bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection
Authors: Errett John S. , Suthar Mehul S. , McMillan Aimee , Diamond Michael S. , Gale Michael 
Published: August 2013

ABSTRACT

Virus recognition and response by the innate immune system are critical components of host defense against infection. Activation of cell-intrinsic immunity and optimal priming of adaptive immunity against West Nile virus (WNV), an emerging vector-borne virus, depend on recognition by RIG-I and MDA5, two cytosolic pattern recognition receptors (PRRs) of the RIG-I-like receptor (RLR) protein family that recognize viral RNA and activate defense programs that suppress infection. We evaluated the individual functions of RIG-I and MDA5 both
in vitro
and
in vivo
in pathogen recognition and control of WNV. Lack of RIG-I or MDA5 alone results in decreased innate immune signaling and virus control in primary cells
in vitro
and increased mortality in mice. We also generated
RIG-I
−/−
×
MDA5
−/−
double-knockout mice and found that a lack of both RLRs results in a complete absence of innate immune gene induction in target cells of WNV infection and a severe pathogenesis during infection
in vivo
, similar to findings for animals lacking MAVS, the central adaptor molecule for RLR signaling. We also found that RNA products from WNV-infected cells but not incoming virion RNA display at least two distinct pathogen-associated molecular patterns (PAMPs) containing 5′ triphosphate and double-stranded RNA that are temporally distributed and sensed by RIG-I and MDA5 during infection. Thus, RIG-I and MDA5 are essential PRRs that recognize distinct PAMPs that accumulate during WNV replication. Collectively, these experiments highlight the necessity and function of multiple related, cytoplasmic host sensors in orchestrating an effective immune response against an acute viral infection.
TMPRSS2 Is an Activating Protease for Respiratory Parainfluenza Viruses
Authors: Abe Masako , Tahara Maino , Sakai Kouji , Yamaguchi Hiromi , Kanou Kazuhiko , Shirato Kazuya , Kawase Miyuki , Noda Masahiro , Kimura Hirokazu , Matsuyama Shutoku , Fukuhara Hideo , Mizuta Katsumi , Maenaka Katsumi , Ami Yasushi , Esumi Mariko , Kato Atsushi , Takeda Makoto 
Published: August 2013

ABSTRACT
Here, we show that human parainfluenza viruses and Sendai virus (SeV), like other respiratory viruses, use TMPRSS2 for their activation. The membrane fusion proteins of respiratory viruses often possess serine and glutamine residues at the P2 and P3 positions, respectively, but these residues were not critical for cleavage by TMPRSS2. However, mutations of these residues affected SeV growth in specific epithelial cell lines, suggesting the importance of these residues for SeV replication in epithelia.
Latency Locus Complements MicroRNA 155 Deficiency
In Vivo
Authors: Sin Sang-Hoon , Kim Yong Baek , Dittmer Dirk P. 
Published: August 2013

ABSTRACT
MicroRNA-155 (miR-155) is expressed in many cancers. It also executes evolutionary conserved functions in normal B cell development. We show that the Kaposi's sarcoma-associated herpesvirus (KSHV) latency locus, which contains an ortholog of miR-155, miR-K12-11, complements B cell deficiencies in miR-155 knockout mice. Germinal center (GC) formation was rescued in spleen, lymph node, and Peyer's patches. Immunoglobulin levels were restored. This demonstrates that KSHV can complement the normal, physiological function of miR-155.
Restriction of Virus Infection but Not Catalytic dNTPase Activity Is Regulated by Phosphorylation of SAMHD1
Authors: Welbourn Sarah , Dutta Sucharita M. , Semmes O. John , Strebel Klaus 
Published: August 2013

