bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenic Mutations within the Hydrophobic Domain of the Prion Protein Lead to the Formation of Protease-Sensitive Prion Species with Increased Lethality
Authors: Coleman Bradley M. , Harrison Christopher F. , Guo Belinda , Masters Colin L. , Barnham Kevin J. , Lawson Victoria A. , Hill Andrew F. 
Published: December 2013

ABSTRACT

Prion diseases are a group of fatal and incurable neurodegenerative diseases affecting both humans and animals. The principal mechanism of these diseases involves the misfolding the host-encoded cellular prion protein, PrP
C
, into the disease-associated isoform, PrP
Sc
. Familial forms of human prion disease include those associated with the mutations G114V and A117V, which lie in the hydrophobic domain of PrP. Here we have studied the murine homologues (G113V and A116V) of these mutations using cell-based and animal models of prion infection. Under normal circumstances, the mutant forms of PrP
C
share similar processing, cellular localization, and physicochemical properties with wild-type mouse PrP (MoPrP). However, upon exposure of susceptible cell lines expressing these mutants to infectious prions, very low levels of protease-resistant aggregated PrP
Sc
are formed. Subsequent mouse bioassay revealed high levels of infectivity present in these cells. Thus, these mutations appear to limit the formation of aggregated PrP
Sc
, giving rise to the accumulation of a relatively soluble, protease sensitive, prion species that is highly neurotoxic. Given that these mutations lie next to the glycine-rich region of PrP that can abrogate prion infection, these findings provide further support for small, protease-sensitive prion species having a significant role in the progression of prion disease and that the hydrophobic domain is an important determinant of PrP conversion.

IMPORTANCE
Prion diseases are transmissible neurodegenerative diseases associated with an infectious agent called a prion. Prions are comprised of an abnormally folded form of the prion protein (PrP) that is normally resistant to enzymes called proteases. In humans, prion disease can occur in individuals who inherited mutations in the prion protein gene. Here we have studied the effects of two of these mutations and show that they influence the properties of the prions that can be formed. We show that the mutants make highly infectious prions that are more sensitive to protease treatment. This study highlights a certain region of the prion protein as being involved in this effect and demonstrates that prions are not always resistant to protease treatment.
Respiratory Syncytial Virus Infection, TLR3 Ligands, and Proinflammatory Cytokines Induce CD161 Ligand LLT1 Expression on the Respiratory Epithelium
Authors: Satkunanathan Stifani , Kumar Naveenta , Bajorek Monika , Purbhoo Marco A. , Culley Fiona J. 
Published: December 2013

ABSTRACTDuring respiratory-virus infection, excessive lymphocyte activation can cause pathology both in acute infection and in exacerbations of chronic respiratory diseases. The costimulatory molecule CD161 is expressed on lymphocyte subsets implicated in promoting respiratory inflammation, including Th2, Th17, mucosally associated invariant T (MAIT) cells, and type 2 innate lymphoid cells. We asked whether the CD161 ligand LLT1 could be expressed on respiratory epithelial cells following respiratory-virus infection as a mechanism by which respiratory-virus infection could promote activation of proinflammatory lymphocytes. In response to respiratory syncytial virus (RSV) infection, expression of LLT1 was upregulated in the BEAS-2B respiratory epithelial cell line and primary human bronchial epithelial cells. Imaging studies revealed that LLT1 expression increased in both RSV-infected and cocultured uninfected cells, suggesting that soluble factors produced during infection stimulate LLT1 expression. TLR3 and TLR2/6 ligands led to a rapid increase in LLT1 mRNA in respiratory epithelial cells, as did the proinflammatory cytokines type I interferons, interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNF-α), which are produced early in respiratory-virus infection. Immunohistochemistry confirmed the increase in LLT1 protein on the epithelial cell surface, and live-cell confocal microscopy demonstrated accumulation of epithelial LLT1 at synapses formed with CD161+T lymphocytes. LLT1 expression by the respiratory epithelium in response to respiratory-virus infection and inflammatory cytokines represents a novel link between innate immunity and lymphocyte activation. As a regulator of CD161+proinflammatory lymphocytes, LLT1 could be a novel therapeutic target in inflammation caused by respiratory-virus infection.IMPORTANCEThe immune response to respiratory-virus infection is essential for clearing the pathogen but, if excessive, can lead to tissue damage and obstruction of the airways. How viral infection activates immune cells in the lungs is not fully understood. Here, we show that LLT1 can be expressed in lung cells in response to infection. LLT1 triggers CD161, a receptor on inflammatory immune cells. This mechanism may promote activation of immune cells in the lungs in viral infection and could be a novel target for therapies aimed at reducing lung inflammation.
Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Induces Prostaglandin E
2
Production through Cyclooxygenase 1, Which Is Dependent on the ERK1/2-p-C/EBP-β Pathway
Authors: Bi Yanmin , Guo Xue-kun , Zhao Haiyan , Gao Li , Wang Lianghai , Tang Jun , Feng Wen-hai 
Published: December 2013

