bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phosphoantigen Burst upon Plasmodium falciparum Schizont Rupture Can Distantly Activate Vγ9Vδ2 T Cells
Authors: Guenot Marianne , Loizon Séverine , Howard Jennifer , Costa Giulia , Baker David A. , Mohabeer Shaneel Y. , Troye-Blomberg Marita , Moreau Jean-François , Déchanet-Merville Julie , Mercereau-Puijalon Odile , Mamani-Matsuda Maria , Behr Charlotte 
Published: July 2015

ABSTRACTMalaria induces potent activation and expansion of the Vγ9Vδ2 subpopulation of γδT cells, which inhibit thePlasmodium falciparumblood cycle through soluble cytotoxic mediators, abrogating merozoite invasion capacity. Intraerythrocytic stages efficiently trigger Vγ9Vδ2 T-cell activation and degranulation through poorly understood mechanisms.P. falciparumblood-stage extracts are known to contain phosphoantigens able to stimulate Vγ9Vδ2 T cells, but how these are presented by intact infected red blood cells (iRBCs) remains elusive. Here we show that, unlike activation by phosphoantigen-expressing cells, Vγ9Vδ2 T-cell activation by intact iRBCs is independent of butyrophilin expression by the iRBC, and contact with an intact iRBC is not required. Moreover, blood-stage culture supernatants proved to be as potent activators of Vγ9Vδ2 T cells as iRBCs. Bioactivity in the microenvironment is attributable to phosphoantigens, as it is dependent on the parasite DOXP pathway, on Vγ9Vδ2 TCR signaling, and on butyrophilin expression by Vγ9Vδ2 T cells. Kinetic studies showed that the phosphoantigens were released at the end of the intraerythrocytic cycle at the time of parasite egress. We document exquisite sensitivity of Vγ9Vδ2 T cells, which respond to a few thousand parasites. These data unravel a novel framework, whereby release of phosphoantigens into the extracellular milieu by sequestered parasites likely promotes activation of distant Vγ9Vδ2 T cells that in turn exert remote antiparasitic functions.
Fecal Microbiota Transplantation Eliminates Clostridium difficile in a Murine Model of Relapsing Disease
Authors: Seekatz Anna M. , Theriot Casey M. , Molloy Caitlyn T. , Wozniak Katherine L. , Bergin Ingrid L. , Young Vincent B. 
Published: July 2015

ABSTRACT

Recurrent
Clostridium difficile
infection (CDI) is of particular concern among health care-associated infections. The role of the microbiota in disease recovery is apparent given the success of fecal microbiota transplantation (FMT) for recurrent CDI. Here, we present a murine model of CDI relapse to further define the microbiota recovery following FMT. Cefoperazone-treated mice were infected with
C. difficile
630 spores and treated with vancomycin after development of clinical disease. Vancomycin treatment suppressed both
C. difficile
colonization and cytotoxin titers. However,
C. difficile
counts increased within 7 days of completing treatment, accompanied by relapse of clinical signs. The administration of FMT immediately after vancomycin cleared
C. difficile
and decreased cytotoxicity within 1 week. The effects of FMT on the gut microbiota community were detectable in recipients 1-day posttransplant. Conversely, mice not treated with FMT remained persistently colonized with high levels of
C. difficile
, and the gut microbiota in these mice persisted at low diversity. These results suggest that full recovery of colonization resistance against
C. difficile
requires the restoration of a specific community structure.
Induction of Multifunctional Broadly Reactive T Cell Responses by a Plasmodium vivax Circumsporozoite Protein Recombinant Chimera
Authors: Cabrera-Mora Monica , Fonseca Jairo Andres , Singh Balwan , Oliveira-Ferreira Joseli , Lima-Junior Josué da Costa , Calvo-Calle J. Mauricio , Moreno Alberto 
Published: July 2015

