bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunization with Low Doses of Recombinant Postfusion or Prefusion Respiratory Syncytial Virus F Primes for Vaccine-Enhanced Disease in the Cotton Rat Model Independently of the Presence of a Th1-Biasing (GLA-SE) or Th2-Biasing (Alum) Adjuvant
Authors: Schneider-Ohrum Kirsten , Cayatte Corinne , Bennett Angie Snell , Rajani Gaurav Manohar , McTamney Patrick , Nacel Krystal , Hostetler Leigh , Cheng Lily , Ren Kuishu , O'Day Terrence , Prince Gregory A. , McCarthy Michael P. 
Published: February 2017

ABSTRACT
Respiratory syncytial virus (RSV) infection of children previously immunized with a nonlive, formalin-inactivated (FI)-RSV vaccine has been associated with serious enhanced respiratory disease (ERD). Consequently, detailed studies of potential ERD are a critical step in the development of nonlive RSV vaccines targeting RSV-naive children and infants. The fusion glycoprotein (F) of RSV in either its postfusion (post-F) or prefusion (pre-F) conformation is a target for neutralizing antibodies and therefore an attractive antigen candidate for a pediatric RSV subunit vaccine. Here, we report the evaluation of RSV post-F and pre-F in combination with glucopyranosyl lipid A (GLA) integrated into stable emulsion (SE) (GLA-SE) and alum adjuvants in the cotton rat model. Immunization with optimal doses of RSV F antigens in the presence of GLA-SE induced high titers of virus-neutralizing antibodies and conferred complete lung protection from virus challenge, with no ERD signs in the form of alveolitis. To mimic a waning immune response, and to assess priming for ERD under suboptimal conditions, an antigen dose de-escalation study was performed in the presence of either GLA-SE or alum. At low RSV F doses, alveolitis-associated histopathology was unexpectedly observed with either adjuvant at levels comparable to FI-RSV-immunized controls. This occurred despite neutralizing-antibody titers above the minimum levels required for protection and with no/low virus replication in the lungs. These results emphasize the need to investigate a pediatric RSV vaccine candidate carefully for priming of ERD over a wide dose range, even in the presence of strong neutralizing activity, Th1 bias-inducing adjuvant, and protection from virus replication in the lower respiratory tract.

IMPORTANCE
RSV disease is of great importance worldwide, with the highest burden of serious disease occurring upon primary infection in infants and children. FI-RSV-induced enhanced disease, observed in the 1960s, presented a major and ongoing obstacle for the development of nonlive RSV vaccine candidates. The findings presented here underscore the need to evaluate a nonlive RSV vaccine candidate during preclinical development over a wide dose range in the cotton rat RSV enhanced-disease model, as suboptimal dosing of several RSV F subunit vaccine candidates led to the priming for ERD. These observations are relevant to the validity of the cotton rat model itself and to safe development of nonlive RSV vaccines for seronegative infants and children.
Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis
Authors: Haley Shannon L. , Tzvetkov Evgeni P. , Meuwissen Samantha , Plummer Joseph R. , McGettigan James P. 
Published: February 2017

ABSTRACT
Vaccine-induced B cells differentiate along two pathways. The follicular pathway gives rise to germinal centers (GCs) that can take weeks to fully develop. The extrafollicular pathway gives rise to short-lived plasma cells (PCs) that can rapidly secrete protective antibodies within days of vaccination. Rabies virus (RABV) postexposure prophylaxis (PEP) requires rapid vaccine-induced humoral immunity for protection. Therefore, we hypothesized that targeting extrafollicular B cell responses for activation would improve the speed and magnitude of RABV PEP. To test this hypothesis, we constructed, recovered, and characterized a recombinant RABV-based vaccine expressing murine B cell activating factor (BAFF) (rRABV-mBAFF). BAFF is an ideal molecule to improve early pathways of B cell activation, as it links innate and adaptive immunity, promoting potent B cell responses. Indeed, rRABV-mBAFF induced a faster, higher antibody response in mice and enhanced survivorship in PEP settings compared to rRABV. Interestingly, rRABV-mBAFF and rRABV induced equivalent numbers of GC B cells, suggesting that rRABV-mBAFF augmented the extrafollicular B cell pathway. To confirm that rRABV-mBAFF modulated the extrafollicular pathway, we used a signaling lymphocytic activation molecule (SLAM)-associated protein (SAP)-deficient mouse model. In response to antigen, SAP-deficient mice form extrafollicular B cell responses but do not generate GCs. rRABV-mBAFF induced similar anti-RABV antibody responses in SAP-deficient and wild-type mice, demonstrating that BAFF modulated immunity through the extrafollicular and not the GC B cell pathway. Collectively, strategies that manipulate pathways of B cell activation may facilitate the development of a single-dose RABV vaccine that replaces current complicated and costly RABV PEP.