ABSTRACT

SAMHD1 is a host protein responsible, at least in part, for the inefficient infection of dendritic, myeloid, and resting T cells by HIV-1. Interestingly, HIV-2 and SIVsm viruses are able to counteract SAMHD1 by targeting it for proteasomal degradation using their Vpx proteins. It has been proposed that SAMHD1 is a dGTP-dependent deoxynucleoside triphosphohydrolase (dNTPase) that restricts HIV-1 by reducing cellular dNTP levels to below that required for reverse transcription. However, nothing is known about SAMHD1 posttranslational modifications and their potential role in regulating SAMHD1 function. We used
32
P labeling and immunoblotting with phospho-specific antibodies to identify SAMHD1 as a phosphoprotein. Several amino acids in SAMHD1 were identified to be sites of phosphorylation using direct mass spectrometry. Mutation of these residues to alanine to prevent phosphorylation or to glutamic acid to mimic phosphorylation had no effect on the nuclear localization of SAMHD1 or its sensitivity to Vpx-mediated degradation. Furthermore, neither alanine nor glutamic acid substitutions had a significant effect on SAMHD1 dNTPase activity in an
in vitro
assay. Interestingly, however, we found that a T592E mutation, mimicking constitutive phosphorylation at a main phosphorylation site, severely affected the ability of SAMHD1 to restrict HIV-1 in a U937 cell-based restriction assay. In contrast, a T592A mutant was still capable of restricting HIV-1. These results indicate that SAMHD1 phosphorylation may be a negative regulator of SAMHD1 restriction activity. This conclusion is supported by our finding that SAMHD1 is hyperphosphorylated in monocytoid THP-1 cells under nonrestrictive conditions.
Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes
Authors: Hill Erik R. , Koganti Siva , Zhi Jizu , Megyola Cynthia , Freeman Alexandra F. , Palendira Umaimainthan , Tangye Stuart G. , Farrell Paul J. , Bhaduri-McIntosh Sumita 
Published: August 2013

ABSTRACTLytic activation of Epstein-Barr virus (EBV) is central to its life cycle and to most EBV-related diseases. However, not every EBV-infected B cell is susceptible to lytic activation. This lack of uniform susceptibility to lytic activation also directly impacts the success of viral oncolytic therapy for EBV cancers, yet determinants of susceptibility to lytic induction signals are not well understood. To determine if host factors influence susceptibility to EBV lytic activation, we developed a technique to separate lytic from refractory cells and reported that EBV lytic activation occurs preferentially in cells with lower levels of signal transducer and activator of transcription 3 (STAT3). Using this tool to detect single cells, we now extend the correlation between STAT3 and lytic versus refractory states to EBV-infected circulating B cells in patients with primary EBV infection, leading us to investigate whether STAT3 controls susceptibility to EBV lytic activation. In loss-of-function and gain-of-function studies in EBV-positive B lymphoma and lymphoblastoid cells, we found that the levels of functional STAT3 regulate susceptibility to EBV lytic activation. This prompted us to identify a pool of candidate cellular genes that might be regulated by STAT3 to limit EBV lytic activation. From this pool, we confirmed increases in transcript levels in refractory cells of a set of genes known to participate in transcription repression. Taken together, our findings place STAT3 at a critical crossroads between EBV latency and lytic activation, processes fundamental to EBV lymphomagenesis.
Role of DC-SIGN in Lassa Virus Entry into Human Dendritic Cells
Authors: Goncalves Ana-Rita , Moraz Marie-Laurence , Pasquato Antonella , Helenius Ari , Lozach Pierre-Yves , Kunz Stefan 
Published: August 2013

ABSTRACT
The arenavirus Lassa virus (LASV) causes a severe hemorrhagic fever with high mortality in humans. Antigen-presenting cells, in particular dendritic cells (DCs), are early and preferred targets of LASV, and their productive infection contributes to the virus-induced immunosuppression observed in fatal disease. Here, we characterized the role of the C-type lectin DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN) in LASV entry into primary human DCs using a chimera of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) expressing the LASV glycoprotein (rLCMV-LASVGP). We found that differentiation of human primary monocytes into DCs enhanced virus attachment and entry, concomitant with the upregulation of DC-SIGN. LASV and rLCMV-LASVGP bound to DC-SIGN via mannose sugars located on the N-terminal GP1 subunit of LASVGP. We provide evidence that DC-SIGN serves as an attachment factor for rLCMV-LASVGP in monocyte-derived immature dendritic cells (MDDC) and can accelerate the capture of free virus. However, in contrast to the phlebovirus Uukuniemi virus (UUKV), which uses DC-SIGN as an authentic entry receptor, productive infection with rLCMV-LASVGP was less dependent on DC-SIGN. In contrast to the DC-SIGN-mediated cell entry of UUKV, entry of rLCMV-LASVGP in MDDC was remarkably slow and depended on actin, indicating the use of different endocytotic pathways. In sum, our data reveal that DC-SIGN can facilitate cell entry of LASV in human MDDC but that its role seems distinct from the function as an authentic entry receptor reported for phleboviruses.
Effects of Cellular Activation on Anti-HIV-1 Restriction Factor Expression Profile in Primary Cells
Authors: Raposo Rui André Saraiva , Abdel-Mohsen Mohamed , Bilska Miroslawa , Montefiori David C. , Nixon Douglas F. , Pillai Satish K. 
Published: August 2013

