bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical Characterization of GSK2336805, a Novel Inhibitor of Hepatitis C Virus Replication That Selects for Resistance in NS5A
Authors: Walker Jill , Crosby Renae , Wang Amy , Woldu Ermias , Vamathevan Jessica , Voitenleitner Christian , You Shihyun , Remlinger Katja , Duan Maoshang , Kazmierski Wieslaw , Hamatake Robert 
Published: October 2013

ABSTRACT
GSK2336805 is an inhibitor of hepatitis C virus (HCV) with picomolar activity on the standard genotype 1a, 1b, and 2a subgenomic replicons and exhibits a modest serum shift. GSK2336805 was not active on 22 RNA and DNA viruses that were profiled. We have identified changes in the N-terminal region of NS5A that cause a decrease in the activity of GSK2336805. These mutations in the genotype 1b replicon showed modest shifts in compound activity (<13-fold), while mutations identified in the genotype 1a replicon had a more dramatic impact on potency. GSK2336805 retained activity on chimeric replicons containing NS5A patient sequences from genotype 1 and patient and consensus sequences for genotypes 4 and 5 and part of genotype 6. Combination and cross-resistance studies demonstrated that GSK2336805 could be used as a component of a multidrug HCV regimen either with the current standard of care or in combination with compounds with different mechanisms of action that are still progressing through clinical development.
Efflux Inhibition with Verapamil Potentiates Bedaquiline in Mycobacterium tuberculosis
Authors: Gupta Shashank , Cohen Keira A. , Winglee Kathryn , Maiga Mamoudou , Diarra Bassirou , Bishai William R. 
Published: October 2013

ABSTRACT

Drug efflux is an important resistance mechanism in
Mycobacterium tuberculosis
. We found that verapamil, an efflux inhibitor, profoundly decreases the MIC of bedaquiline and clofazimine to
M. tuberculosis
by 8- to 16-fold. This exquisite susceptibility was noted among drug-susceptible and drug-resistant clinical isolates. Thus, efflux inhibition is an important sensitizer of bedaquiline and clofazimine, and efflux may emerge as a resistance mechanism to these drugs.
Can Levofloxacin Be a Useful Alternative to Trimethoprim-Sulfamethoxazole for Treating Stenotrophomonas maltophilia Bacteremia?
Authors: Cho Sun Young , Kang Cheol-In , Kim Jungok , Ha Young Eun , Chung Doo Ryeon , Lee Nam Yong , Peck Kyong Ran , Song Jae-Hoon 
Published: October 2013

ABSTRACT

A retrospective study was conducted to evaluate the efficacy of levofloxacin in the treatment of
Stenotrophomonas maltophilia
bacteremia. The 30-day mortality rates were similar between the trimerthoprim-sulfamethoxazole (TMP-SMX) and levofloxacin treatment groups. Adverse events related to antibiotics occurred more frequently in patients receiving TMP-SMX, and recurrent bacteremia due to levofloxacin-resistant
S. maltophilia
strains developed in patients treated with levofloxacin. Our data suggest that levofloxacin can be a useful alternative option for treating
S. maltophilia
infections.
Differentiation of Antigen-Specific T Cells with Limited Functional Capacity during Mycobacterium tuberculosis Infection
Authors: Jeong Yun Hee , Jeon Bo-Young , Gu Sun-Hwa , Cho Sang-Nae , Shin Sung Jae , Chang Jun , Ha Sang-Jun 
Published: October 2013

