bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Anti-Inflammatory Role of VEGFR2/Src Kinase Inhibitor in Herpes Simplex Virus 1-Induced Immunopathology
Authors: Sharma Shalini , Mulik Sachin , Kumar Naveen , Suryawanshi Amol , Rouse Barry T. 
Published: April 2011

ABSTRACT

Corneal neovascularization represents a key step in the blinding inflammatory stromal keratitis (SK) lesion caused by ocular infection with herpes simplex virus (HSV). In this report, we describe a novel approach for limiting the angiogenesis caused by HSV infection of the mouse eye. We show that topical or systemic administration of the Src kinase inhibitor (TG100572) that inhibits downstream molecules involved in the vascular endothelial growth factor (VEGF) signaling pathway resulted in markedly diminished levels of HSV-induced angiogenesis and significantly reduced the severity of SK lesions. Multiple mechanisms were involved in the inhibitory effects. These included blockade of IL-8/CXCL1 involved in inflammatory cells recruitment that are a source of VEGF, diminished cellular infiltration in the cornea, and reduced proliferation and migration of CD4
+
T cells into the corneas. As multiple angiogenic factors (VEGF and basic fibroblast growth factor [bFGF]) play a role in promoting angiogenesis during SK and since Src kinases are involved in signaling by many of them, the use of Src kinase inhibition represents a promising way of limiting the severity of SK lesions the most common cause of infectious blindness in the Western world.
Rescue of Infectious Particles from Preassembled Alphavirus Nucleocapsid Cores
Authors: Snyder Jonathan E. , Azizgolshani Odisse , Wu Bingbing , He Yingpei , Lee Aih Cheun , Jose Joyce , Suter Daniel M. , Knobler Charles M. , Gelbart William M. , Kuhn Richard J. 
Published: April 2011

ABSTRACT

Alphaviruses are small, spherical, enveloped, positive-sense, single-stranded, RNA viruses responsible for considerable human and animal disease. Using microinjection of preassembled cores as a tool, a system has been established to study the assembly and budding process of Sindbis virus, the type member of the alphaviruses. We demonstrate the release of infectious virus-like particles from cells expressing Sindbis virus envelope glycoproteins following microinjection of Sindbis virus nucleocapsids purified from the cytoplasm of infected cells. Furthermore, it is shown that nucleocapsids assembled
in vitro
mimic those isolated in the cytoplasm of infected cells with respect to their ability to be incorporated into enveloped virions following microinjection. This system allows for the study of the alphavirus budding process independent of an authentic infection and provides a platform to study viral and host requirements for budding.
Cytomegalovirus e127 Protein Interacts with the Inhibitory CD200 Receptor
Authors: Foster-Cuevas Mildred , Westerholt Tina , Ahmed Mohamed , Brown Marion H. , Barclay A. Neil , Voigt Sebastian 
Published: April 2011

ABSTRACT
CD200 is a cell surface glycoprotein that binds an inhibitory receptor (CD200R) on myeloid cells. CD200 orthologues are present in many species of virus, and we show that the rat cytomegalovirus CD200 orthologue (e127) is expressed at the cell surface on infected cells. It binds the host CD200R with the same affinity as that of the host protein, and thus this protein acts as a close mimic of the host protein and has the potential to downregulate immune responses to the virus.
Enzyme Digests Eliminate Nonfunctional Env from HIV-1 Particle Surfaces, Leaving Native Env Trimers Intact and Viral Infectivity Unaffected
Authors: Crooks Ema T. , Tong Tommy , Osawa Keiko , Binley James M. 
Published: April 2011