ABSTRACTPlasmodium vivaxis the most widespread species ofPlasmodium, causing up to 50% of the malaria cases occurring outside sub-Saharan Africa. An effective vaccine is essential for successful control and potential eradication. A well-characterized vaccine candidate is the circumsporozoite protein (CSP). Preclinical and clinical trials have shown that both antibodies and cellular immune responses have been correlated with protection induced by immunization with CSP. On the basis of our reported approach of developing chimericPlasmodium yoeliiproteins to enhance protective efficacy, we designed PvRMC-CSP, a recombinant chimeric protein based on theP. vivaxCSP (PvCSP). In this engineered protein, regions of the PvCSP predicted to contain human T cell epitopes were genetically fused to an immunodominant B cell epitope derived from the N-terminal region I and to repeat sequences representing the two types of PvCSP repeats. The chimeric protein was expressed in soluble form with high yield. As the immune response to PvCSP has been reported to be genetically restricted in the murine model, we tested the immunogenicity of PvRMC-CSP in groups of six inbred strains of mice. PvRMC-CSP was able to induce robust antibody responses in all the mouse strains tested. Synthetic peptides representing the allelic forms of theP. vivaxCSP were also recognized to a similar extent regardless of the mouse strain. Furthermore, the immunization regimen induced high frequencies of multifunctional CD4+and CD8+PvRMC-CSP-specific T cells. The depth and breadth of the immune responses elicited suggest that immunization with PvRMC-CSP can circumvent the genetic restriction of the immune response toP. vivaxCSP. Interestingly, PvRMC-CSP was also recognized by naturally acquired antibodies from individuals living in areas where malaria is endemic. These features make PvRMC-CSP a promising vaccine candidate for further development.
Type II Secretion-Dependent Degradative and Cytotoxic Activities Mediated by Stenotrophomonas maltophilia Serine Proteases StmPr1 and StmPr2
Authors: DuMont Ashley L. , Karaba Sara M. , Cianciotto Nicholas P. 
Published: July 2015

ABSTRACT

Stenotrophomonas maltophilia
is an emerging opportunistic pathogen that primarily causes pneumonia and bacteremia in immunocompromised individuals. We recently reported that
S. maltophilia
strain K279a encodes the Xps type II secretion system and that Xps promotes rounding, actin rearrangement, detachment, and death in the human lung epithelial cell line A549. Here, we show that Xps-dependent cell rounding and detachment occur with multiple human and murine cell lines and that serine protease inhibitors block Xps-mediated rounding and detachment of A549 cells. Using genetic analysis, we determined that the serine proteases StmPr1 and StmPr2, which were confirmed to be Xps substrates, are predominantly responsible for secreted proteolytic activities exhibited by strain K279a, as well as the morphological and cytotoxic effects on A549 cells. Supernatants from strain K279a also promoted the degradation of type I collagen, fibrinogen, and fibronectin in a predominantly Xps- and protease-dependent manner, although some Xps-independent degradation of fibrinogen was observed. Finally, Xps, and predominantly StmPr1, degraded interleukin 8 (IL-8) secreted by A549 cells during coculture with strain K279a. Our findings indicate that while StmPr1 and StmPr2 are predominantly responsible for A549 cell rounding, extracellular matrix protein degradation, and IL-8 degradation, additional Xps substrates also contribute to these activities. Altogether, our data provide new insight into the virulence potential of the
S. maltophilia
Xps type II secretion system and its StmPr1 and StmPr2 substrates.
GlnR-Mediated Regulation of
ectABCD
Transcription Expands the Role of the GlnR Regulon to Osmotic Stress Management
Authors: Shao ZhiHui , Deng WanXin , Li ShiYuan , He JuanMei , Ren ShuangXi , Huang WeiRen , Lu YinHua , Zhao GuoPing , Cai ZhiMing , Wang Jin 
Published: July 2015