ABSTRACTDespite the generation ofMycobacterium tuberculosis-specific T cell immune responses during the course of infection, only 5 to 10% of exposed individuals develop active disease, while others develop a latent infection. This phenomenon suggests defectiveM. tuberculosis-specific immunity, which necessitates more careful characterization ofM. tuberculosis-specific T cell responses. Here, we longitudinally analyzed the phenotypes and functions ofM. tuberculosis-specific T cells. In contrast to the functional exhaustion of T cells observed after chronic infection,M. tuberculosis-specific CD8+T cells differentiated into either effector (CD127loCD62Llo) or effector memory (CD127hiCD62Llo) cells, but not central memory cells (CD127hiCD62Lhi), with low programmed death 1 (PD-1) expression, even in the presence of high levels of bacteria. Additionally,M. tuberculosis-specific CD8+and CD4+T cells produced substantial levels of tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ), but not interleukin 2 (IL-2), uponin vitrorestimulation. AmongM. tuberculosis-specific CD8+T cells, CD127hieffector memory cells displayed slower ongoing turnover but greater survival potential. In addition, these cells produced more IFN-γ and TNF-α and displayed lytic activity upon antigen stimulation. However, the effector function ofM. tuberculosis-specific CD8+CD127hieffector memory T cells was inferior to that of canonical CD8+CD127himemory T cells generated after acute lymphocytic choriomeningitis virus infection. Collectively, our data demonstrate thatM. tuberculosis-specific T cells can differentiate into memory T cells during the course ofM. tuberculosisinfection independent of the bacterial burden but with limited functionality. These results provide a framework for further understanding the mechanisms ofM. tuberculosisinfection that can be used to develop more effective vaccines.
Erythropoietin Protects against Murine Cerebral Malaria through Actions on Host Cellular Immunity
Authors: Wei Xu , Li Ying , Sun Xiaodan , Zhu Xiaotong , Feng Yonghui , Liu Jun , Jiang Yongjun , Shang Hong , Cui Liwang , Cao Yaming 
Published: October 2013

ABSTRACTCerebral malaria (CM) is associated with excessive host proinflammatory responses and endothelial activation. The hematopoietic hormone erythropoietin (EPO) possesses neuroprotective functions in animal models of ischemic-hypoxic, traumatic, and inflammatory injuries. In thePlasmodium bergheiANKA model of experimental CM (ECM), recombinant human EPO (rhEPO) has shown evident protection against ECM. To elucidate the mechanism of EPO in this ECM model, we investigated the effect of rhEPO on host cellular immune responses. We demonstrated that improved survival of mice with ECM after rhEPO treatment was associated with reduced endothelial activation and improved integrity of the blood-brain barrier. Our results revealed that rhEPO downregulated the inflammatory responses by directly inhibiting the levels and functions of splenic dendritic cells. Conversely, rhEPO treatment led to significant expansion of regulatory T cells and increased expression of the receptor cytotoxic T lymphocyte antigen 4 (CTLA-4). The data presented here provide evidence of the direct effect of rhEPO on host cellular immunity during ECM.
Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies
Authors: Reddy K. Sony , Pandey Alok K. , Singh Hina , Sahar Tajali , Emmanuel Amlabu , Chitnis Chetan E. , Chauhan Virander S. , Gaur Deepak 
Published: October 2013

ABSTRACT

Plasmodium falciparum
reticulocyte binding-like homologous protein 5 (PfRH5) is an essential merozoite ligand that binds with its erythrocyte receptor, basigin. PfRH5 is an attractive malaria vaccine candidate, as it is expressed by a wide number of
P. falciparum
strains, cannot be genetically disrupted, and exhibits limited sequence polymorphisms. Viral vector-induced PfRH5 antibodies potently inhibited erythrocyte invasion. However, it has been a challenge to generate full-length recombinant PfRH5 in a bacterial-cell-based expression system. In this study, we have produced full-length recombinant PfRH5 in
Escherichia coli
that exhibits specific erythrocyte binding similar to that of the native PfRH5 parasite protein and also, importantly, elicits potent invasion-inhibitory antibodies against a number of
P. falciparum
strains. Antibasigin antibodies blocked the erythrocyte binding of both native and recombinant PfRH5, further confirming that they bind with basigin. We have thus successfully produced full-length PfRH5 as a functionally active erythrocyte binding recombinant protein with a conformational integrity that mimics that of the native parasite protein and elicits potent strain-transcending parasite-neutralizing antibodies.
P. falciparum
has the capability to develop immune escape mechanisms, and thus, blood-stage malaria vaccines that target multiple antigens or pathways may prove to be highly efficacious. In this regard, antibody combinations targeting PfRH5 and other key merozoite antigens produced potent additive inhibition against multiple worldwide
P. falciparum
strains. PfRH5 was immunogenic when immunized with other antigens, eliciting potent invasion-inhibitory antibody responses with no immune interference. Our results strongly support the development of PfRH5 as a component of a combination blood-stage malaria vaccine.
Rapid Nutritional Remodeling of the Host Cell upon Attachment of Legionella pneumophila
Authors: Bruckert William M. , Price Christopher T. , Abu Kwaik Yousef 
Published: October 2013