ABSTRACT

Atypical porcine reproductive and respiratory syndrome (PRRS) caused by highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) is characterized by high fever and high mortality. However, the mechanism underlying the fever induction is still unknown. Prostaglandin E
2
(PGE
2
), synthesized by cyclooxygenase type 1/2 (COX-1/2) enzymes, is essential for inducing fever. In this study, we found that PGE
2
, together with COX-1, was significantly elevated by HP-PRRSV. We subsequently demonstrated that extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphorylated ERK (p-ERK) were the key nodes to trigger COX-1 expression after HP-PRRSV infection. Furthermore, we proved the direct binding of p-C/EBP-β to the COX-1 promoter by luciferase reporter and chromatin immunoprecipitation assays. In addition, silencing of C/EBP-β remarkably impaired the enhancement of COX-1 production induced by HP-PRRSV infection. Taken together, our results indicate that HP-PPRSV elicits the expression of COX-1 through the ERK1/2-p-C/EBP-β signaling pathway, resulting in the increase of PGE
2
, which might be the cause of high fever in infected pigs. Our findings might provide new insights into the molecular mechanisms underlying the pathogenesis of HP-PRRSV infection.

IMPORTANCE
The atypical PRRS caused by HP-PRRSV was characterized by high fever, high morbidity, and high mortality in pigs of all ages, yet how HP-PRRSV induces high fever in pigs remains unknown. In the present study, we found out that HP-PRRSV infection could increase PGE
2
production by upregulation of COX-1, and we subsequently characterized the underlying mechanisms about how HP-PRRSV enhances COX-1 production. PGE
2
plays a critical role in inducing high temperature in hosts during pathogen infections. Thus, our findings here could help us have a better understanding of HP-PRRSV pathogenesis.
Interaction with Cellular CD4 Exposes HIV-1 Envelope Epitopes Targeted by Antibody-Dependent Cell-Mediated Cytotoxicity
Authors: Veillette Maxime , Désormeaux Anik , Medjahed Halima , Gharsallah Nour-Elhouda , Coutu Mathieu , Baalwa Joshua , Guan Yongjun , Lewis George , Ferrari Guido , Hahn Beatrice H. , Haynes Barton F. , Robinson James E. , Kaufmann Daniel E. , Bonsignori Mattia , Sodroski Joseph , Finzi Andrés 
Published: December 2013

ABSTRACTAnti-HIV-1 envelope glycoprotein (Env) antibodies without broadly neutralizing activity correlated with protection in the RV144 clinical trial, stimulating interest in other protective mechanisms involving antibodies, such as antibody-dependent cell-mediated cytotoxicity (ADCC). Env epitopes targeted by many antibodies effective at mediating ADCC are poorly exposed on the unliganded Env trimer. Here we investigated the mechanism of exposure of ADCC epitopes on Env and showed that binding of Env and CD4 within the same HIV-1-infected cell effectively exposes these epitopes. Env capacity to transit to the CD4-bound conformation is required for ADCC epitope exposure. Importantly, cell surface CD4 downregulation by Nef and Vpu accessory proteins and Vpu-mediated BST-2 antagonism modulate exposure of ADCC-mediating epitopes and reduce the susceptibility of infected cells to this effector functionin vitro. Significantly, Env conformational changes induced by cell surface CD4 are conserved among Env from HIV-1 and HIV-2/SIVmac lineages. Altogether, our observations describe a highly conserved mechanism required to expose ADCC epitopes that might help explain the evolutionary advantage of downregulation of cell surface CD4 by the HIV-1 Vpu and Nef proteins.IMPORTANCEHIV-1 envelope epitopes targeted by many antibodies effective at mediating antibody-dependent cell-mediated cytotoxicity (ADCC) are poorly exposed on the unliganded envelope trimer. Here we investigated the mechanism of exposure of these epitopes and found that envelope interaction with the HIV-1 CD4 receptor is required to expose some of these epitopes. Moreover, our results suggest that HIV-1 CD4 downregulation might help avoid the killing of HIV-1-infected cells by this immune mechanism.
INTERPRETATION OF CONVENTIONAL MASS
Authors: LEE SUNGJUN , KIM KWANG PYO 
Published: December 2013

