bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stimulation of NF-κB Activity by the HIV Restriction Factor BST2
Authors: Tokarev Andrey , Suarez Marissa , Kwan Wilson , Fitzpatrick Kathleen , Singh Rajendra , Guatelli John 
Published: December 2012

ABSTRACT

BST2 (HM1.24; CD317; tetherin) is an interferon-inducible transmembrane protein that restricts the release of several enveloped viruses, including HIV, from infected cells. Before its activity as an antiviral factor was described, BST2 was identified as an inducer of NF-κB activity. Here we show that human BST2 induces NF-κB in a dose-dependent manner. This activity is separable from the restriction of virus release: a YxY sequence in the cytoplasmic domain of BST2 is required for the induction of NF-κB but is dispensable for restriction, whereas the glycosylphosphatidylinositol (GPI) addition site in the protein's ectodomain is required for restriction but is largely dispensable for the induction of NF-κB. Mutations predicted to disrupt the coiled-coil structure of the BST2 ectodomain impaired both signaling and restriction, but disruption of the tetramerization interface differentially affected signaling. The induction of NF-κB by BST2 was impaired by inhibition of transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) or by calcium chelation, suggesting potential linkage to the mitogen-activated protein kinase and endoplasmic reticulum (ER) stress response pathways. Consistent with a role for TAK1, BST2 coimmunoprecipitated with TAK1 and the TAK1-associated pseudophosphatase TAB1; these interactions required the YxY sequence in BST2. Moreover, signaling by BST2 was blocked by expression of an IκB-mutant that inhibits the canonical pathway of NF-κB activation. The expression of HIV-1 Vpu inhibited the induction of NF-κB by BST2; this inhibition required Vpu's ability to bind the cellular β-TrCP-E3-ubiquitin ligase complex. The expression of HIV-1 lacking
vpu
augmented the induction of NF-κB activity by BST2, suggesting that BST2 can act as a virus sensor. This augmentation was also inhibited by Vpu in a β-TrCP-dependent manner. The role of BST2 in the host-pathogen relationship is apparently multifaceted: signaling during the innate immune response, sensing of viral gene expression, and direct restriction of virus release. HIV-1 Vpu counteracts each of these functions.
F-Actin Modulates Measles Virus Cell-Cell Fusion and Assembly by Altering the Interaction between the Matrix Protein and the Cytoplasmic Tail of Hemagglutinin
Authors: Wakimoto Hiroshi , Shimodo Masakatsu , Satoh Yuto , Kitagawa Yoshinori , Takeuchi Kaoru , Gotoh Bin , Itoh Masae 
Published: December 2012

ABSTRACT
Actin filament (F-actin) is believed to be involved in measles virus (MV) assembly as a cellular factor, but the precise roles remain unknown. Here we show that Phe at position 50 of the MV matrix (M) protein is important for its association with F-actin, through which the function of the M protein is regulated. In plasmid-expressed or MV-infected cells, a coimmunoprecipitation study revealed that the wild-type M (M-WT) protein associated strongly with F-actin but only weakly with the cytoplasmic tail of the hemagglutinin (H) protein. Since the F50P mutation allowed the M protein the enhanced interaction with the H protein in return for the sharply declined association with F-actin, the mutant M (M-F50P) protein strongly inhibited MV cell-cell fusion and promoted the uptake of the H protein into virus particles. The abundantly incorporated H protein resulted in the increase in infectivity of the F50P virus, although the virus contained a level of genome RNA equal to that of the WT virus. When the structure of F-actin was disrupted with cytochalasin D, the M-WT protein liberated from F-actin interacted with the H protein as tightly as the M-F50P protein, suppressing cell-cell fusion and promoting virus assembly comparably efficiently as the M-F50P protein. The cell-cell fusion activity of the WT virus appeared to be upheld by F-actin, which prevents the M protein interaction with the H protein. Our results indicate that F-actin in association with the M protein alters the interaction between the M and H proteins, thereby modulating MV cell-cell fusion and assembly.
Molecular Mechanism behind Rotavirus NSP1-Mediated PI3 Kinase Activation: Interaction between NSP1 and the p85 Subunit of PI3 Kinase
Authors: Bagchi Parikshit , Nandi Satabdi , Nayak Mukti Kant , Chawla-Sarkar Mamta 
Published: December 2012