ABSTRACT

Upon entry of
Legionella pneumophila
into amoebas and macrophages, host-mediated farnesylation of the AnkB effector enables its anchoring to the
Legionella
-containing vacuole (LCV) membrane. On the LCV, AnkB triggers docking of K
48
-linked polyubiquitinated proteins that are degraded by the host proteasomes to elevate cellular levels of amino acids needed for intracellular proliferation. Interference with AnkB function triggers
L. pneumophila
to exhibit a starvation response and differentiate into the nonreplicative phase in response to the basal levels of cellular amino acids that are not sufficient to power intracellular proliferation of
L. pneumophila
. Therefore, we have determined whether the biological function of AnkB is temporally and spatially triggered upon bacterial attachment to the host cell to circumvent a counterproductive bacterial differentiation into the nonreplicative phase upon bacterial entry. Here, we show that upon attachment of
L. pneumophila
to human monocyte-derived macrophages (hMDMs), the host farnesylation and ubiquitination machineries are recruited by the Dot/Icm system to the plasma membrane exclusively beneath sites of bacterial attachment. Transcription and injection of
ankB
is triggered by attached extracellular bacteria followed by rapid farnesylation and anchoring of AnkB to the cytosolic side of the plasma membrane beneath bacterial attachment, where K
48
-linked polyubiquitinated proteins are assembled and degraded by the proteasomes, leading to a rapid rise in the cellular levels of amino acids. Our data represent a novel strategy by an intracellular pathogen that triggers rapid nutritional remodeling of the host cell upon attachment to the plasma membrane, and as a result, a gratuitous surplus of cellular amino acids is generated to support proliferation of the incoming pathogen.
Factor H-Dependent Alternative Pathway Inhibition Mediated by Porin B Contributes to Virulence of Neisseria meningitidis
Authors: Lewis Lisa A. , Vu David M. , Vasudhev Shreekant , Shaughnessy Jutamas , Granoff Dan M. , Ram Sanjay 
Published: October 2013

ABSTRACTThe identification of “factor H binding protein (fHbp)-null” invasive meningococcal isolates and the realization that widespread use of fHbp-based vaccines could herald selection of such strains prompted us to characterize novel mechanisms of alternative pathway (AP) inhibition on meningococci. Of seven strains engineered to lack four known AP-inhibiting molecules, capsular polysaccharide, lipooligosaccharide sialic acid, fHbp, and neisserial surface protein A (quadruple mutants), four strains inhibited human AP-mediated C3 deposition. All four expressed the porin B2 (PorB2) molecule, and three strains belonged to the hypervirulent ST-11 lineage. Consistent with reduced C3 deposition, the rate of C3a generation by a PorB2 isolate was lower than that by a PorB3 strain. Allelic replacement of PorB3 with PorB2, in both encapsulated and unencapsulated strains, confirmed the role of PorB2 in AP inhibition. Expression of PorB2 increased resistance to complement-dependent killing relative to that seen in an isogenic PorB3-expressing strain. Adult rabbit and mouse APs were unimpeded on all mutants, and human fH inhibited nonhuman C3 deposition on PorB2-expressing strains, which provided functional evidence for human fH-dependent AP regulation by PorB2. Low-affinity binding of full-length human fH to quadruple mutants expressing PorB2 was demonstrated. fH-like protein 1 (FHL-1; contains fH domains 1 through 7) and fH domains 6 and 7 fused to IgG Fc bound to one PorB2-expressing quadruple mutant, which suggested that fH domains 6 and 7 may interact with PorB2. These results associate PorB2 expression with serum resistance and presage the appearance of fHbp-null and hypervirulent ST-11 isolates that may evade killing by fHbp-based vaccines.IMPORTANCEThe widespread use of antimeningococcal vaccines based on factor H (fH) binding protein (fHbp) is imminent. Meningococci that lack fHbp were recently isolated from persons with invasive disease, and these fHbp-null strains could spawn vaccine failure. Our report provides a molecular basis for an explanation of how fHbp-null strains may evade the host immune system. Meningococci possess several mechanisms to subvert killing by the alternative pathway (AP) of complement, including production of the fHbp and NspA fH binding proteins. Here we show that a meningococcal protein called porin B2 (PorB2) contributes to inhibition of the AP on the bacterial surface. A majority of the “fHbp-null” isolates identified, as well as all members of a “hypervirulent” lineage (called ST-11), express PorB2. Our findings highlight the potential for the emergence of fHbp-negative strains that are able to regulate the AP and may be associated with fHbp vaccine failure.
The General Phosphotransferase System Proteins Localize to Sites of Strong Negative Curvature in Bacterial Cells
Authors: Govindarajan Sutharsan , Elisha Yair , Nevo-Dinur Keren , Amster-Choder Orna 
Published: October 2013