The conventional mass is not a precise physical quantity but useful virtual one in mass metrology. Because the precise level of conventional mass is related to the OIML class, it is necessary to check if the assignment of weight class is under control. The documents of OIML (International Organization of Legal Metrology) D 28 and R 111 describe the limitation of the quantity in real application. In this presentation, we are trying to interpret and review the concept of conventional mass, for example, by estimating buoyancy deviation and maximum permissible error, in weight calibrations in Korea. Note from Publisher: This article contains the abstract only.
Antiapoptotic Effect of Simvastatin Ameliorates Myocardial Ischemia/Reperfusion Injury
Authors: Hadi Najah R. , Al-amran Fadhil , Yousif Maitham , Zamil Suhaad T. 
Published: December 2013

Background. Myocardial ischemial reperfusion represents a clinically relevant problem associated with thrombolysis, angioplasty, and coronary bypass surgery. Injury of myocardium due to ischemial reperfusion includes cardiac contractile dysfunction, arrhythmias, and irreversible myocytes damage. These changes are considered to be the consequence of imbalance between the formation of oxidants and the availability of endogenous antioxidants in the heart. Objective. This study was undertaken to investigate the potential role of Simvastatin in the amelioration of myocardial I/R injury induced by ligation of coronary artery in a rat model. Materials and Methods. Adult male Swiss Albino rats were randomized into 4 equal groups. Group (1): sham group: rats underwent the same anesthetic and surgical procedures as those in the control group except ligation of LAD coronary artery, group (2): control group: rats were subjected to regional ischemia for 25 min and reperfusion for 2 hours by ligation of LAD coronary artery, group (3): control vehicle group: rats received vehicle of Simvastatin (normal saline) via IP injection and were subjected to regional ischemia for 25 min and reperfusion for 2 hours by ligation of LAD coronary artery, group (4): Simvastatin treated group: rats were pretreated with Simvastatin 1 mg/kg i.p. 1 hr before ligation of LAD coronary artery. At the end of experiment (2 hr of reperfusion), blood samples were collected from the heart for the measurement of plasma level of cardiac troponin I (cTnI). After that the heart was harvested and divided into 3 parts; one part was used for measurement of apoptosis, another part was homogenized for the measurement of tissue tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α, and the last part for histopathology study. Results. Compared with the sham group, levels of myocardial TNF-α and IL-1β, IL-6, MCP-1, and MIP-1α and plasma cTnI were increased (P<0.05). Histologically, all rats in control group showed significant (P<0.05) cardiac injury. Furthermore, all rats in control group showed significant (P<0.05) apoptosis. Simvastatin significantly counteracted the increase in myocardium level of TNF-α, IL-1B, IL-6, MCP-1 and MIP-1α, plasma cTnI, and apoptosis (P< 0.05). Histological analysis revealed that Simvastatin markedly reduced (P< 0.05) the severity of heart injury in the rats that underwent LAD ligation procedure. Conclusions. The results of the present study reveal that Simvastatin may ameliorate myocardial I/R injury in rats via interfering with inflammatory reactions and apoptosis which were induced by I/R injury.
Metastasis Suppressor KISS1 Seems to Reverse the Warburg Effect by Enhancing Mitochondrial Biogenesis
Authors: Liu Wen , Beck Benjamin H. , Vaidya Kedar S. , Nash Kevin T. , Feeley Kyle P. , Ballinger Scott W. , Pounds Keke M. , Denning Warren L. , Diers Anne R. , Landar Aimee , Dhar Animesh , Iwakuma Tomoo , Welch Danny R. 
Published: December 2013