ABSTRACT
Our previous study had reported on the interaction of rotavirus NSP1 with cellular phosphoinositide 3-kinase (PI3K) during activation of the PI3K pathway (P. Bagchi et al., J. Virol. 84:6834–6845, 2010). In this study, we have analyzed the molecular mechanism behind this interaction. Results showed that this interaction is direct and that both α and β isomers of the PI3K regulatory subunit p85 and full-length NSP1 are important for this interaction, which results in efficient activation of the PI3K/Akt pathway during rotavirus infection.
N-Terminal Phosphorylation Sites of Herpes Simplex Virus 1 ICP0 Differentially Regulate Its Activities and Enhance Viral Replication
Authors: Mostafa Heba H. , Thompson Thornton W. , Davido David J. 
Published: December 2012

ABSTRACT

The herpes simplex virus 1 (HSV-1) infected cell protein 0 (ICP0) is an immediate-early phosphoprotein that transactivates viral gene expression. Evidence suggests that phosphorylation regulates the functions of ICP0, and three regions (termed regions I, II, and III) in the protein are known to be phosphorylated. Mutation of the putative phosphorylation sites within region I, termed Phos 1, which lies in the N-terminal portion of ICP0, impairs the E3 ubiquitin (Ub) ligase and ND10-disrupting activities of ICP0 in cell culture and diminishes viral replication. To identify the specific phosphorylation site(s) or residues responsible for the phenotypes observed with Phos 1, individual residues within region I were mutated to alanine (S224A, T226A, T231A, and T232A) and one double mutant S224A/T226A was constructed. Tissue culture studies demonstrated that the S224A, S224A/T226A, T231A, and T232A mutants were unable to dissociate the cellular protein PML from ND10 and that the S224/T226A mutant was defective in its ability to dissociate the cellular protein Sp100 from ND10. Additionally, the transactivation activity of ICP0 was impaired in the S224A and S224A/T226A mutants. The S224A and S224A/T226A mutant forms were more stable than wild-type ICP0, suggesting that their ability to autoubiquitinate was limited. Moreover, one ICP0 ubiquitination target, USP-7, was also more stable after infection with these two mutants. Lastly, the replication of the S224A and S224A/T226A mutant viruses was reduced in cell culture and
in vivo
. Overall, our data suggest that specific phosphorylation sites within region I differentially regulate the activities of ICP0, which are required for efficient viral replication.
Pin1 Interacts with the Epstein-Barr Virus DNA Polymerase Catalytic Subunit and Regulates Viral DNA Replication
Authors: Narita Yohei , Murata Takayuki , Ryo Akihide , Kawashima Daisuke , Sugimoto Atsuko , Kanda Teru , Kimura Hiroshi , Tsurumi Tatsuya 
Published: December 2012

ABSTRACT

Peptidyl-prolyl
cis-trans
isomerase NIMA-interacting 1 (Pin1) protein is known as a regulator which recognizes phosphorylated Ser/Thr-Pro motifs and increases the rate of
cis
and
trans
amide isomer interconversion, thereby altering the conformation of its substrates. We found that Pin1 knockdown using short hairpin RNA (shRNA) technology resulted in strong suppression of productive Epstein-Barr virus (EBV) DNA replication. We further identified the EBV DNA polymerase catalytic subunit, BALF5, as a Pin1 substrate in glutathione
S
-transferase (GST) pulldown and immunoprecipitation assays. Lambda protein phosphatase treatment abolished the binding of BALF5 to Pin1, and mutation analysis of BALF5 revealed that replacement of the Thr178 residue by Ala (BALF5 T178A) disrupted the interaction with Pin1. To further test the effects of Pin1 in the context of virus infection, we constructed a BALF5-deficient recombinant virus. Exogenous supply of wild-type BALF5 in HEK293 cells with knockout recombinant EBV allowed efficient synthesis of viral genome DNA, but BALF5 T178A could not provide support as efficiently as wild-type BALF5. In conclusion, we found that EBV DNA polymerase BALF5 subunit interacts with Pin1 through BALF5 Thr178 in a phosphorylation-dependent manner. Pin1 might modulate EBV DNA polymerase conformation for efficient, productive viral DNA replication.
A Hydrogen Peroxide-Inactivated Virus Vaccine Elicits Humoral and Cellular Immunity and Protects against Lethal West Nile Virus Infection in Aged Mice
Authors: Pinto Amelia K. , Richner Justin M. , Poore Elizabeth A. , Patil Pradnya P. , Amanna Ian J. , Slifka Mark K. , Diamond Michael S. 
Published: December 2012