IMPORTANCE
Effective RABV PEP is currently resource- and cost-prohibitive in regions of the world where RABV is most prevalent. In order to diminish the requirements for rabies immunoglobulin (RIG) and multiple vaccinations for effective prevention of clinical rabies, a more rapidly protective vaccine is needed. This work presents a successful approach to rapidly generate antibody-secreting PCs in response to vaccination by targeting the extrafollicular B cell pathway. We demonstrate that the improved early antibody responses induced by rRABV-mBAFF confer improved protection against RABV in a PEP model. Significantly, activation of the early extrafollicular B cell pathway, such as that demonstrated here, could improve the efficacy of vaccines targeting other pathogens against which rapid protection would decrease morbidity and mortality.
HIV-1 Vpu Downmodulates ICAM-1 Expression, Resulting in Decreased Killing of Infected CD4
+
T Cells by NK Cells
Authors: Sugden Scott M. , Pham Tram N. Q. , Cohen Éric A. 
Published: February 2017

ABSTRACT

HIV-1 Vpu is known to alter the expression of numerous cell surface molecules. Given the ever-increasing list of Vpu targets identified to date, we undertook a proteomic screen to discover novel cell membrane proteins modulated by this viral protein. Plasma membrane proteome isolates from Vpu-inducible T cells were subjected to
s
table isotope labeling of amino acids in cell culture (SILAC)-based mass spectrometry analysis, and putative targets were validated by infection of primary CD4
+
T cells. We report here that while intercellular adhesion molecule 1 (ICAM-1) and ICAM-3 are upregulated by HIV-1 infection, expression of Vpu offsets this increase by downregulating these molecules from the cell surface. Specifically, we show that Vpu is sufficient to downregulate and deplete ICAM-1 in a manner requiring the Vpu transmembrane domain and a dual-serine (S52/S56) motif necessary for recruitment of the beta-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP) component of the Skp, Cullin, F-box (SCF
β-TrCP
) E3 ubiquitin ligase. Vpu interacts with ICAM-1 to induce its proteasomal degradation. Interestingly, the E3 ubiquitin ligase component β-TrCP-1 is dispensable for ICAM-1 surface downregulation yet is necessary for ICAM-1 degradation. Functionally, Vpu-mediated ICAM-1 downregulation lowers packaging of this adhesion molecule into virions, resulting in decreased infectivity. Importantly, while Vpu-mediated downregulation of ICAM-3 has a limited effect on the conjugation of NK cells to HIV-1-infected CD4
+
T cells, downregulation of ICAM-1 by Vpu results in a reduced ability of NK cells to bind and kill infected T cells. Vpu-mediated ICAM-1 downregulation may therefore represent an evolutionary compromise in viral fitness by impeding the formation of cell-to-cell contacts between immune cells and infected T cells at the cost of decreased virion infectivity.

IMPORTANCE
The major barrier to eradicating HIV-1 infection is the establishment of treatment-resistant reservoirs early in infection. Vpu-mediated ICAM-1 downregulation may contribute to the evasion of cell-mediated immunity during acute infection to promote viral dissemination and the development of viral reservoirs. By aiding the immune system to clear infection prior to the development of reservoirs, novel treatments designed to disrupt Vpu-mediated ICAM-1 downregulation may be beneficial during acute infection or as a prophylactic treatment.
Risk assessment models for venous thromboembolism in acutely ill medical patients
Authors: Stuck Anna , Spirk David , Schaudt Jil , Kucher Nils 
Published: February 2017