ABSTRACT
HIV-1 viruses and virus-like particles (VLPs) bear nonnative “junk” forms of envelope (Env) glycoprotein that may undermine the development of antibody responses against functional gp120/gp41 trimers, thereby blunting the ability of particles to elicit neutralizing antibodies. Here, we sought to better understand the nature of junk Env with a view to devising strategies for its removal. Initial studies revealed that native trimers were surprisingly stable in the face of harsh conditions, suggesting that junk Env is unlikely to arise by trimer dissociation or gp120 shedding. Furthermore, the limited gp120 shedding that occurs immediately after synthesis of primary HIV-1 isolate Envs is not caused by aberrant cleavage at the tandem gp120/gp41 cleavage sites, which were found to cleave in a codependent manner. A major VLP contaminant was found to consist of an early, monomeric form of gp160 that is glycosylated in the endoplasmic reticulum (gp160ER) and then bypasses protein maturation and traffics directly into particles. gp160ER was found to bind two copies of monoclonal antibody (MAb) 2G12, consistent with its exclusively high-mannose glycan profile. These findings prompted us to evaluate enzyme digests as a way to remove aberrant Env. Remarkably, sequential glycosidase-protease digests led to a complete or near-complete removal of junk Env from many viral strains, leaving trimers and viral infectivity largely intact. “Trimer VLPs” may be useful neutralizing antibody immunogens.
Spatial Relationships between Markers for Secretory and Endosomal Machinery in Human Cytomegalovirus-Infected Cells versus Those in Uninfected Cells
Authors: Das Subhendu , Pellett Philip E. 
Published: April 2011

ABSTRACT

Human cytomegalovirus (HCMV) induces extensive remodeling of the secretory apparatus to form the cytoplasmic virion assembly compartment (cVAC), where virion tegumentation and envelopment take place. We studied the structure of the cVAC by confocal microscopy to assess the three-dimensional distribution of proteins specifically associated with individual secretory organelles. In infected cells, early endosome antigen 1 (EEA1)-positive vesicles are concentrated at the center of the cVAC and, as previously seen, are distinct from structures visualized by markers for the endoplasmic reticulum, Golgi apparatus, and
trans
-Golgi network (TGN). EEA1-positive vesicles can be strongly associated with markers for recycling endosomes, to a lesser extent with markers associated with components of the endosomal sorting complex required for transport III (ESCRT III) machinery, and then with markers of late endosomes. In comparisons of uninfected and infected cells, we found significant changes in the structural associations and colocalization of organelle markers, as well as in net organelle volumes. These results provide new evidence that the HCMV-induced remodeling of the membrane transport apparatus involves much more than simple relocation and expansion of preexisting structures and are consistent with the hypothesis that the shift in identity of secretory organelles in HCMV-infected cells results in new functional profiles.
A Pre-Immediate-Early Role for Tegument ICP0 in the Proteasome-Dependent Entry of Herpes Simplex Virus
Authors: Delboy Mark G. , Nicola Anthony V. 
Published: April 2011

ABSTRACT
Herpes simplex virus (HSV) entry requires host cell 26S proteasomal degradation activity at a postpenetration step. When expressed in the infected cell, the HSV immediate-early protein ICP0 has E3 ubiquitin ligase activity and interacts with the proteasome. The cell is first exposed to ICP0 during viral entry, since ICP0 is a component of the inner tegument layer of the virion. The function of tegument ICP0 is unknown. Deletion of ICP0 or mutations in the N-terminal RING finger domain of ICP0 results in the absence of ICP0 from the tegument. We show here that these mutations negatively influenced the targeting of incoming capsids to the nucleus. Inhibitors of the chymotrypsin-like activity of the proteasome the blocked entry of virions containing tegument ICP0, including ICP0 mutants that are defective in USP7 binding. However, ICP0-deficient virions were not blocked by proteasomal inhibitors and entered cells via a proteasome-independent mechanism. ICP0 appeared to play a postpenetration role in cells that supported either endocytosis or nonendosomal entry pathways for HSV. The results suggest that ICP0 mutant virions are defective upstream of viral gene expression at a pre-immediate-early step in infection. We propose that proteasome-mediated degradation of a virion or host protein is regulated by ICP0 to allow efficient delivery of entering HSV capsids to the nuclear periphery.
Common HIV-1 Peptide Variants Mediate Differential Binding of KIR3DL1 to HLA-Bw4 Molecules
Authors: Fadda Lena , O'Connor Geraldine M. , Kumar Swati , Piechocka-Trocha Alicja , Gardiner Clair M. , Carrington Mary , McVicar Daniel W. , Altfeld Marcus 
Published: April 2011