AbstractCancer cells tend to utilize aerobic glycolysis even under normoxic conditions, commonly called the “Warburg effect.” Aerobic glycolysis often directly correlates with malignancy, but its purpose, if any, in metastasis remains unclear. When wild-type KISS1 metastasis suppressor is expressed, aerobic glycolysis decreases and oxidative phosphorylation predominates. However, when KISS1 is missing the secretion signal peptide (ΔSS), invasion and metastasis are no longer suppressed and cells continue to metabolize using aerobic glycolysis. KISS1-expressing cells have 30% to 50% more mitochondrial mass than ΔSS-expressing cells, which are accompanied by correspondingly increased mitochondrial gene expression and higher expression of PGC1α, a master coactivator that regulates mitochondrial mass and metabolism. PGC1α-mediated downstream pathways (i.e., fatty acid synthesis and β-oxidation) are differentially regulated by KISS1, apparently reliant upon direct KISS1 interaction with NRF1, a major transcription factor involved in mitochondrial biogenesis. Since the downstream effects could be reversed using short hairpin RNA to KISS1 or PGC1α, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism, and metastasis. Cancer Res; 74(3); 954–63. ©2013 AACR.
Distinction between Asymptomatic Monoclonal B-cell Lymphocytosis with Cyclin D1 Overexpression and Mantle Cell Lymphoma: From Molecular Profiling to Flow Cytometry
Authors: Espinet Blanca , Ferrer Ana , Bellosillo Beatriz , Nonell Lara , Salar Antonio , Fernández-Rodríguez Concepción , Puigdecanet Eulàlia , Gimeno Javier , Garcia-Garcia Mar , Vela Maria Carmen , Luño Elisa , Collado Rosa , Navarro José Tomás , de la Banda Esmeralda , Abrisqueta Pau , Arenillas Leonor , Serrano Cristina , Lloreta Josep , Miñana Belén , Cerutti Andrea , Florensa Lourdes , Orfao Alberto , Sanz Ferran , Solé Francesc , Dominguez-Sola David , Serrano Sergio 
Published: December 2013

Abstract
Purpose: According to current diagnostic criteria, mantle cell lymphoma (MCL) encompasses the usual, aggressive variants and rare, nonnodal cases with monoclonal asymptomatic lymphocytosis, cyclin D1–positive (MALD1). We aimed to understand the biology behind this clinical heterogeneity and to identify markers for adequate identification of MALD1 cases.
Experimental Design: We compared 17 typical MCL cases with a homogeneous group of 13 untreated MALD1 cases (median follow-up, 71 months). We conducted gene expression profiling with functional analysis in five MCL and five MALD1. Results were validated in 12 MCL and 8 MALD1 additional cases by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in 24 MCL and 13 MALD1 cases by flow cytometry. Classification and regression trees strategy was used to generate an algorithm based on CD38 and CD200 expression by flow cytometry.
Results: We found 171 differentially expressed genes with enrichment of neoplastic behavior and cell proliferation signatures in MCL. Conversely, MALD1 was enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 were differentially expressed between MCL and MALD1 and confirmed by flow cytometry (median CD38, 89% vs. 14%; median CD200, 0% vs. 24%, respectively). Assessment of both proteins allowed classifying 85% (11 of 13) of MALD1 cases whereas 15% remained unclassified. SOX11 expression by qRT-PCR was significantly different between MCL and MALD1 groups but did not improve the classification.
Conclusion: We show for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. Assessment of CD38/CD200 by flow cytometry is useful to distinguish most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment. Clin Cancer Res; 20(4); 1007–19. ©2013 AACR.
Controlled type II diabetes mellitus has no major influence on platelet micro-RNA expression
Authors: Nührenberg Thomas , Fiebich Bernd L. , Amann Michael , Kumar Asit , Binder Harald , Hoffmann Isabell , Valina Christian , Hochholzer Willibald , Trenk Dietmar , Neumann Franz-Josef , Stratz Christian 
Published: December 2013