ABSTRACT
Expression of cell-intrinsic antiviral factors suppresses HIV-1 replication. We hypothesized that cellular activation modulates host restriction and susceptibility to HIV-1 infection. We measured the gene expression of 34 antiviral factors in healthy peripheral blood mononuclear cells (PBMC). Cellular activation induced expression of interferon-stimulated gene 15 (ISG15), tripartite motif 5α (TRIM5α), bone marrow stromal cell antigen 2 (BST-2)/tetherin, and certain apolipoprotein B mRNA editing enzyme 3 (APOBEC3) family members. Expression of RTF1, RNA polymerase II-associated factor 1 (PAF1), TRIM11, TRIM26, and BST-2/tetherin correlated with decreased HIV-1 infectivity. This report demonstrates synchronous effects of activation-induced antiviral genes on HIV-1 infectivity, providing candidates for pharmacological manipulation.
Clinical Effect of Acupuncture on Cervical Spondylotic Radiculopathy: Results of a Case Series
Authors: Nakajima Miwa , Inoue Motohiro , Itoi Megumi , Kitakoji Hiroshi 
Published: August 2013

Objective To observe the effectiveness of acupuncture applied to the cervical region of patients with upper extremity radicular symptoms due to cervical spondylotic radiculopathy (CSR). Methods 15 subjects diagnosed with CSR and with upper extremity pain and/or paraesthesiae for 13.1±18.0 months were selected. The 15 patients had 16 affected limbs and scored a total of 17 symptom scores of pain and/or paraesthesiae. All patients were treated with acupuncture once a week for 4 weeks at up to 10 sites in the cervical paraspinal region centred on the affected area. The severity of the symptoms was recorded using a visual analogue scale (VAS) and functional evaluation was conducted using a Neck Disability Index (NDI). Results A significant reduction over time was seen for both mean VAS (p<0.0001) and NDI (p<0.0001). Changes were still significant at 4-week follow-up. A 50% reduction in symptoms was scored for 15 of the 17 symptoms scored. Conclusions Favourable results were seen in nearly 90% of cases. These results show that acupuncture treatment to the cervical region may be effective as a conservative therapy for treating CSR.
Shaping medicinal product information: a before and after study exploring physicians’ perspectives on the summary of product characteristics
Authors: Vromans Lisette , Doyle Gerardine , Petak-Opel Silvia , Rödiger Alexander , Röttgermann Martina , Schlüssel Elke , Stetter Eva 
Published: August 2013

ObjectiveTo establish, in the context of the revised European Pharmacovigilance Directive and based on physicians’ perspectives, how Summaries of Product Characteristics (SmPCs) could be more user friendly and better support physicians’ interactions with patients, thereby improving patients’ own understanding of their medicines.DesignQualitative focus group discussions (step 1), development of an alternative SmPC (step 2) and an online quantitative survey (step 3) comparing the alternative SmPC to the currently approved version.SettingOffice-based physicians (n=218) from all federal states of Germany.Participants218 German physicians participated, with an equal representation of office-based general practitioners and specialists. For step 1 (n=18), physicians were recruited who frequently consulted SmPCs.Outcome measuresPlanned and performed: Mayring's qualitative content analysis of focus group discussions (step 1), rating on a five-point Likert scale of preference of current versus alternative SmPCs (step 3).ResultsPhysicians confirmed the importance of SmPCs as a comprehensive source of medicinal product information, but were moderately satisfied with the current SmPCs, utilised it infrequently and were more likely to engage additional sources of information. The alternative SmPC was consistently preferred. It differed in the way information for particular patient groups was presented, included additional sections (synopsis, checklist for patient information) and used a tabular format. Physicians indicated that SmPCs should be available with search and hyperlink functions, as well as be automatically updated and integrated in available practice software or similar solutions.ConclusionsThis research contributes to the development of an official, reliable medicinal product information system meeting the needs of a modern information society while providing the reliability of an officially authorised source. In the context of health literacy, SmPCs should be established as the primary information source for healthcare professionals to ensure compliant and safe utilisation of medicinal products.
Who does what in prehospital critical care? An analysis of competencies of paramedics, critical care paramedics and prehospital physicians
Authors: von Vopelius-Feldt Johannes , Benger Jonathan 
Published: August 2013