ABSTRACTEpidemiological studies have shown the protective effect of KIR3DL1/HLA-Bw4 genotypes in human immunodeficiency virus type 1 (HIV-1) infection; however, the functional correlates for the protective effect remain unknown. We investigated whether human leukocyte antigen (HLA)-Bw4-presented HIV-1 peptides could affect the interaction between the inhibitory natural killer (NK) cell receptor KIR3DL1 and its ligand HLA-Bw4. Distinct HIV-1 epitopes differentially modulated the binding of KIR3DL1 to HLA-Bw4. Furthermore, cytotoxic T lymphocyte (CTL) escape mutations within the immunodominant HLA-B57 (Bw4)-restricted Gag epitope TSTLQEQIGW abrogated KIR3DL1 binding to HLA-B57, suggesting that sensing of CTL escape variants by NK cells can contribute to the protective effect of the KIR3DL1/HLA-Bw4 compound genotype.
Disulfiram Reactivates Latent HIV-1 in a Bcl-2-Transduced Primary CD4
+
T Cell Model without Inducing Global T Cell Activation
Authors: Xing Sifei , Bullen Cynthia K. , Shroff Neeta S. , Shan Liang , Yang Hung-Chih , Manucci Jordyn L. , Bhat Shridhar , Zhang Hao , Margolick Joseph B. , Quinn Thomas C. , Margolis David M. , Siliciano Janet D. , Siliciano Robert F. 
Published: April 2011

ABSTRACT

Highly active antiretroviral therapy (HAART) can reduce plasma HIV-1 levels to below the detection limit. However, due to the latent reservoir in resting CD4
+
cells, HAART is not curative. Elimination of this reservoir is critical to curing HIV-1 infection. Agents that reactivate latent HIV-1 through nonspecific T cell activation are toxic. Here we demonstrate in a primary CD4
+
T cell model that the FDA-approved drug disulfiram reactivates latent HIV-1 without global T cell activation. The extent to which disulfiram reactivates latent HIV-1 in patient cells is unclear, but the drug alone or in combination may be useful in future eradication strategies.
Broadly Cross-Neutralizing Antibodies in HIV-1 Patients with Undetectable Viremia
Authors: Medina-Ramírez M. , Sánchez-Merino V. , Sánchez-Palomino S. , Merino-Mansilla A. , Ferreira C. B. , Pérez I. , González N. , Alvarez A. , Alcocer-González J. M. , García F. , Gatell J. M. , Alcamí J. , Yuste E. 
Published: April 2011

ABSTRACT
Several recent studies have identified HIV-infected patients able to produce a broad neutralizing response, and the detailed analyses of their sera have provided valuable information to improve future vaccine design. All these studies have excluded patients on antiretroviral treatment and with undetectable viral loads, who have an improved B cell profile compared to untreated patients. To better understand the induction of neutralizing antibodies in patients on antiretroviral treatment with undetectable viremia, we have screened 508 serum samples from 364 patients (173 treated and 191 untreated) for a broadly neutralizing antibody (bNAb) response using a new strategy based on the use of recombinant viruses. Sera able to neutralize a minipanel of 6 recombinant viruses, including envelopes from 5 different subtypes, were found in both groups. After IgG purification, we were able to confirm the presence of IgG-associated broadly neutralizing activity in 3.7% (7 of 191) of untreated patients with detectable viremia and 1.7% (3 of 174) of aviremic patients receiving antiretroviral treatment. We thus confirm the possibility of induction of a broad IgG-associated neutralizing response in patients on antiretroviral treatment, despite having undetectable viremia. This observation is in stark contrast to the data obtained from long-term nonprogressors, whose little neutralizing activity has been attributed to the low levels of viral replication.
Human Cytomegalovirus Induces the Activity and Expression of Acetyl-Coenzyme A Carboxylase, a Fatty Acid Biosynthetic Enzyme Whose Inhibition Attenuates Viral Replication
Authors: Spencer Cody M. , Schafer Xenia L. , Moorman Nathaniel J. , Munger Joshua 
Published: April 2011