SummaryDiabetes mellitus as a major contributor to cardiovascular disease burden induces dysfunctional platelets. Platelets contain abundant miRNAs, which are linked to inflammatory responses and, thus, may play a role in atherogenesis. While diabetes mellitus affects plasma miRNAs, no data exist on platelet miRNA profiles in this disease. Therefore, this study sought to explore the miRNA profile of platelets in patients with diabetes mellitus that is unrelated to the presence or absence of coronary artery disease (CAD). Platelet miRNA profiles were assessed in stable diabetic and non-diabetic patients (each n=30); 15 patients in each group had CAD. Platelet miRNA was isolated from leucocyte-depleted platelet-rich plasma, and miRNA profiling was performed using LNA micro-array technology (miRBase18.0, containing 1,917 human miRNAs). Effects of diabetes mellitus were explored by univariate statistical tests for each miRNA, adjusted for potential confounders, and by developing a multivariable signature; evaluated by resampling techniques. Platelets in non-diabetic patients demonstrated miRNA expression profiles comparable to previous data. The miRNA profiles of platelets in diabetics were similar. Statistical analysis unveiled three miRNAs (miR-377–5p, miR-628–3p, miR-3137) with high reselection probabilities in resampling techniques, corresponding to signatures with modest discriminatory performance. Functional annotation of predicted targets for these miRNAs pointed towards an influence of diabetes mellitus on mRNA processing. We did not find major differences in platelet miRNA profiles between diabetics and non-diabetics. Minor differences pertained to miRNAs associated with mRNA processing. Thus, described differences in plasma miRNAs between diabetic and non-diabetic patients cannot be explained by plain changes in platelet miRNA profile.
Long-Term Results of Intensified, N-Terminal-Pro-B-Type Natriuretic Peptide–Guided Versus Symptom-Guided Treatment in Elderly Patients With Heart Failure
Authors: Sanders-van Wijk Sandra , Maeder Micha T. , Nietlispach Fabian , Rickli Hans , Estlinbaum Werner , Erne Paul , Rickenbacher Peter , Peter Martin , Pfisterer Matthias P. , Brunner-La Rocca Hans-Peter 
Published: December 2013

Background—
Therapy guided by N-terminal-pro-B-type natriuretic peptide (NT-proBNP) levels may improve outcomes in patients with chronic heart failure (HF), especially in younger patients with reduced left ventricular ejection fraction. It remains unclear whether treatment effects persist after discontinuation of the NT-proBNP–guided treatment strategy.

Methods and Results—

Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure randomized 499 patients with HF aged ≥60 years with left ventricular ejection fraction ≤45% to intensified, NT-proBNP–guided versus standard, symptom-guided therapy into prespecified age groups (60–74 and ≥75 years) during 18 months. A total of 329 patients (92%) alive at 18 months agreed to long-term follow-up. HF medication was intensified to a larger extent in the NT-proBNP–guided group. During long-term, NT-proBNP–guided therapy did not improve hospital-free (primary end point: hazard ratio, 0.87; 95% confidence interval, 0.71–1.06;
P
=0.16) or overall survival (hazard ratio, 0.85; 95% confidence interval, 0.64–1.13;
P
=0.25) but did improve HF hospitalization-free survival (hazard ratio, 0.70; 95% confidence interval, 0.55–0.90;
P
=0.005). Patients aged 60 to 74 years had benefit from NT-proBNP–guided therapy on the primary end point and HF hospitalization-free survival, whereas patients aged ≥75 years did not (
P
<0.10 for interaction). In landmark analysis, there was no regression to the mean after cessation of the NT-proBNP–guided strategy. More intensified HF medication at month 12 was associated with better long-term HF hospitalization-free and overall survival.

Conclusions—
Intensified, NT-proBNP–guided therapy did not improve the primary end point compared with symptom-guided therapy but did improve HF hospitalization-free survival. Within the subgroup of patients aged 60 to 74 years, it improved clinical outcome including the primary end point. These effects did not disappear after cessation of the NT-proBNP–guided strategy on the long-term. This is possibly attributable to a more intensified HF medical therapy in the NT-proBNP–guided group.

Clinical Trial Registration—

URL:
http://www.isrctn.org
. Unique identifier: ISRCTN43596477.