ABSTRACT

The bacterial cell poles are emerging as subdomains where many cellular activities take place, but the mechanisms for polar localization are just beginning to unravel. The general phosphotransferase system (PTS) proteins, enzyme I (EI) and HPr, which control preferential use of carbon sources in bacteria, were recently shown to localize near the
Escherichia coli
cell poles. Here, we show that EI localization does not depend on known polar constituents, such as anionic lipids or the chemotaxis receptors, and on the cell division machinery, nor can it be explained by nucleoid occlusion or localized translation. Detection of the general PTS proteins at the budding sites of endocytotic-like membrane invaginations in spherical cells and their colocalization with the negative curvature sensor protein DivIVA suggest that geometric cues underlie localization of the PTS system. Notably, the kinetics of glucose uptake by spherical and rod-shaped
E. coli
cells are comparable, implying that negatively curved “pole-like” sites support not only the localization but also the proper functioning of the PTS system in cells with different shapes. Consistent with the curvature-mediated localization model, we observed the EI protein from
Bacillus subtilis
at strongly curved sites in both
B. subtilis
and
E. coli
. Taken together, we propose that changes in cell architecture correlate with dynamic survival strategies that localize central metabolic systems like the PTS to subcellular domains where they remain active, thus maintaining cell viability and metabolic alertness.

IMPORTANCE
Despite their tiny size and the scarcity of membrane-bounded organelles, bacteria are capable of sorting macromolecules to distinct subcellular domains, thus optimizing functionality of vital processes. Understanding the cues that organize bacterial cells should provide novel insights into the complex organization of higher organisms. Previously, we have shown that the general proteins of the phosphotransferase system (PTS) signaling system, which governs utilization of carbon sources in bacteria, localize to the poles of
Escherichia coli
cells. Here, we show that geometric cues, i.e., strong negative membrane curvature, mediate positioning of the PTS proteins. Furthermore, localization to negatively curved regions seems to support the PTS functionality.
The Gravity Anomaly Map of North America
Authors: Hanna W. F. , Sweeney R. E. , Hildenbrand T. G. , Tanner J. G. , McConnell R. K. , Godson R. H. 
Published: October 2013

Abstract
The recently developed Gravity Anomaly Map of North America is the product of a 12-year multinational effort to compile, critically edit, and merge gravity anomaly data on a continental and global scale (Gravity Anomaly Map Committee, 1987). This color-pixel map is printed on four quadrant sheets at a scale of 1:5,000,000 and includes a fifth sheet showing a color index map and data references. This map is the first at such a global scale to include several hundreds of thousands of precise bits of surface data of Canada, the United States, Mexico, and Central America, as well as other high-quality surface data from neighboring continental and oceanic areas. A 1:20,000,000 version of the map is shown on Plate 1A.
The prospect of producing a gravity anomaly map of North America was formally advanced in 1975 by way of a cooperative agreement between the U.S. Geological Survey and the Society of Exploration Geophysicists. Before these cooperators linked to specialists of Canada, Mexico, and other countries, they agreed that an updated version of the gravity anomaly map of the United States should first be developed. In 1983, following publication of the U.S. map, the Society of Exploration Geophysicists and the U.S. Geological Survey concluded that the planned Centennial Map Series of the Decade of North American Geology program would be an excellent medium for publication of the gravity anomaly map of North America as well as the magnetic anomaly map of North America. The cooperating groups subsequently coordinated with the Geological Society of America, and the map was published in 1988.
Independent appraiser assessment of the quality, methodological rigour and transparency of the development of the 2008 international consensus statement on concussion in sport
Authors: White Peta E , Shee Anna Wong , Finch Caroline F 
Published: October 2013

