Kisiday John D. , McIlwraith C. Wayne , Rodkey William G. , Frisbie David D. , Steadman J.Richard 
Published: March 2012

Objective: To evaluate the effects of single- and double-spin preparations of platelet-rich plasma (PRP) on anabolic and catabolic activities of cartilage and meniscal explants in vitro. Methods: Single- and double-spin PRP was prepared using laboratory processing or commercial kits. The cellular contents were quantified, and each PRP was mixed in equal quantities with cell culture medium and added to cartilage or meniscus explant cultures, with or without interleukin 1 β (IL-1β). Extracellular matrix synthesis was quantified over 24 hours via 35S-sulfate and 3H-proline incorporation, while gene expression of catabolic enzymes was evaluated using real-time PCR. Results: The platelet concentration in single-spin laboratory PRP was 59% higher than blood. Platelet and white blood cell concentrations in single-spin laboratory and kit PRP were not significantly different, while the double-spin kit resulted in approximately 2.5-fold higher platelet and approximately 400-fold higher white blood cell concentrations. In cartilage cultures without IL-1β, radiolabel incorporation in single-spin PRP cultures was significantly higher than in double-spin cultures. Similar results were obtained for 35S-sulfate incorporation in meniscus cultures without IL-1β. In IL-1β, radiolabel incorporation was largely similar among all PRPs. After 24 hours of culture, ADAMTS-4 gene expression in cartilage was lowest for single-spin PRP, while expression in the double-spin kit was not significantly different from double-spin laboratory PRP in which platelets were concentrated 6-fold. Conclusions This study suggests that single-spin PRP preparations may be the most advantageous for intra-articular applications and that double-spin systems should be considered with caution.
Thrombopoietin receptor down-modulation by JAK2 V617F: restoration of receptor levels by inhibitors of pathologic JAK2 signaling and of proteasomes
Authors: Pecquet Christian , Diaconu Carmen C. , Staerk Judith , Girardot Michael , Marty Caroline , Royer Yohan , Defour Jean-Philippe , Dusa Alexandra , Besancenot Rodolphe , Giraudier Stephane , Villeval Jean-Luc , Knoops Laurent , Courtoy Pierre J. , Vainchenker William , Constantinescu Stefan N. 
Published: March 2012

Abstract
The constitutively active JAK2 V617F mutant is the major determinant of human myeloproliferative neoplasms (MPNs). We show that coexpression of murine JAK2 V617F and the murine thrombopoietin (Tpo) receptor (TpoR, c-MPL) in hematopoietic cell lines or heterozygous knock-in of JAK2 V617F in mice leads to down-modulation of TpoR levels. Enhanced TpoR ubiquitinylation, proteasomal degradation, reduced recycling, and maturation are induced by the constitutive JAK2 V617F activity. These effects can be prevented in cell lines by JAK2 and proteasome inhibitors. Restoration of TpoR levels by inhibitors could be detected in platelets from JAK2 inhibitor-treated myelofibrosis patients that express the JAK2 V617F mutant, and in platelets from JAK2 V617F knock-in mice that were treated in vivo with JAK2 or proteasome inhibitors. In addition, we show that Tpo can induce both proliferative and antiproliferative effects via TpoR at low and high JAK2 activation levels, respectively, or on expression of JAK2 V617F. The antiproliferative signaling and receptor down-modulation by JAK2 V617F were dependent on signaling via TpoR cytosolic tyrosine 626. We propose that selection against TpoR antiproliferative signaling occurs by TpoR down-modulation and that restoration of down-modulated TpoR levels could become a biomarker for the treatment of MPNs.
The hypersensitive sites of the murine β-globin locus control region act independently to affect nuclear localization and transcriptional elongation
Authors: Bender M. A. , Ragoczy Tobias , Lee Jongjoo , Byron Rachel , Telling Agnes , Dean Ann , Groudine Mark 
Published: March 2012

Abstract
The β-globin locus control region (LCR) is necessary for high-level β-globin gene transcription and differentiation-dependent relocation of the β-globin locus from the nuclear periphery to the central nucleoplasm and to foci of hyperphosphorylated Pol II “transcription factories” (TFys). To determine the contribution of individual LCR DNaseI hypersensitive sites (HSs) to transcription and nuclear location, in the present study, we compared β-globin gene activity and location in erythroid cells derived from mice with deletions of individual HSs, deletions of 2 HSs, and deletion of the whole LCR and found all of the HSs had a similar spectrum of activities, albeit to different degrees. Each HS acts as an independent module to activate expression in an additive manner, and this is correlated with relocation away from the nuclear periphery. In contrast, HSs have redundant activities with respect to association with TFys and the probability that an allele is actively transcribed, as measured by primary RNA transcript FISH. The limiting effect on RNA levels occurs after β-globin genes associate with TFys, at which time HSs contribute to the amount of RNA arising from each burst of transcription by stimulating transcriptional elongation.