ABSTRACT
We have previously reported that human cytomegalovirus (HCMV) infection induces large-scale changes to host cell glycolytic, nucleic acid, and phospholipid metabolism. Here we explore the viral mechanisms involved in fatty acid biosynthetic activation. Our results indicate that HCMV targets ACC1, the rate-limiting enzyme of fatty acid biosynthesis, through multiple mechanisms. HCMV infection was found to activate ACC1 expression, increasing the abundance of both ACC1 mRNA and protein. Viral gene expression but not viral DNA replication was found to be necessary for HCMV-mediated induction of ACC1 levels. HCMV infection was also found to increase the proteolytic processing of SREBP-2, a transcription factor whose proteolytic cleavage is known to activate a variety of phospholipid metabolic genes. Processing of SREBP-2 was found to be dependent on mTOR activity; pharmaceutical inhibition of mTOR blocked HCMV-induced SREBP-2 processing and prevented the induction of fatty acid biosynthesis and ACC1 expression. Independent of the increases in ACC1 expression, HCMV infection also induced ACC1's enzymatic activity. Inhibition of ACC1 through either RNA interference (RNAi) or inhibitor treatment was found to attenuate HCMV replication, and HCMV replication was sensitive to ACC1 inhibition even at the later stages of infection, suggesting a late role for fatty acid biosynthesis during HCMV replication. These findings indicate that HCMV infection actively modulates numerous functional aspects of a key metabolic regulatory enzyme that is important for high-titer viral replication.
Feasibility of using routinely collected inpatient data to monitor quality and inform choice: a case study using the UK inflammatory bowel disease audit
Authors: Roberts Stephen E , Williams John G , Cohen David R , Akbari Ashley , Groves Sam , Button Lori A 
Published: April 2011

ObjectiveTo assess the utility and cost of using routinely collected inpatient data for large-scale audit.DesignComparison of audit data items collected nationally in a designed audit of inflammatory bowel disease (UK IBD audit) with routinely collected inpatient data; surveys of audit sites to compare costs.SettingNational Health Service hospitals across England, Wales and Northern Ireland that participated in the UK IBD audit.PatientsPatients in the UK IBD audit.InterventionsNone.Main outcome measuresPercentage agreement between designed audit data items collected for the UK IBD audit and routine inpatient data items; costs of conducting the designed UK IBD audit and the routine data audit.ResultsThere were very high matching rates between the designed audit data and routine data for a small subset of basic important information collected in the UK IBD audit, including mortality; major surgery; dates of admission, surgery, discharge and death; principal diagnoses; and sociodemographic patient characteristics. There were lower matching rates for other items, including source of admission, primary reason for admission, most comorbidities, colonoscopy and sigmoidoscopy. Routine data did not cover most detailed information collected in the UK IBD audit. Using routine data was much less costly than collecting designed audit data.ConclusionAlthough valuable for large population-based studies, and less costly than designed data, routine inpatient data are not suitable for the evaluation of individual patient care within a designed audit.
Bone-marrow plasma cell burden correlates with IgM paraprotein concentration in Waldenström macroglobulinaemia
Authors: Pasricha Sant-Rayn , Juneja Surender K , Westerman David A , Came Neil A 
Published: April 2011

AimsCorrelations between the marrow histopathology and clinical findings in Waldenström macroglobulinaemia (WM) are not well defined, and the pathophysiology of the plasma cell involvement is poorly understood. The authors used a standardised immunohistological approach to the enumeration of B lymphocyte and plasma cell compartments in the bone-marrow trephine to investigate associations between bone-marrow morphology and clinical/laboratory indices.MethodsIn 80 newly diagnosed, untreated cases of WM, the authors determined the degree and pattern of B lymphocyte (CD20+) and plasma cell (CD138+) infiltration in the bone-marrow trephine, as defined by immunohistochemistry, and correlated the disease in the marrow with components of the international scoring system for WM (age, serum IgM paraprotein level, haemoglobin, platelet count and β2microglobulin). Plasma cell clonality was assessed by κ and λ staining.ResultsSerum IgM paraprotein concentration was related to the plasma cell burden in the bone marrow (coefficient 0.231, p<0.005), but not the B lymphocytic infiltrate. Overall lymphoplasmacytic disease burden weakly correlated with severity of anaemia (coefficient 0.236, p=0.055). In 28/28 evaluated cases, plasma cells exhibited light chain restriction that was concordant with both that of the B lymphocytic infiltrate and paraprotein.ConclusionsBone-marrow features, in particular the degree of plasma cell infiltration, correlate with IgM paraprotein concentration at diagnosis in WM. The plasma cell compartment in this condition appears to be part of the neoplastic clone. In WM, specific evaluation of the plasma cell compartment in the bone marrow at baseline and following therapy may be valuable.
Microbial diversity of active layer and permafrost in an acidic wetland from the Canadian High Arctic
Authors: Wilhelm Roland C. , Niederberger Thomas D. , Greer Charles , Whyte Lyle G. 
Published: April 2011