ABSTRACT

Ectoine and hydroxyectoine are excellent compatible solutes for bacteria to deal with environmental osmotic stress and temperature damages. The biosynthesis cluster of ectoine and hydroxyectoine is widespread among microorganisms, and its expression is activated by high salinity and temperature changes. So far, little is known about the mechanism of the regulation of the transcription of
ect
genes and only two MarR family regulators (EctR1 in methylobacteria and the EctR1-related regulator CosR in
Vibrio cholerae
) have been found to negatively regulate the expression of
ect
genes. Here, we characterize GlnR, the global regulator for nitrogen metabolism in actinomycetes, as a negative regulator for the transcription of ectoine/hydroxyectoine biosynthetic genes (
ect
operon) in
Streptomyces coelicolor
. The physiological role of this transcriptional repression by GlnR is proposed to protect the intracellular glutamate pool, which acts as a key nitrogen donor for both the nitrogen metabolism and the ectoine/hydroxyectoine biosynthesis.

IMPORTANCE
High salinity is deleterious, and cells must evolve sophisticated mechanisms to cope with this osmotic stress. Although production of ectoine and hydroxyectoine is one of the most frequently adopted strategies, the in-depth mechanism of regulation of their biosynthesis is less understood. So far, only two MarR family negative regulators, EctR1 and CosR, have been identified in methylobacteria and
Vibrio
, respectively. Here, our work demonstrates that GlnR, the global regulator for nitrogen metabolism, is a negative transcriptional regulator for
ect
genes in
Streptomyces coelicolor
. Moreover, a close relationship is found between nitrogen metabolism and osmotic resistance, and GlnR-mediated regulation of
ect
transcription is proposed to protect the intracellular glutamate pool. Meanwhile, the work reveals the multiple roles of GlnR in bacterial physiology.
Orientia tsutsugamushi Strain Ikeda Ankyrin Repeat-Containing Proteins Recruit SCF1 Ubiquitin Ligase Machinery via Poxvirus-Like F-Box Motifs
Authors: Beyer Andrea R. , VieBrock Lauren , Rodino Kyle G. , Miller Daniel P. , Tegels Brittney K. , Marconi Richard T. , Carlyon Jason A. 
Published: July 2015

ABSTRACT

A rising theme among intracellular microbes is the delivery of ankyrin repeat-containing effectors (Anks) that interact with target proteins to co-opt host cell functions.
Orientia tsutsugamushi
, an obligate intracellular bacterium and the etiologic agent of scrub typhus, encodes one of the largest Ank repertoires of any sequenced microorganism. They have been previously identified as type 1 secretion system substrates. Here,
in silico
and manual sequence analyses revealed that a large proportion of
O. tsutsugamushi
strain Ikeda Anks bear a eukaryotic/poxvirus-like F-box motif, which is known to recruit host cell SCF1 ubiquitin ligase machinery. We assessed the Anks for the ability to serve as F-box proteins. Coimmunoprecipitation assays demonstrated that F-box-containing Anks interact with overexpressed and/or endogenous SCF1 components. When coexpressed with FLAG-Ank4_01 or FLAG-Ank9, a glutathione
S
-transferase (GST)-tagged version of the SCF1 component SKP1 localized to subcellular sites of FLAG-Ank accumulation. The abilities of recombinant Anks to interact and colocalize with SKP1 were F-box dependent. GST-SKP1 precipitated
O. tsutsugamushi
-derived Ank9 from infected host cells, verifying both that the pathogen expresses Ank9 during infection and the protein's capability to bind SKP1. Aligning
O. tsutsugamushi
, poxviral, and eukaryotic F-box sequences delineated three F-box residues that are highly conserved and likely to be functionally important. Substitution of these residues ablated the ability of GFP-Ank9 to interact with GST-SKP1. These results demonstrate that
O. tsutsugamushi
strain Ikeda Anks can co-opt host cell polyubiquitination machinery, provide the first evidence that an
O. tsutsugamushi
Ank does so during infection, and advance overall understanding of microbial F-box proteins.

