bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secretion Modification Region-Derived Peptide Disrupts HIV-1 Nef's Interaction with Mortalin and Blocks Virus and Nef Exosome Release
Authors: Shelton Martin N. , Huang Ming-Bo , Ali Syed A. , Powell Michael D. , Bond Vincent C. 
Published: October 2011

ABSTRACTNef is secreted from infected cells in exosomes and is found in abundance in the sera of HIV-infected individuals. Secreted exosomal Nef (exNef) induces apoptosis in uninfected CD4+T cells and may be a key component of HIV pathogenesis. The exosomal pathway has been implicated in HIV-1 virus release, suggesting a possible link between these two viral processes. However, the underlying mechanisms and cellular components of exNef secretion have not been elucidated. We have previously described a Nef motif, the secretion modification region (SMR; amino acids 66 to 70), that is required for exNef secretion.In silicomodeling data suggest that this motif can form a putative binding pocket. We hypothesized that the Nef SMR binds a cellular protein involved in protein trafficking and that inhibition of this interaction would abrogate exNef secretion. By using tandem mass spectrometry and coimmunoprecipitation with a novel SMR-based peptide (SMRwt) that blocks exNef secretion and HIV-1 virus release, we identified mortalin as an SMR-specific cellular protein. A second set of coimmunoprecipitation experiments with full-length Nef confirmed that mortalin interacts with Nef via Nef's SMR motif and that this interaction is disrupted by the SMRwtpeptide. Overexpression and microRNA knockdown of mortalin revealed a positive correlation between exNef secretion levels and mortalin protein expression. Using antibody inhibition we demonstrated that the Nef/mortalin interaction is necessary for exNef secretion. Taken together, this work constitutes a significant step in understanding the underlying mechanism of exNef secretion, identifies a novel host-pathogen interaction, and introduces an HIV-derived peptide with antiviral properties.
Single-Chain Fv-Based Anti-HIV Proteins: Potential and Limitations
Authors: West Anthony P. , Galimidi Rachel P. , Gnanapragasam Priyanthi N. P. , Bjorkman Pamela J. 
Published: October 2011

ABSTRACT
The existence of very potent, broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) offers the potential for prophylaxis against HIV-1 infection by passive immunization or gene therapy. Both routes permit the delivery of modified forms of IgGs. Smaller reagents are favored when considering ease of tissue penetration and the limited capacities of gene therapy vectors. Immunoadhesin (single-chain fragment variable [scFv]-Fc) forms of IgGs are one class of relatively small reagent that has been explored for delivery by adeno-associated virus. Here we investigated the neutralization potencies of immunoadhesins compared to those of their parent IgGs. For the antibodies VRC01, PG9, and PG16, the immunoadhesins showed modestly reduced potencies, likely reflecting reduced affinities compared to those of the parent IgG, and the VRC01 immunoadhesin formed dimers and multimers with reduced neutralization potencies. Although scFv forms of neutralizing antibodies may exhibit affinity reductions, they provide a means of building reagents with multiple activities. Attachment of the VRC01 scFv to PG16 IgG yielded a bispecific reagent whose neutralization activity combined activities from both parent antibodies. Although the neutralization activity due to each component was partially reduced, the combined reagent is attractive since fewer strains escaped neutralization.
Transcriptional Repression and RNA Silencing Act Synergistically To Demonstrate the Function of the Eleventh Component of the Vaccinia Virus Entry-Fusion Complex
Authors: Wolfe Cindy L. , Ojeda Suany , Moss Bernard 
Published: October 2011

ABSTRACTPoxviruses have an elaborate system for infecting cells comprising several proteins for attachment and a larger number dedicated to membrane fusion and entry. Thus far, 11 proteins have been identified as components of the vaccinia virus (VACV) entry-fusion complex (EFC), and 10 of these proteins have been shown to be required for entry. J5, the remaining functionally uncharacterized component of the complex, is conserved in all poxviruses, has a predicted C-terminal transmembrane domain, and is an N-terminally truncated paralog of two other EFC proteins. To determine the role of J5, we constructed a mutant that inducibly regulates J5 transcription. Although the virus yield was reduced only about 80% without inducer, the inability to isolate a J5 deletion mutant suggested an essential function. To enhance stringency, we employed RNA silencing alone and together with transcriptional repression of the inducible mutant. The yield of infectious virus was reduced 4- to 5-fold by repression, 2-fold by silencing, and 60-fold by the combination of the two. Virus particles made under the latter conditions appeared to contain a full complement of proteins excluding J5 but had very low infectivity. Further studies indicated that after binding to cells, J5-deficient virions had a defect in core entry and an inability to induce syncytium formation. In addition, we confirmed that J5 is associated with the EFC by affinity purification. These data indicate that J5 is a functional component of the EFC and highlights the advantage of combining transcriptional repression and RNA silencing for stringent reduction of gene expression.
Apparent Expression of Varicella-Zoster Virus Proteins in Latency Resulting from Reactivity of Murine and Rabbit Antibodies with Human Blood Group A Determinants in Sensory Neurons
Authors: Zerboni Leigh , Sobel Raymond A. , Lai Michelle , Triglia Richard , Steain Megan , Abendroth Allison , Arvin Ann 
Published: October 2011