ABSTRACT

West Nile virus (WNV) is an emerging pathogen that is now the leading cause of mosquito-borne and epidemic encephalitis in the United States. In humans, a small percentage of infected individuals develop severe neuroinvasive disease, with the greatest relative risk being in the elderly and immunocompromised, two populations that are difficult to immunize effectively with vaccines. While inactivated and subunit-based veterinary vaccines against WNV exist, currently there is no vaccine or therapy available to prevent or treat human disease. Here, we describe the generation and preclinical efficacy of a hydrogen peroxide (H
2
O
2
)-inactivated WNV Kunjin strain (WNV-KUNV) vaccine as a candidate for further development. Both young and aged mice vaccinated with H
2
O
2
-inactivated WNV-KUNV produced robust adaptive B and T cell immune responses and were protected against stringent and lethal intracranial challenge with a heterologous virulent North American WNV strain. Our studies suggest that the H
2
O
2
-inactivated WNV-KUNV vaccine is safe and immunogenic and may be suitable for protection against WNV infection in vulnerable populations.
Dueling Regulatory Properties of a Transcriptional Activator (MtrA) and Repressor (MtrR) That Control Efflux Pump Gene Expression in Neisseria gonorrhoeae
Authors: Zalucki Yaramah M. , Dhulipala Vijaya , Shafer William M. 
Published: December 2012

ABSTRACT

MtrA is a member of the AraC family of transcriptional regulators and has been shown to play an important role in enhancing transcription of the
mtrCDE
operon, which encodes a tripartite multidrug efflux pump, when gonococci are exposed to a sublethal level of antimicrobials. Heretofore, the DNA-binding properties of MtrA were unknown. In order to understand how MtrA activates
mtrCDE
expression, we successfully purified MtrA and found that it could bind specifically to the
mtrCDE
promoter region. The affinity of MtrA for the
mtrCDE
promoter increased 2-fold in the presence of a known effector and substrate of the MtrCDE pump, the nonionic detergent Triton X-100 (TX-100). When placed in competition with MtrR, the transcriptional repressor of
mtrCDE
, MtrA was found to bind with apparent lower affinity than MtrR to the same region. However, preincubation of MtrA with TX-100 prior to addition of the promoter-containing DNA probe increased MtrA binding and greatly reduced its dissociation from the promoter upon addition of MtrR. Two independent approaches (DNase I footprinting and a screen for bases important in MtrA binding) defined the MtrA-binding site 20–30 bp upstream of the known MtrR-binding site. Collectively, these results suggest that the MtrA and MtrR-binding sites are sterically close and that addition of an effector increases the affinity of MtrA for the
mtrCDE
promoter such that MtrR binding is negatively impacted. Our results provide a mechanism for transcriptional activation of
mtrCDE
by MtrA and highlight the complexity of transcriptional control of drug efflux systems possessed by gonococci.

IMPORTANCE
Antibiotic resistance in
Neisseria gonorrhoeae
has been increasing in recent years, such that in 2007 the Centers for Disease Control and Prevention listed
N. gonorrhoeae
as a “superbug.” One of the major contributors to antibiotic resistance in
N. gonorrhoeae
is the MtrCDE efflux pump. Until now, most work on the regulation of the genes encoding this efflux pump has been done on the transcriptional repressor, MtrR. This study is the first one to purify and define the DNA-binding ability of the transcriptional activator, MtrA. Understanding how levels of the MtrCDE efflux pump are regulated increases our knowledge of gonococcal biology and how the gonococcus can respond to various stresses, including antimicrobials.
Employment status and the prevalence of poor self-rated health. Findings from UK individual-level repeated cross-sectional data from 1978 to 2004
Authors: Popham Frank , Gray Linsay , Bambra Clare 
Published: December 2012