AimIn recent years, considerable effort has been devoted to the development and revisions to an international consensus statement on concussion in sport (ICSCS). The aim of this study was to obtain expert views on the methodological rigour and transparency with which the 2008 ICSCS was developed, as a precursor to the development of the 2012 update.MethodsDelegates registered for the 2012 fourth International Conference on Concussion in Sport, selected local concussion researchers not involved in any prior international consensus meetings, and all authors of the 2008 ICSCS published paper were invited to assess the methodological rigour and transparency with which the 2008 ICSCS was developed. The online Appraisal of Guidelines for Research and Evaluation (AGREE) II assessment tool, with six quality domains, was used and domain scores were expressed as a percentage of the maximum possible score for that domain.Results18 appraisers completed the online AGREE II assessment. Ten appraisers said they would recommend the 2008 ICSCS for use (without modification) and seven said they would recommend its use with some modification. The ‘scope and purpose’ and ‘clarity of presentation’ were rated highest, both scoring 78%. The lowest scoring domain was ‘applicability’ with a score of 55%.ConclusionsThe quality of the ICSCS is important because it is used to guide return-to-play decisions and the management of sport-related concussions. This appraisal of the 2008 ICSCS suggests that a greater focus is needed on the actual implementation of future ICSCS and the relationship between implementation and desired health outcomes.
Declining incidence of surgery for Achilles tendon rupture follows publication of major RCTs: evidence-influenced change evident using the Finnish registry study
Authors: Mattila Ville M , Huttunen Tuomas T , Haapasalo Heidi , Sillanpää Petri , Malmivaara Antti , Pihlajamäki Harri 
Published: October 2013

ObjectivesAcute Achilles tendon ruptures are common among highly active people. Recently published studies have provided increasing evidence to support non-surgical treatment. This study aimed to assess the incidence trends of surgically treated, acute Achilles tendon ruptures. Our hypothesis, based on the recent literature showing no difference in functional results between surgical and non-surgical treatment, was that the incidence of surgery would be declining.MethodsWe conducted a nationwide hospital register-based study. All patients 18 years of age or older with a diagnosis of acute Achilles tendon injury, and treated with Achilles tendon repair from 1987 to 2011 in Finland were included in the study.ResultsDuring the 25-year study period in Finland, a total of 15 252 patients received surgical treatment for an acute Achilles tendon rupture. The incidence of surgical treatment of acute Achilles tendon rupture in men was 11.1/100 000 person-years in 1987 and 20.5/100 000 person-years in 2011. The corresponding figures in women were 2.5/100 000 person-years in 1987 and 4.2/100 000 person-years in 2011. The highest rates occurred in 2008 in men and 2007 in women, and since then the decrease has been 42% in men and 55% in women.ConclusionsDuring the past few years, the rate of surgically treated acute Achilles tendon ruptures has declined remarkably. The findings of the present study indicate that orthopaedic surgeons have chosen more often non-surgical treatment option for acute Achilles ruptures. This can be considered as an example, how high-quality scientific evidence can lead to a rapid change in clinical practice.
Knee Arthroscopy Cohort Southern Denmark (KACS): protocol for a prospective cohort study
Authors: Thorlund Jonas Bloch , Christensen Robin , Nissen Nis , Jørgensen Uffe , Schjerning Jeppe , Pørneki Jens Christian , Englund Martin , Lohmander L Stefan 
Published: October 2013

BackgroundMeniscus surgery is a high-volume surgery carried out on 1 million patients annually in the USA. The procedure is conducted on an outpatient basis and the patients leave the hospital a few hours after surgery. A critical oversight of previous studies is their failure to account for the type of meniscal tears. Meniscus tears can be categorised as traumatic or non-traumatic. Traumatic tears (TT) are usually observed in younger, more active individuals in an otherwise ‘healthy’ meniscus and joint. Non-traumatic tears (NTT) (ie, degenerative tears) are typically observed in the middle-aged (35–55 years) and older population but the aetiology is largely unclear. Knowledge about the potential difference of the effect of arthroscopic meniscus surgery on patient symptoms between patients with traumatic and NTT is sparse. Furthermore, little is known about the natural time course of patient perceived pain, function and quality of life after meniscus surgery and factors affecting these outcomes. The aim of this prospective cohort study is to investigate the natural time course of patient-reported outcomes in patients undergoing meniscus surgery, with particular emphasis on the role of type of symptom onset.Methods/designThis prospective cohort study enrol patients assigned for meniscus surgery. At the baseline (PRE surgery), patient characteristics are assessed using an email-based questionnaire also comprising several validated questionnaires assessing general health, knee-specific characteristics and patient's expectations of the surgery. Follow-up will be conducted at 12 and 52 weeks after meniscus surgery. The major outcomes will be differences in changes, from before to 52 weeks after surgery, in each of the five domains on the Knee injury and Osteoarthritis Outcome Score (KOOS) between patients undergoing surgery for traumatic compared with non-traumatic meniscus tears.DisseminationThe study findings will be disseminated in peer-reviewed journals and presented at national and international conferences.Trial registration numberClinicalTrials.gov Identifier:NCT01871272.