ABSTRACT

Analyses of varicella-zoster virus (VZV) protein expression during latency have been discordant, with rare to many positive neurons detected. We show that ascites-derived murine and rabbit antibodies specific for VZV proteins
in vitro
contain endogenous antibodies that react with human blood type A antigens in neurons. Apparent VZV neuronal staining and blood type A were strongly associated (by a χ
2
test, α = 0.0003). Adsorption of ascites-derived monoclonal antibodies or antiserum with type A erythrocytes or the use of
in vitro
-derived VZV monoclonal antibodies eliminated apparent VZV staining. Animal-derived antibodies must be screened for anti-blood type A reactivity to avoid misidentification of viral proteins in the neurons of the 30 to 40% of individuals who are blood type A.
Human Coronavirus-Induced Neuronal Programmed Cell Death Is Cyclophilin D Dependent and Potentially Caspase Dispensable
Authors: Favreau Dominique J. , Meessen-Pinard Mathieu , Desforges Marc , Talbot Pierre J. 
Published: October 2011

ABSTRACT

Human coronaviruses (HCoV) are recognized respiratory pathogens. Some HCoV strains, including HCoV-OC43, can invade the central nervous system, where they infect neurons, with unclear consequences. We have previously reported that HCoV-OC43 infection of human neurons activates the unfolded-protein response and caspase-3 and induces cell death and that the viral spike (S) glycoprotein is involved in the process. We now report on underlying mechanisms associated with the induction of programmed cell death (PCD) after infection by the reference HCoV-OC43 virus (rOC/ATCC) and a more neurovirulent and cytotoxic HCoV-OC43 variant harboring two point mutations in the S glycoprotein (rOC/U
S183-241
). Even though caspase-3 and caspase-9 were both activated after infection, the use of caspase inhibitors neither reduced nor delayed virus-induced PCD, suggesting that these proteases are not essential in the process. On the other hand, the proapoptotic proteins BAX, cytochrome
c
(CytC), and apoptosis-inducing factor (AIF) were relocalized toward the mitochondria, cytosol, and nucleus, respectively, after infection by both virus variants. Moreover, LA-N-5 neuronal cells treated with cyclosporine (CsA), an inhibitor of the mitochondrial permeabilization transition pore (mPTP), or knocked down for cyclophilin D (CypD) were completely protected from rOC/ATCC-induced neuronal PCD, underlining the involvement of CypD in the process. On the other hand, CsA and CypD knockdown had moderate effects on rOC/U
S183-241
-induced PCD. In conclusion, our results are consistent with mitochondrial AIF and cyclophilin D being central in HCoV-OC43-induced PCD, while caspases appear not to be essential.
Kaposi's Sarcoma-Associated Herpesvirus-Encoded MicroRNA miR-K12-11 Attenuates Transforming Growth Factor Beta Signaling through Suppression of SMAD5
Authors: Liu Yunhua , Sun Rui , Lin Xianzhi , Liang Deguang , Deng Qiang , Lan Ke 
Published: October 2011