ObjectivesTo assess, using individual level data, how the proportion of people in different employment statuses may have played a role in the prevalence of poor self-rated health from 1978 to 2004 as there have been major changes in employment patterns in advanced market democracies and employment is an important correlate of health.DesignIndividual-level analysis of repeated cross-sectional surveys.SettingUK.Participants125 125 men and 139 535 women of working age (25–59).Outcome measureSelf-rated general health.ResultsCompared to 1978 there was evidence of higher levels of poor health in the subsequent years. For example, in 2004, the prevalence of poor health was 2.8 (95% CI 1.7 to 3.9) and 1.3 (0.1 to 2.5) percentage points higher than 1978 for men and women, respectively, after adjusting for age. After additional adjustment for socio-economic characteristics, annual differences compared to 1978 increased (5.4 (4.2 to 6.5) and 4.4 (3.2 to 5.6) for men and women in 2004). Further adjustment for employment status, however, attenuated the annual differences in poor health (0.7 (−0.3 to 1.7) for men and 1.5 (0.3 to 2.6) for women in 2004).ConclusionsThese results suggest that the proportion of people in different employment statuses, particularly the proportion in sickness- or disability-related economic inactivity, could play an important role in the prevalence of poor self-rated health in the UK. Whether decreasing economic inactivity would enhance population health is an open question that needs further investigation.Trial registrationThis observational study was not registered.
Targeting Tumor-Infiltrating Macrophages Decreases Tumor-Initiating Cells, Relieves Immunosuppression, and Improves Chemotherapeutic Responses
Authors: Mitchem Jonathan B. , Brennan Donal J. , Knolhoff Brett L. , Belt Brian A. , Zhu Yu , Sanford Dominic E. , Belaygorod Larisa , Carpenter Danielle , Collins Lynne , Piwnica-Worms David , Hewitt Stephen , Udupi Girish Mallya , Gallagher William M. , Wegner Craig , West Brian L. , Wang-Gillam Andrea , Goedegebuure Peter , Linehan David C. , DeNardo David G. 
Published: December 2012

Abstract
Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination, and the induction of immune suppression. Cancer stem cells are far from a static cell population; rather, their presence seems to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact immune responses have on tumor stem cell differentiation or expansion is not well understood. In this study, we show that targeting tumor-infiltrating macrophages (TAM) and inflammatory monocytes by inhibiting either the myeloid cell receptors colony-stimulating factor-1 receptor (CSF1R) or chemokine (C–C motif) receptor 2 (CCR2) decreases the number of tumor-initiating cells (TIC) in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses. Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3, thereby facilitating macrophage-mediated suppression of CD8+ T lymphocytes. Together, our findings show how targeting TAMs can effectively overcome therapeutic resistance mediated by TICs. Cancer Res; 73(3); 1128–41. ©2012 AACR.
Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma
Authors: Barrett Caitlyn W. , Ning Wei , Chen Xi , Smith Jesse Joshua , Washington Mary K. , Hill Kristina E. , Coburn Lori A. , Peek Richard M. , Chaturvedi Rupesh , Wilson Keith T. , Burk Raymond F. , Williams Christopher S. 
Published: December 2012