IMPORTANCE
Ankyrin repeat-containing proteins (Anks) are important virulence factors of intracellular bacteria that mediate protein-protein interactions with host cell targets.
Orientia tsutsugamushi
, which causes a debilitating infection called scrub typhus in one of the most densely populated regions of the world, encodes one of the largest Ank armamentariums of any sequenced bacterium. This study demonstrates that
O. tsutsugamushi
strain Ikeda Anks also bear F-box motifs that interact with host cell polyubiquitination machinery. By proving that an
Orientia
-derived Ank interacts with SKP1 in infected cells, this evidences the first bona fide
Orientia
effector and the first example of an endogenous F-box-containing Ank–mammalian-host ligand interaction for any intracellular bacterium. Also, importantly, this work identifies key residues that are essential for microbial F-box function.
Protocol for a systematic review of the effects of interventions to inform or educate caregivers about childhood vaccination in low and middle-income countries
Authors: Lukusa Lungeni A , Mbeye Nyanyiwe N , Adeniyi Folasade B , Wiysonge Charles S 
Published: July 2015

IntroductionDespite their proven effectiveness in reducing childhood infectious diseases, the uptake of vaccines remains suboptimal in low and middle-income countries. Identifying strategies for transmitting accurate vaccine information to caregivers would boost childhood vaccination coverage in these countries. The purpose of this review is to assess the effects on childhood vaccination coverage of interventions for informing or educating caregivers about the importance of vaccines in low and middle-income countries, as defined by the World Bank.Methods and analysisEligible study designs include randomised controlled trials (RCTs) as well as non-randomised controlled trials (non-RCTs). We will conduct a comprehensive search of both peer-reviewed and grey literature available up to 31 May 2015. We will search PubMed, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, Cumulative Index of Nursing and Allied Health, prospective trial registries and reference lists of relevant publications. Two authors will independently screen the search output, retrieve full texts of potentially eligible studies and assess the latter against predefined inclusion criteria. Disagreements between the two authors will be resolved through consensus and arbitration by a third author. We will pool data from studies with homogenous interventions and outcomes, using random-effects meta-analysis. We will assess statistical heterogeneity using the χ2test of homogeneity (with signiﬁcance defined at the 10% α-level) and quantify it using Higgins’ inconsistency index. We will explore the cause of any observed statistical heterogeneity using subgroup analysis, with subgroups defined by study design (RCTs vs non-RCTs) and type of intervention (information vs educational interventions).Ethics and disseminationThe proposed systematic review will collect and analyse secondary data that are not associated with individuals. The review will make a significant contribution to the knowledge base of interventions for improving childhood vaccination coverage in low and middle-income countries.Protocol registration numberPROSPERO, CRD42014010141.
Phase I Clinical Pharmacology Study of F14512, a New Polyamine-Vectorized Anticancer Drug, in Naturally Occurring Canine Lymphoma
Authors: Tierny Dominique , Serres François , Segaoula Zacharie , Bemelmans Ingrid , Bouchaert Emmanuel , Pétain Aurélie , Brel Viviane , Couffin Stéphane , Marchal Thierry , Nguyen Laurent , Thuru Xavier , Ferré Pierre , Guilbaud Nicolas , Gomes Bruno 
Published: July 2015