The abundance and structure of archaeal and bacterial communities from the active layer and the associated permafrost of a moderately acidic (pH < 5.0) High Arctic wetland (Axel Heiberg Island, Nunavut, Canada) were investigated using culture- and molecular-based methods. Aerobic viable cell counts from the active layer were ∼100-fold greater than those from the permafrost (2.5 × 105 CFU·(g soil dry mass)–1); however, a greater diversity of isolates were cultured from permafrost, as determined by 16S rRNA gene sequencing. Isolates from both layers demonstrated growth characteristics of a psychrotolerant, halotolerant, and acidotolerant community. Archaea constituted 0.1% of the total 16S rRNA gene copy number and, in the 16S rRNA gene clone library, predominantly (71% and 95%) consisted of Crenarchaeota related to Group I. 1b. In contrast, bacterial communities were diverse (Shannon’s diversity index, H = ∼4), with Acidobacteria constituting the largest division of active layer clones (30%) and Actinobacteria most abundant in permafrost (28%). Direct comparisons of 16S rRNA gene sequence data highlighted significant differences between the bacterial communities of each layer, with the greatest differences occurring within Actinobacteria. Comparisons of 16S rRNA gene sequences with those from other Arctic permafrost and cold-temperature wetlands revealed commonly occurring taxa within the phyla Chloroflexi, Acidobacteria, and Actinobacteria (families Intrasporangiaceae and Rubrobacteraceae).
The Fluorescence Theatre: a cost-effective device using theatre gels for fluorescent protein and dye screening
Authors: Heil John R. , Nordeste Ricardo F. , Charles Trevor C. 
Published: April 2011

Here we report a simple cost-effective device for screening colonies on plates for expression of the monomeric red fluorescent protein mRFP1 and the fluorescent dye Nile red. This device can be built from any simple light source, in our case a Quebec Colony Counter, and cost-effective theatre gels. The device can be assembled in as little as 20 min, and it produces excellent results when screening a large number of colonies.
PROVENGE (Sipuleucel-T) in Prostate Cancer: The First FDA-Approved Therapeutic Cancer Vaccine
Authors: Cheever Martin A. , Higano Celestia S. 
Published: April 2011

AbstractSipuleucel-T (PROVENGE; Dendreon) is the first therapeutic cancer vaccine to be approved by the U.S. Food and Drug Administration. In men who have metastatic castration-resistant prostate cancer with no or minimal symptoms, sipuleucel-T prolongs median survival by 4.1 months compared with results in those treated with placebo. At 3 years, the proportion of patients in the vaccine group who were alive was 50% higher than that in the control group (31.7% versus 21.7%, respectively). Sipuleucel-T, which is designed to elicit an immune response to prostatic acid phosphatase, uses the patient's own immune system to recognize and combat his cancer. Currently, no other agents are available that offer a survival benefit for this population of asymptomatic patients who have not been treated with chemotherapy, except for docetaxel (whose inherent toxicities often lead patients and physicians to delay administration until symptoms develop). Straightforward strategies to increase the efficacy of sipuleucel-T are likely to provide even greater benefit. The preclinical and clinical development of sipuleucel-T is reviewed, and approaches to enhance efficacy are considered herein. Clin Cancer Res; 17(11); 3520–6. ©2011 AACR.
Targeting Oncogenic ALK: A Promising Strategy for Cancer Treatment
Authors: Grande Enrique , Bolós María-Victoria , Arriola Edurne 
Published: April 2011

AbstractRecently, the anaplastic lymphoma kinase (ALK) has been found to be altered in several solid and hematologic tumors. Novel drugs targeting this tyrosine kinase receptor are under development, and early clinical trials are showing promising activity in non–small cell lung cancer patients with ALK+ tumors. Here, we review the structure and function of the ALK receptor, the mechanisms associated with its deregulation in cancer, methods for ALK detection in tumor samples, its potential as a new marker for candidate patient selection for tailored therapy, and novel drugs under development that target ALK. Mol Cancer Ther; 10(4); 569–79. ©2011 AACR.