IntroductionEmergency medical services in the UK are facing the challenge of responding to an increasing number of calls, often for non-emergency care, while also providing critical care to the few severely ill or injured patients. In response, paramedic training in the UK has been extended and there are regional strategies to improve prehospital critical care (PHCC). We describe the clinical competencies of three groups of prehospital providers in the UK with the aim of informing future planning of the delivery of PHCC.MethodsWe used a data triangulation approach to obtain lists of competencies for paramedics, critical care paramedics (CCPs) and PHCC physicians of the Great Western Ambulance Service. Data sources were professional guidance documents, equipment available to the provider, log sheets of prehospital care episodes, direct observations and a survey of providers.ResultsWe identified 389, 441 and 449 competencies for paramedics, CCPs and PHCC physicians, respectively. Competencies of CCPs and PHCC physicians which exceeded those of paramedics can be arranged in four distinct clusters: induction and maintenance of anaesthesia, procedural sedation, advanced cardiovascular management and complex invasive interventions.DiscussionParamedics possess a considerable number of competencies which allow them to diagnose and treat a variety of conditions. CCPs and PHCC physicians possess a few additional critical care competencies which are potentially life-saving but are required infrequently and can carry significant risks. Concentration of training and clinical exposure for a small group of providers in critical care teams can help optimising benefits and reducing risks of PHCC.
Rectal douching and implications for rectal microbicides among populations vulnerable to HIV in South America: a qualitative study
Authors: Galea Jerome T , Kinsler Janni J , Imrie John , Nureña César R , Sánchez Jorge , Cunningham William E 
Published: August 2013

ObjectiveWhile gel-formulated rectal microbicides (RM) are the first to enter clinical trials, rectal douching in preparation for anal intercourse is a common practice; thus RMs formulated as douches may be a convenient alternative to gels. Nonetheless, little is known about potential users’ thoughts regarding douche-formulated RMs or rectal douching practices, data that is needed to inform the advancement of douche-based RMs. This qualitative study examined thoughts regarding douches, their use as an RM and current douching practices among men who have sex with men and transgender women.Methods12 focus groups and 36 in-depth interviews were conducted (N=140) to examine the overall acceptability of RM, of which one component focused on rectal douching. Focus groups and interviews were recorded, transcribed verbatim and coded; text relating to rectal douching was extracted and analysed. Sociodemographic information was collected using a self-administered questionnaire.ResultsSupport for a douche-formulated RM centred on the possibility of combined precoital hygiene and HIV protection, and it was believed that a deeply penetrating liquid douche would confer greater HIV protection than a gel. Drawbacks included rectal dryness, impracticality and portability issues, and potential side effects. Non-commercial douching apparatus use was common and liquids used included detergents, vinegar, bleach, lemon juice and alcohol.ConclusionsA douche-formulated RM, while desirable and perceived as more effective than a gel-formulated RM, also generated questions regarding practicality and side effects. Of immediate concern were the non-commercial liquids already being used that likely damage rectal epithelia, potentially increasing HIV infection risk. Precoital rectal douching is common and an RM formulated as such is desirable, but education on rectal douching practices is needed now.
Surface Characterization of Phenylpropanolamine Drug by Inverse Gas Chromatography
Authors: Kumar B. Praveen , Rani P. Reddi , Reddy T. Madhusudana , Reddy K. S. 
Published: August 2013