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs (pre-miRNAs). Current studies have shown that these miRNAs are involved in regulation of viral and host gene expression, implicating a role in the maintenance of viral latency and suppression of antiviral innate immunity. However, the functions of these miRNAs remain largely unknown. On the basis of the sequence homology between oncogenic miR-155 and KSHV-encoded miR-K12-11, we hypothesized that miR-K12-11 could attenuate transforming growth factor β (TGF-β) signaling, facilitating viral infection and tumorigenesis. In the present study, we demonstrated that ectopic expression of miR-K12-11 in Ramos, a TGF-β-sensitive cell line, downregulated TGF-β signaling and facilitated cell proliferation upon TGF-β treatment by directly targeting SMAD5, an important mediator in TGF-β signaling. In addition, the downregulation of SMAD5 by miR-K12-11 was further confirmed in a
de novo
KSHV infection system or latently infected KSHV-positive B-lymphoma cell lines. More importantly, repression of miR-K12-11 by a specific sponge inhibitor restored the expression of SMAD5 in both
de novo
-infected and latently infected cells. Finally, we found that restoration of SMAD5, in addition to the TGF-β type II receptor, which was epigenetically silenced by the latent viral protein latency-associated nuclear antigen, sensitized BC3 cells to the cytostatic effect of TGF-β signaling. Taken together, our findings highlight a novel mechanism in which miR-K12-11 downregulates TGF-β signaling and suggest that viral miRNAs and proteins may exert a dichotomy regulation in virus-induced oncogenesis by targeting the same signaling pathway.
Risk factors of recurrent hamstring injuries: a systematic review
Authors: de Visser HM , Reijman M , Heijboer MP , Bos PK 
Published: October 2011

BackgroundAlthough recurrent hamstring injury is a frequent problem with a significant impact on athletes, data on factors determining the risk for a recurrent hamstring injury are scarce.ObjectiveTo systematically review the literature and provide an overview of risk factors for re-injury of acute hamstring muscle injuries.Study designProspective studies on risk factors for re-injury following acute hamstring injuries were systematically reviewed. Medical databases and reference lists of the included articles were searched. Two reviewers independently selected potential studies and assessed methodological quality; one reviewer extracted the data. A best-evidence synthesis of all studied risk factors was performed.ResultsOf the 131 articles identified, five prospective follow-up studies fulfilled our inclusion criteria. These studies reported a recurrence incidence of 13.9–63.3% in the same playing season up to 2 years after initial injury. Limited evidence for three risk factors and one protective factor for recurrent hamstring injury was found; patients with a recurrent hamstring injury had an initial injury with a larger volume size as measured on MRI (47.03 vs 12.42 cm3), more often had a Grade 1 initial trauma (Grade 0: 0–30.4%; Grade 1: 60.9–100%; Grade 2: 8.7%) and more often had a previous ipsilateral anterior cruciate ligament (ACL) reconstruction (66.6% vs 17.1%) independent of graft selection. Athletes in a rehabilitation programme with agility/stabilisation exercises rather than strength/stretching exercises had a lower risk for re-injury (7.7% vs 70%). No significant relationship with re-injury was found for 11 related determinants. There was conflicting evidence that a larger cross-sectional area is a risk factor for recurrent hamstring injury.ConclusionsThere is limited evidence that athletes with a larger volume size of initial trauma, a Grade 1 hamstring injury and a previous ipsilateral ACL reconstruction are at increased risk for recurrent hamstring injury. Athletes seem to be at lower risk for re-injury when following agility/stabilisation exercises.
Asymptomatic coronary heart disease in patients with type 2 diabetes with vascular complications: a cross-sectional study
Authors: Tsujimoto Tetsuro , Kajio Hiroshi , Takahashi Yoshihiko , Kishimoto Miyako , Noto Hiroshi , Yamamoto-Honda Ritsuko , Kamimura Munehiro , Morooka Miyako , Kubota Kazuo , Shimbo Takuro , Hiroe Michiaki , Noda Mitsuhiko 
Published: October 2011

BackgroundRecent studies have suggested that microvascular and macrovascular diseases are associated with coronary events.ObjectiveTo test the hypothesis that asymptomatic coronary heart disease (CHD) may be present in many patients with diabetes with vascular complications.DesignFrom April 2009 to August 2010, the authors conducted a cross-sectional study to assess the prevalence of asymptomatic CHD among patients with type 2 diabetes with vascular complications at a national diabetes centre in Japan. Eligibility criteria included patients with type 2 diabetes with no known CHD and one or more of the following four criteria: (1) proliferative diabetic retinopathy or after photocoagulation; (2) estimated glomerular filtration rate <30 ml/min/1.73 m2or an estimated glomerular filtration rate <45 ml/min/1.73 m2plus albuminuria; (3) peripheral arterial disease; and (4) cerebrovascular disease. Each patient underwent a stress single-photon emission computed tomography; patients with myocardial perfusion abnormalities then underwent coronary angiography.ResultsA total of 1008 patients with type 2 diabetes were screened, and 122 eligible patients consented to participate. Stress single-photon emission computed tomography revealed myocardial perfusion abnormalities in 96 (79%) patients. Of the 112 patients who completed the study protocol, 59 (53%) had asymptomatic CHD with ≥50% diameter stenosis. Additionally, 35 (31%) patients had multivessel disease or left main disease, and 42 (38%) had a coronary artery with ≥75% diameter stenosis. In the multivariate logistic-regression analysis to identify coronary risk factors associated with asymptomatic CHD, the only significant predictor was male sex (OR 6.18; 95% CI 2.30 to 16.64; p<0.001).ConclusionsAsymptomatic CHD with ≥50% diameter stenosis and myocardial perfusion abnormalities was detected in more than half of the patients with type 2 diabetes with vascular complications.
Aurora-B protein expression is linked to initial response to taxane-based first-line chemotherapy in stage III ovarian carcinoma
Authors: Beussel S , Hasenburg A , Bogatyreva L , Hauschke D , Werner M , Lassmann S 
Published: October 2011