SummaryAlthough the use of thromboprophylaxis is recommended for acutely ill medical patients at increased risk of venous thromboembolism (VTE), it remains unclear which risk assessment model (RAM) should be routinely used to identify at-risk patients requiring thromboprophylaxis. We therefore aimed to describe existing RAMs, and to compare these tools in terms of validity and applicability for clinical decisionmaking. We performed a comprehensive systematic search in MEDLINE from the date of initiation until May 2016 for studies in acutely ill medical patients investigating validity of RAMs for VTE. Two reviewers independently screened the title, abstract, and full text, and evaluated the characteristics of studies, and the composition, evidence of validation, and results on validity of the RAMs. We included 11 studies assessing eight RAMs: 4-Element RAM, Caprini RAM, a full logistic model, Geneva risk score, IMPROVE-RAM, Kucher Model, a “Multivariable Model”, and Padua Prediction Score. The 4-Element RAM, IMPROVE-RAM, Multivariable Model, and full logistic model had derivation by identifying factors with predictive power. The other four RAMs were empirically generated based on consensus guidelines, published data, and clinical expertise. The Kucher Model, the Padua Prediction Score, the Geneva Risk Score and the IMPROVE-RAM underwent multicenter external validation. The Kucher Model, the Padua Prediction Score, and the Geneva Risk Score improved rates of thromboprophylaxis or clinical outcomes. In conclusion, existing RAMs to evaluate the need of thromboprophylaxis in acutely ill medical patients are difficult to compare and none fulfills the criteria of an ideal RAM. Nevertheless, the adequacy of thromboprophylaxis may be improved by implementing one of the validated RAMs.
Imaging analyses of coagulation-dependent initiation of fibrinolysis on activated platelets and its modification by thrombin-activatable fibrinolysis inhibitor
Authors: Brzoska Tomasz , Suzuki Yuko , Sano Hideto , Suzuki Seiichirou , Tomczyk Martyna , Tanaka Hiroki , Urano Tetsumei 
Published: February 2017

SummaryUsing intravital confocal microscopy, we observed previously that the process of platelet phosphatidylserine (PS) exposure, fibrin formation and lysine binding site-dependent plasminogen (plg) accumulation took place only in the centre of thrombi, not at their periphery. These findings prompted us to analyse the spatiotemporal regulatory mechanisms underlying coagulation and fibrinolysis. We analysed the fibrin network formation and the subsequent lysis in an in vitro experiment using diluted platelet-rich plasma supplemented with fluorescently labelled coagulation and fibrinolytic factors, using confocal laser scanning microscopy. The structure of the fibrin network formed by supplemented tissue factor was uneven and denser at the sites of coagulation initiation regions (CIRs) on PS-exposed platelets. When tissue type plasminogen activator (tPA; 7.5 nM) was supplemented, labelled plg (50 nM) as well as tPA accumulated at CIRs, from where fibrinolysis started and gradually expanded to the peripheries. The lysis time at CIRs and their peripheries (50 µm from the CIR) were 27.9 ± 6.6 and 44.4 ± 9.7 minutes (mean ± SD, n=50 from five independent experiments) after the addition of tissue factor, respectively. Recombinant human soluble thrombomodulin (TMα; 2.0 nM) attenuated the CIR-dependent plg accumulation and strongly delayed fibrinolysis at CIRs. A carboxypeptidase inhibitor dose-dependently enhanced the CIR-de- pendent fibrinolysis initiation, and at 20 µM it completely abrogated the TMα-induced delay of fibrinolysis. Our findings are the first to directly present crosstalk between coagulation and fibrinolysis, which takes place on activated platelets’ surface and is further controlled by thrombin-activatable fibrinolysis inhibitor (TAFI).Supplementary Material to this article is available online at www.thrombosis-online.com.
Chewing versus Swallowing Ticagrelor to Accelerate Platelet Inhibition in Acute Coronary Syndrome - the CHEERS study
Authors: Katz Moshe , Regev Ehud , Sabbag Avi , Mazin Israel , Abu-Much Arsalan , Kukuy Andrew , Mazo Anna , Erez Aharon , Berkovitch Anat , Narodistky Michael , Barbash Israel , Segev Amit , Beigel Roy , Matetzky Shlomi , Asher Elad , Frydman Shir 
Published: February 2017