The surface thermodynamic properties can be used to understand the interactive potential of a drug surface with a solid or liquid excipient during its formulation and drug release process. The retention data were measured for n-alkanes and polar solutes at intervals of 5 K in the temperature range 318.15–333.15 K by Inverse Gas Chromatography (IGC) on the solid surface of phenylpropanolamine (PPA) drug. The retention data were used to evaluate the dispersive surface free energy, γSd, and Lewis acid-base parameters, Ka and Kb, for the PPA drug. The values, γSd, were decreasing linearly with increase of temperature and at 323.15 K the value was found to be 26.01±0.40 mJ/m2. The specific components of enthalpy of adsorption of polar solutes have been applied to evaluate Lewis acid-base parameters. The Ka and Kb values were found to be 0.451±0.033 and 0.824±0.622, respectively, which suggests that the PPA surface contains more basic sites and interact strongly in the acidic environment.
Targeting FSTL1 Prevents Tumor Bone Metastasis and Consequent Immune Dysfunction
Authors: Kudo-Saito Chie , Fuwa Takafumi , Murakami Kouichi , Kawakami Yutaka 
Published: August 2013

Abstract
Bone metastasis greatly deteriorates the quality of life in patients with cancer. Although mechanisms have been widely investigated, the relationship between cancer bone metastasis and antitumor immunity in the host has been much less studied. Here, we report a novel mechanism of bone metastasis mediated by FSTL1, a follistatin-like glycoprotein secreted by Snail+ tumor cells, which metastasize frequently to bone. We found that FSTL1 plays a dual role in bone metastasis—in one way by mediating tumor cell invasion and bone tropism but also in a second way by expanding a population of pluripotent mesenchymal stem-like CD45−ALCAM+ cells derived from bone marrow. CD45−ALCAM+ cells induced bone metastasis de novo, but they also generated CD8low T cells with weak CTL activity in the periphery, which also promoted bone metastasis in an indirect manner. RNA interference-mediated attenuation of FSTL1 in tumor cells prevented bone metastasis along with the parallel increase in ALCAM+ cells and CD8low T cells. These effects were accompanied by heightened antitumor immune responses in vitro and in vivo. In clinical specimens of advanced breast cancer, ALCAM+ cells increased with FSTL1 positivity in tumor tissues, but not in adjacent normal tissues, consistent with a causal connection between these molecules. Our findings define FSTL1 as an attractive candidate therapeutic target to prevent or treat bone metastasis, which remains a major challenge in patients with cancer. Cancer Res; 73(20); 6185–93. ©2013 AACR.
Activation of MAPK Pathways due to DUSP4 Loss Promotes Cancer Stem Cell-like Phenotypes in Basal-like Breast Cancer
Authors: Balko Justin M. , Schwarz Luis J. , Bhola Neil E. , Kurupi Richard , Owens Phillip , Miller Todd W. , Gómez Henry , Cook Rebecca S. , Arteaga Carlos L. 
Published: August 2013

Abstract
Basal-like breast cancer (BLBC) is an aggressive disease that lacks a clinically approved targeted therapy. Traditional chemotherapy is effective in BLBC, but it spares the cancer stem cell (CSC)-like population, which is likely to contribute to cancer recurrence after the initial treatment. Dual specificity phosphatase-4 (DUSP4) is a negative regulator of the mitogen-activated protein kinase (MAPK) pathway that is deficient in highly aggressive BLBCs treated with chemotherapy, leading to aberrant MAPK activation and resistance to taxane-induced apoptosis. Herein, we investigated how DUSP4 regulates the MAP–ERK kinase (MEK) and c-jun-NH2-kinase (JNK) pathways in modifying CSC-like behavior. DUSP4 loss increased mammosphere formation and the expression of the CSC-promoting cytokines interleukin (IL)-6 and IL-8. These effects were caused in part by loss of control of the MEK and JNK pathways and involved downstream activation of the ETS-1 and c-JUN transcription factors. Enforced expression of DUSP4 reduced the CD44+/CD24− population in multiple BLBC cell lines in a MEK-dependent manner, limiting tumor formation of claudin-low SUM159PT cells in mice. Our findings support the evaluation of MEK and JNK pathway inhibitors as therapeutic agents in BLBC to eliminate the CSC population. Cancer Res; 73(20); 6346–58. ©2013 AACR.