Abstract
The glutathione peroxidases, a family of selenocysteine-containing redox enzymes, play pivotal roles in balancing the signaling, immunomodulatory, and deleterious effects of reactive oxygen species (ROS). The glutathione peroxidase GPX3 is the only extracellular member of this family, suggesting it may defend cells against ROS in the extracellular environment. Notably, GPX3 hypermethylation and underexpression occur commonly in prostate, gastric, cervical, thyroid, and colon cancers. We took a reverse genetics approach to investigate whether GPX3 would augment inflammatory colonic tumorigenesis, a process characterized by oxidative stress and inflammation, comparing Gpx3−/− mice in an established two-stage model of inflammatory colon carcinogenesis. Gpx3-deficient mice exhibited an increased tumor number, though not size, along with a higher degree of dysplasia. In addition, they exhibited increased inflammation with redistribution toward protumorigenic M2 macrophage subsets, increased proliferation, hyperactive WNT signaling, and increased DNA damage. To determine the impact of acute gene loss in an established colon cancer line, we silenced GPX3 in human Caco2 cells, resulting in increased ROS production, DNA damage and apoptosis in response to oxidative stress, combined with decreased contact-independent growth. Taken together, our results suggested an immunomodulatory role for GPX3 that limits the development of colitis-associated carcinoma. Cancer Res; 73(3); 1245–55. ©2012 AACR.
Polymorphisms in Inflammation Pathway Genes and Endometrial Cancer Risk
Authors: Delahanty Ryan J. , Xiang Yong-Bing , Spurdle Amanda , Beeghly-Fadiel Alicia , Long Jirong , Thompson Deborah , Tomlinson Ian , Yu Herbert , Lambrechts Diether , Dörk Thilo , Goodman Marc T. , Zheng Ying , Salvesen Helga B. , Bao Ping-Ping , Amant Frederic , Beckmann Matthias W. , Coenegrachts Lieve , Coosemans An , Dubrowinskaja Natalia , Dunning Alison , Runnebaum Ingo B. , Easton Douglas , Ekici Arif B. , Fasching Peter A. , Halle Mari K. , Hein Alexander , Howarth Kimberly , Gorman Maggie , Kaydarova Dylyara , Krakstad Camilla , Lose Felicity , Lu Lingeng , Lurie Galina , O'Mara Tracy , Matsuno Rayna K. , Pharoah Paul , Risch Harvey , Corssen Madeleine , Trovik Jone , Turmanov Nurzhan , Wen Wanqing , Lu Wei , Cai Qiuyin , Zheng Wei , Shu Xiao-Ou 
Published: December 2012

Abstract
Background: Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis.
Methods: To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P &lt; 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls.
Results: Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85–0.99); CXCL3, 1.16 (1.05–1.29); IL6, 1.08 (1.00–1.17); MSR1, 0.90 (0.82–0.98); and MMP9, 0.91 (0.87–0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples.
Conclusions: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer.
Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(2); 216–23. ©2012 AACR.
Tumoral Lymphocytic Infiltration and Expression of the Chemokine CXCL10 in Breast Cancers from the Ontario Familial Breast Cancer Registry
Authors: Mulligan Anna Marie , Raitman Irene , Feeley Linda , Pinnaduwage Dushanthi , Nguyen Linh T. , O'Malley Frances P. , Ohashi Pamela S. , Andrulis Irene L. 
Published: December 2012

AbstractPurpose: Breast carcinomas, including basal and hereditary cases, often present with a prominent tumoral lymphocytic infiltrate. Chemokines could play a role in attracting these cells and contribute to tumor progression. We explored tumoral expression of CXCL10 and determined the relationship between CXCL10 and lymphocytic infiltrate in a cohort of breast cancers.Experimental Design: Using tissue microarrays of 364 breast tumors, we evaluated expression of CXCL10 and its receptor, CXCR3, in relation to histopathologic features, biomarkers, and lymphocyte markers. In addition, we overexpressed CXCL10 and CXCR3 in MCF7 breast cancer cells and monitored T-lymphocyte migration and invasion.Results: Forty-five percent of tumors expressed CXCL10, and a significant association was found with CXCR3 and lymphocytic infiltrate. Further characterization of the lymphocytic infiltrate revealed an association with CXCL10 expression for peritumoral CD4+ and CD8+ lymphocytes. CD8+ intratumoral lymphocytes, FOXP3+ regulatory T cells (Tregs), and T-BET+ TH1 cells were associated with BRCA1 and basal tumors. Conditioned media from MCF7 cells overexpressing both CXCL10 and CXCR3 increased T-lymphocyte migration and invasion.Conclusions: Our findings suggest that CXCL10 may act in a paracrine manner, affecting the tumor microenvironment, and in an autocrine manner, acting on the tumor cells themselves and may play a role in tumor invasiveness and progression. The CXCL10-CXCR3 axis can serve as a potential target in BRCA1 and basal breast cancers, which present with a prominent lymphocytic infiltrate and a poor prognosis. Clin Cancer Res; 19(2); 336–46. ©2012 AACR.