AimsAurora kinases are central to cell proliferation and considered to be prognostic/predictive markers and therapeutic targets for epithelial cancers. Here, the prognostic/predictive value of Aurora-B protein expression was evaluated in patients with serous, FIGO stage III ovarian carcinomas treated with taxane- or platinum-based first-line chemotherapy (1st-CTx).MethodsImmunohistochemistry was performed on tissue microarrays, including 80 ovarian carcinomas and 18 non-neoplastic ovaries, previously characterised for Aurora-A protein expression. None or marginal (score 0+1), moderate (score 2) and strong (score 3) Aurora-B protein expression was correlated with clinico-pathological parameters as well as recurrence-free survival (RFS) and overall survival (OS).ResultsWhile non-neoplastic ovaries were negative for Aurora-B, almost all (79/80; 99%) ovarian carcinomas exhibited Aurora-B positive tumour cells, with score 1 in 41/80 (51%), score 2 in 23/80 (29%) and score 3 in 15/80 (19%) cases. Aurora-B and Aurora-A protein expression correlated significantly (p=0.002). In optimal debulked patients, Aurora-B protein expression was associated with RFS (p=0.011, n=53) and marginally with OS (p=0.460; n=53). Moreover, Aurora-B protein expression was predictive for RFS of optimal debulked patients with taxane-based (p=0.006; n=32), but not with platinum-based (p=0.720; n=20) 1st-CTx. Aurora-B protein expression was not linked to OS in optimal debulked patients with either of the two 1st-CTx.ConclusionsAurora-B protein expression frequently occurs in serous, FIGO stage III ovarian carcinomas, making it a ‘drugable’ molecular target in the majority of ovarian carcinoma patients. Moreover, Aurora-B protein expression is predictive for initial response to taxane-based 1st-CTx in optimal debulked, late stage ovarian carcinoma patients.
Fibroid in pregnancy: characteristics, complications, and management
Authors: Zaima Ahmed , Ash Alok 
Published: October 2011

ABSTRACT
Fibroid in pregnancy is common in clinical obstetric practice. The topic is becoming more relevant in contemporary obstetrics due to the demographic shift towards delayed childbearing, the rising rate of obesity, and many pregnancies occurring after the treatment of fibroids. However, there are conflicting reports in the literature on many so-called fibroid complications in pregnancy, and there are inadequate data on the optimum management strategy. An evidence base is lacking on the pregnancy outcome of many conventional and newer treatment modalities of fibroids. This review addresses the characteristics and behaviour of fibroids during pregnancy, their incidence and demography, diagnosis, the complications that can arise during pregnancy and their antenatal management, the labour pattern, mode of delivery and the postpartum course, with critical appraisal of the literature together with certain special situations such as pregnancy after various types of myomectomy and uterine arterial embolisation.
Adaptive Basal Phosphorylation of eIF2α Is Responsible for Resistance to Cellular Stress–Induced Cell Death in Pten-Null Hepatocytes
Authors: Zeng Ni , Li Yang , He Lina , Xu Xiaoling , Galicia Vivian , Deng Chuxia , Stiles Bangyan L. 
Published: October 2011