SummaryIt was the study objective to evaluate whether chewing a 180 mg loading dose of ticagrelor versus an equal dose of traditional oral administration, enhances inhibition of platelet aggregation 1 hour (h) after administering a ticagrelor loading dose in non-ST elevation myocardial infarction (NSTEMI) patients. Dual anti-platelet therapy represents standard care for treating NSTEMI patients. Ticagrelor is a direct acting P2Y12 inhibitor and, unlike clopidogrel and prasugrel, does not require metabolic activation. Fifty NSTEMI patients were randomised to receive either a chewing loading dose of 180 mg ticagrelor or an equal standard oral dose of ticagrelor. Platelet reactivity was evaluated by VerifyNow at baseline, 1 and 4 h post-loading dose. Results are reported in P2Y12 reaction units. Patients then continued to receive standard 90 mg oral ticagrelor twice daily. Baseline characteristics did not differ between the two groups. P2Y12 reaction units in the chewing group compared with the standard group at 0, 1 and 4 h after ticagrelor loading dose were: 245 vs 239 (p=0.59), 45 vs 130 (p=0.001) and 39 vs 60 (p=0.12), respectively, corresponding to a relative inhibition of platelet aggregation of 83 % vs only 47 % at 1 h (p< 0.001), and 84 % vs 77 % (p=0.59) at 4 h. Major adverse cardiac and cardiovascular events at 30 days were low (2 %), occurring in only one patient in the standard group. In conclusion, chewing a 180 mg ticagrelor loading dose is feasible and facilitates both faster and improved early inhibition of platelet aggregation in NSTEMI patients, compared with a standard oral-loading dose.Supplementary Material to this article is available online at www.thrombosis-online.com.
Race and Sex Differences in Post–Myocardial Infarction Angina Frequency and Risk of 1-Year Unplanned Rehospitalization
Authors: Hess Connie N. , Kaltenbach Lisa A. , Doll Jacob A. , Cohen David J. , Peterson Eric D. , Wang Tracy Y. 
Published: February 2017

Background:
Race and sex disparities in in-hospital treatment and outcomes of patients with acute myocardial infarction (MI) have been described, but little is known about race and sex differences in post-MI angina and long-term risk of unplanned rehospitalization. We examined race and sex differences in post-MI angina frequency and 1-year unplanned rehospitalization to identify factors associated with unplanned rehospitalization, testing for whether race and sex modify these relationships.

Methods:
Using TRANSLATE-ACS (Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome) data, we examined 6-week and 1-year angina frequency and 1-year unplanned rehospitalization stratified by race and sex among MI patients treated with percutaneous coronary intervention. We used multivariable logistic regression to assess factors associated with unplanned rehospitalization and tested for interactions among angina frequency, race, and sex.

Results:

A total of 11 595 MI patients survived to 1 year postdischarge; there were 66.6% white male patients, 24.3% white female patients, 5.3% black male patients, and 3.8% black female patients. Overall, 29.7% had angina at 6 weeks, and 20.6% had angina at 1 year postdischarge. Relative to white patients, black patients were more likely to have angina at 6 weeks (female: 44.2% versus 31.8%; male: 33.5% versus 27.1%; both
P
<0.0001) and 1 year (female: 49.4% versus 38.9%; male: 46.3% versus 31.1%; both
P
<0.0001). Rates of 1-year unplanned rehospitalization were highest among black female patients (44.1%), followed by white female patients (38.4%), black male patients (36.4%), and white male patients (30.2%,
P
<0.0001). In the multivariable model, 6-week angina was most strongly associated with unplanned rehospitalization (hazard ratio, 1.49; 95% confidence interval, 1.36–1.62;
P
<0.0001); this relationship was not modified by race or sex (adjusted 3-way
P
interaction
=0.41).

Conclusions:
One-fifth of MI patients treated with percutaneous coronary intervention report 1-year postdischarge angina, with black and female patients more likely to have angina and to be rehospitalized. Better treatment of post-MI angina may improve patient quality of life and quality of care and help to lower rates of rehospitalization overall and particularly among black and female patients, given their high prevalence of post-MI angina.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01088503.
Language dominance and the perception of the Majorcan Catalan /ʎ/−/ʒ/ contrast: Asymmetrical phonological representations
Authors: Ramírez Marta , Simonet Miquel 
Published: February 2017