Abstract
Purpose: F14512 is a new topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells and increases topoisomerase II poisoning. F14512 is currently in a phase I/II clinical trial in patients with acute myeloid leukemia. The aim of this study was to investigate F14512 potential in a new clinical indication. Because of the many similarities between human and dog lymphomas, we sought to determine the tolerance, efficacy, pharmacokinetic/pharmacodynamic (PK/PD) relationship of F14512 in this indication, and potential biomarkers that could be translated into human trials.
Experimental Design: Twenty-three dogs with stage III–IV naturally occurring lymphomas were enrolled in the phase I dose-escalation trial, which consisted of three cycles of F14512 i.v. injections. Endpoints included safety and therapeutic efficacy. Serial blood samples and tumor biopsies were obtained for PK/PD and biomarker studies.
Results: Five dose levels were evaluated to determine the recommended dose. F14512 was well tolerated, with the expected dose-dependent hematologic toxicity. F14512 induced an early decrease of tumoral lymph node cells, and a high response rate of 91% (21/23) with 10 complete responses, 11 partial responses, 1 stable disease, and 1 progressive disease. Phosphorylation of histone H2AX was studied as a potential PD biomarker of F14512.
Conclusions: This trial demonstrated that F14512 can be safely administered to dogs with lymphoma resulting in strong therapeutic efficacy. Additional evaluation of F14512 is needed to compare its efficacy with standards of care in dogs, and to translate biomarker and efficacy findings into clinical trials in humans. Clin Cancer Res; 21(23); 5314–23. ©2015 AACR.
SPARC Expression Did Not Predict Efficacy of nab-Paclitaxel plus Gemcitabine or Gemcitabine Alone for Metastatic Pancreatic Cancer in an Exploratory Analysis of the Phase III MPACT Trial
Authors: Hidalgo Manuel , Plaza Carlos , Musteanu Monica , Illei Peter , Brachmann Carrie B. , Heise Carla , Pierce Daniel , Lopez-Casas Pedro P. , Menendez Camino , Tabernero Josep , Romano Alfredo , Wei Xinyu , Lopez-Rios Fernando , Von Hoff Daniel D. 
Published: July 2015

Abstract
Purpose: nab-Paclitaxel plus gemcitabine was superior to gemcitabine alone for patients with metastatic pancreatic cancer (MPC) in the phase III MPACT trial. This study evaluated the association of secreted protein acidic and rich in cysteine (SPARC) levels with efficacy as an exploratory endpoint.
Experimental Design: Patients with previously untreated MPC (N = 861) received nab-paclitaxel plus gemcitabine or gemcitabine alone. Baseline SPARC level was measured in the tumor stroma and epithelia (archival biopsies) and plasma. Experiments were performed in pancreatic cancer mouse models in which SPARC was intact or deleted.
Results: SPARC was measured in the tumor stroma of 256 patients (30%), the tumor epithelia of 301 patients (35%), and plasma of 343 patients (40%). Stroma-evaluable samples were from metastases (71%), from the pancreas (11%), or of unidentifiable origin (insufficient tissue to determine; 17%). For all patients, stromal SPARC level [high (n = 71) vs. low (n = 185)] was not associated with overall survival (OS; HR, 1.019; P = 0.903); multivariate analysis confirmed this lack of association. There was no association between stromal SPARC level and OS in either treatment arm. Neither tumor epithelial SPARC nor plasma SPARC was associated with OS. Results from a SPARC knockout mouse model treated with nab-paclitaxel plus gemcitabine revealed no correlation between SPARC expression and tumor progression or treatment efficacy.
Conclusions: SPARC levels were not associated with efficacy in patients with MPC. This exploratory analysis does not support making treatment decisions regarding nab-paclitaxel plus gemcitabine or gemcitabine alone in MPC based on SPARC expression. Clin Cancer Res; 21(21); 4811–8. ©2015 AACR.
Translating Pembrolizumab to Clinical Practice: Speak Immunology and Learn Fast!
Authors: van Elsas Andrea , van Eenennaam Hans , Haanen John B. 
Published: July 2015

Abstract
T-cell checkpoint inhibitors treat the cancer patient's immune system potentially inducing significant long-term survival. Pembrolizumab demonstrates clinical activity in patients diagnosed with melanoma and other cancers. Its mode of action suggests a rationale for combination with other treatment modalities, urging oncologists to brush up their knowledge of immunology. Clin Cancer Res; 21(19); 4251–3. ©2015 AACR.
See related article by Patnaik et al., p. 4286
Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer
Authors: Ayeni Deborah , Politi Katerina , Goldberg Sarah B. 
Published: July 2015