Abstract
The α-subunit of eukaryotic initiation factor 2 (eIF2α) is a key translation regulator that plays an important role in cellular stress responses. In the present study, we investigated how eIF2α phosphorylation can be regulated by a tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) and how such regulation is used by PTEN-deficient hepatocytes to adapt and cope with oxidative stress. We found that eIF2α was hyperphosphorylated when Pten was deleted, and this process was AKT dependent. Consistent with this finding, we found that the Pten-null cells developed resistance to oxidative glutamate and H2O2-induced cellular toxicity. We showed that the messenger level of CReP (constitutive repressor of eIF2α phosphorylation), a constitutive phosphatase of eIF2α, was downregulated in Pten-null hepatocytes, providing a possible mechanism through which PTEN/AKT pathway regulates eIF2α phosphorylation. Ectopic expression of CReP restored the sensitivity of the Pten mutant hepatocytes to oxidative stress, confirming the functional significance of the downregulated CReP and upregulated phospho-eIF2α in the resistance of Pten mutant hepatocytes to cellular stress. In summary, our study suggested a novel role of PTEN in regulating stress response through modulating the CReP/eIF2α pathway. Mol Cancer Res; 9(12); 1708–17. ©2011 AACR.
Platelet function profiles in the elderly: Results of a pharmacodynamic study in patients on clopidogrel therapy and effects of switching to prasugrel 5 mg in patients with high platelet reactivity
Authors: Tamburino Claudia , Capodanno Davide , Miccichè Eligio , D’Urso Lucia , Calvi Valeria , Angiolillo Dominick , Tamburino Corrado , Capranzano Piera 
Published: October 2011

SummaryStudies specifically designed to assess clopidogrel response in the elderly as well as treatment alternatives to improve platelet inhibition in this highrisk population are lacking. This study aimed to define phar-macodynamic (PD) profiles, including high platelet reactivity (HPR) rates, among elderly patients on maintenance clopidogrel therapy and to assess the PD effects of prasugrel 5 mg/day in elderly with HPR. This was a prospective observational PD study enrolling consecutive ≥75-year-old patients on maintenance clopidogrel therapy (75 mg/day) who were tested for clopidogrel response by the VerifyNow P2Y12 assay and light transmittance aggregometry (LTA). HPR rates were estimated using multiple definitions. HPR patients identified by the VerifyNow P2Y12 assay [P2Y12 reaction unit (PRU) ≥230] were switched to prasugrel 5 mg/day, and platelet function testing was performed after 15 days of treatment. PD testing was completed in 100 patients. The HPR prevalence varied between 25% and 32%, depending on the definition used. A PRU ≥230 was observed in 25 patients; of these, 20 switched to prasugrel 5 mg/day. This resulted in significant reduction in PRU mean values (279.8 ± 45.1 vs. 171.7 ± 65.2, p=0.0002) with an absolute between-treatment difference of 108.1 (95% confidence intervals 75.2–140.9). Accordingly, switching to prasugrel 5 mg/day overcame HPR in most (80%) patients. Consistently, all LTA measures were significantly lower after prasugrel compared with clopidogrel. In conclusion, a considerable proportion of elderly patients exhibit HPR while on standard clopidogrel therapy. Switching to 5 mg/day prasugrel in elderly patients with HPR is associated with enhanced platelet inhibition and overcomes HPR in the majority of these patients.
Vaccination strategies in atherosclerosis
Authors: Kuiper Johan , de Jager Saskia 
Published: October 2011

SummaryThe treatment of atherosclerosis is currently based on lipid lowering in combination with anti-inflammatory therapies that slow the progression of atherosclerosis. Still, we are not able to fully inhibit the formation or progression of atherosclerotic lesions. A very effective strategy in other disease pathologies is vaccination, in which the body is challenged with the culprit protein or micro-organism in order to create a highly specific humoral immune-response. Immunisation can typically be divided into active or passive immunisation. Active immunisation occurs naturally when the body is exposed to certain microbes or antigens, but also artificially in the case of vaccination. Exposure to a microbe or antigen will result in the production of (antigen specific) antibodies. Passive immunisation is defined as the transfer of humoral immunity (as a result of antibody transfer). Another mechanism to ensure immune-protection is tolerance induction. Immune tolerance occurs naturally to prevent immune responses to ‘self-antigens’, but can also be induced to non-self antigens. Acquired tolerance to foreign antigens is accompanied by suppression of cellular and/or humoral immune response to the introduced antigen. In its most effective way, vaccination can result in a lifelong protection against the targeted pathology, and therefore the development of an atherosclerosis-specific vaccination is of high importance in the future prevention of atherosclerosis. One of the difficulties in developing effective vaccination strategies for atherosclerosis is the selection of a specific antigen to target. So far vaccination strategies have been based on targeting of lipidantigens, inflammation-derived antigens, and recently cell-based vaccination strategies have been employed; but also the cardiovascular ‘side-effects’ of infection-based vaccines are worthy of our attention. This review describes the current status-quo on classical antibody associated vaccination strategies but also includes promising immunemodulation approaches that may lead to a clinical application.