Purpose: Bilinguals tend to experience “difficulties” with contrasts specific to their nondominant language. This study investigates the discrimination of the /ʎ/-/ʒ/ contrast of Majorcan Catalan by two groups of Catalan–Spanish bilinguals differing in their linguistic experience, Catalan- versus Spanish-dominant. Methodology: Participants completed a categorical discrimination task to examine their perception of the following pairwise comparisons, relevant to assessing the perceptibility of the Majorcan Catalan /ʎ/-/ʒ/ contrast: [ʎ]-[ʒ], [ʎ]-[j], and [ʒ]-[j]. Data: Data consisted of arcsine-transformed proportion-correct responses obtained by means of a categorical discrimination task using the odd-item-out AXB paradigm. Findings: The results indicate that Spanish-dominant bilinguals are less accurate than Catalan-dominant ones in terms of their discrimination of the sounds involved in the /ʎ/-/ʒ/ contrast. Catalan-dominant participants discriminate any pairs involving [ʒ] very accurately. Interestingly, however, all participants find the [ʎ]-[j] pair difficult to discriminate. Originality: This study examines perception of a contrast not examined before, and its results suggest a surprising pattern of asymmetry in phonological representations of the target contrast. Significance: The results suggest that language dominance in the Catalan–Spanish contact community modulates discrimination of the /ʎ/-/ʒ/ contrast. The findings also suggest that Catalan-dominant listeners’ representation of /ʎ/ and /ʒ/ may be asymmetrical: The representation of /ʎ/ may be fuzzier than that of /ʒ/.
Role of myeloid-derived suppressor cells in allogeneic hematopoietic cell transplantation
Authors: Koehn Brent H , Blazar Bruce R 
Published: February 2017

Abstract
Graft-versus-host disease (GVHD) can be a devastating complication for as many as a third of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). A role for myeloid cells in the amplification of GVHD has been demonstrated; however, less is understood about a potential regulatory role that myeloid cells play or whether such cells may be manipulated and applied therapeutically. Myeloid-derived suppressor cells (MDSCs) are a naturally occurring immune regulatory population that are engaged and expand shortly after many forms of immune distress, including cancer, trauma, and infection. As MDSCs are often associated with chronic disease, inflammation, and even the promotion of tumor growth (regarding angiogenesis/metastasis), they can appear to be predictors of poor outcomes and therefore, vilified; yet, this association doesn't match with their perceived function of suppressing inflammation. Here, we explore the role of MDSC in GVHD in an attempt to investigate potential synergies that may be promoted, leading to better patient outcomes after allo-HCT.
‘Iraqi’ cinema since the US-led invasion of 2003
Authors: Ginsberg Terri 
Published: February 2017

Abstract
During the 1950–70s, film production in Iraq was relatively prolific. Private industry eventually gave way to nationalization under Ba‘th Party rule. Not unlike Iraqi cinema of the colonial era, most post-independence Iraqi cinema had the ideological aim of propping up the new regime while supplying light entertainment to the populace. A minor auteur cinema did develop, which produced a small number of critical independent films, but the movement was short-lived. The bulk of quality film production in Iraq occurred during the period of nationalization. This development eventually led to the establishment of a film school in Baghdad. Since the Iran–Iraq War, national film production in Iraq effectively ended. This is not to say that films publicized as ‘Iraqi’ have not been produced in recent years; on the contrary, a small but noteworthy number of ‘Iraqi’ films have been made, primarily for international distribution, largely by Iraqi ex-patriots to (and from) Europe and with financial support from private foreign sources. This article discusses two such films, Zaman: The Man from the Reeds (Alwan, 2003), and Ahlaam (al-Daradji, 2006), comparing and contrasting their differing but overlapping strategies, which evidence the suffering of Iraqis living under conditions of war and violence. These strategies at the same time in varying ways distract or distort attention from the real determinants of those conditions. By extension the article draws critical connections between the aims and orientations of new ‘Iraqi’ cinema and the hasbara cultural initiatives of contemporary Israel.
Ejection of Stars with Relativistic Velocities
Authors: Dryomova G. , Dryomov V. , Tutukov A. 
Published: February 2017

Abstract
We present the results of numerical simulations performed in terms of modified Hills' scenario involving two supermassive black holes (SMBHs). In contrast to the classic Hills scenario (Hills 1988), here one component of the ordinary stellar binary system is replaced with a SMBH that provides a kinetic resource for ejecting a star (the secondary component of the binary) with relativistic velocity (RVS). We examine the conditions that favor relativistic ejections of stars, depending on the pericentric approach, the mass ratio of two SMBHs, and the orbital configuration of the binary system. Applying the simple criteria helped us to sort out the results of numerical simulations by the outcome: conservation of the orbital configuration of the binary system, dynamic recapture of the star by the central SMBH, emission of hypervelocity stars (HVSs), and RVS ejection. In the framework of N-body simulations we estimate the probability for a star to survive in the cross-field of two SMBHs during the ejection with relativistic velocity, and discuss the probability of the detection of RVSs in our Galaxy in the cases where such stars are generated in distant interacting galaxies undergoing a merger of their central parts occupied by SMBHs.