Abstract
Third-generation mutant-specific EGFR tyrosine kinase inhibitors are showing robust clinical activity, particularly in lung cancers harboring the EGFRT790M mutation, yet acquired resistance to these agents emerges. Additional mutations in EGFR can confer resistance that, depending on their genomic context, could determine new drug sensitivities of the cancer cells. Clin Cancer Res; 21(17); 3818–20. ©2015 AACR.
See related articles by Ercan et al., p. 3913 and Niederst et al., p. 3924
A Crossroad Between West, East and Orient – The Case of Albanian Culture
Authors: Sawicka Irena 
Published: July 2015

A Crossroad Between West, East and Orient – The Case of Albanian CultureAlbania is a unique example of authentic mentally-coded multiculturalism. The influence of a certain type of culture on believes shared by all Albanians is connected with either a specific period in history or specific territory. Modern Albania inherits various influences. As a unique European society Albanians do not define their identity through affiliation to a specific cultural (religious) circle. Nowadays Albanian national identity is devoid of religious context. It is based on the idea of Illyrian origin, great figures of Albanian history, mythology, language separateness. Religious components make up a surface of purely ethnographic character. Albanians attach greater importance to traditional values connected with the medieval clan law (besa ‘a word, a promise of keeping the word, commitment’, honor, the cult of a visitor, clan vengeance, the institution of a sworn virgin and so on). Kultura albańska – zderzenie Zachodu, Wschodu i Orientu Albania jest unikalnym przykładem prawdziwej, zakodowanej mentalnie multikulturowości. Wpływ określonego typu kultury na poglądy wspólne wszystkim Albańczykom związany jest bądź z określonym okresem historycznym, bądź z określonym terytorium. Dzisiejsza Albania dziedziczy różne wpływy i, jako unikalne w Europie społeczeństwo, Albańczycy nie określają swojej tożsamości poprzez przynależność do określonego kręgu kulturowego (religijnego). Współcześnie tożsamość narodowa Albańczyków zbudowana jest więc bez kontekstu religijnego. Opiera się na koncepcji pochodzenia od Ilirów, wielkich postaciach historii albańskiej, mitologii, odrębności językowej. Elementy religijne stanowią warstwę powierzchowną, czysto etnograficzną. Większą wagę przywiązują Albańczycy do wartości tradycyjnych, związanych ze średniowiecznym prawem rodowym (besa ‘słowo, obietnica, zobowiązanie’, honor, kult gościa, danego słowa i in.).
Empire, Colony, and Globalization. A Brief History of the Nahuatl Language
Authors: Olko Justyna , Sullivan John 
Published: July 2015

Empire, Colony, and Globalization. A Brief History of the Nahuatl LanguageThis paper is the first attempt to outline the cultural and sociopolitical history of Nahuatl, one of the most important native languages of America, beginning with preconquest times, focusing on its role in the Aztec empire, and continuing through the colonial period until the present. We discuss the most important elements of the Nahua writing tradition, its changes under contact with European culture and Spanish, as well as modern threats to its survival. We finish with current prospects for revitalization. Imperium, kolonia i globalizacja. Krótka historia języka nahuatl Artykuł jest pierwszą próbą zarysowania kulturowej i społeczno-politycznej historii języka nahuatl, jednego z najważniejszych języków tubylczych Ameryki, począwszy od czasów przedhiszpańskich, a zwłaszcza jego roli w imperium azteckim, przez czasy kolonialne aż po sytuację obecną. Przedmiotem dyskusji są najważniejsze elementy związane z tradycją piśmiennictwa w tym języku, jego zmiany pod wpływem kontaktu z kulturą europejską i językiem hiszpańskim, aktualne zagrożenia oraz możliwe scenariusze jego rewitalizacji.