bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human thrombomodulin regulates complement activation as well as the coagulation cascade in xeno‐immune response
Authors: Kim Hwajung , Hawthorne Wayne J. , Kang Hee Jung , Lee Yoo Jin , Hwang Jong‐Ik , Hurh Sunghoon , Ro Han , Jeong Jong Cheol , Cho Bumrae , Yang Jaeseok , Ahn Curie 
Published: July 2015

AbstractBackgroundWith the introduction of the α1, 3‐galactosyltransferase gene‐knockout (GT‐KO) pig and its pivotal role in preventing hyperacute rejection (HAR), coagulation remains a considerable obstacle yet to be overcome in order to provide long‐term xenograft survival. Thrombomodulin (TBM) plays a critical anticoagulant and anti‐inflammatory role in its part of the protein C pathway. Many studies have demonstrated the strong anticoagulant effects of TBM in xenotransplantation, but its complement regulatory effects have not been appropriately examined. Here, we investigate whether TBM can regulate complement activation as well as coagulation in response to xenogeneic stimuli.MethodsWe transfected porcine endothelial cells (MPN‐3) with adenovirus vectors containing the human TBM gene (ad‐hTBM), or a control gene containing GFP (ad‐GFP). The expression level of ad‐hTBM was measured by flow cytometry. To confirm the anticoagulant effect of TBM, coagulation time was measured after treatment with recalcified human plasma in ad‐hTBM‐transfected MPN‐3, and a thrombin activity assay was performed after treatment with 50% human serum in ad‐hTBM‐infected MPN‐3.ResultsThrombin generation was significantly decreased in a dose‐dependent manner in ad‐TBM group, and coagulation time was increased in the ad‐hTBM group when compared to the ad‐GFP group. Complement‐dependent serum toxicity assays were performed after treatment with 20% human serum or heat‐inactivated human serum by LDH assay. Complement‐dependent toxicity was significantly attenuated in the ad‐hTBM group, but complement‐independent toxicity was not attenuated in the ad‐hTBM group. These results suggest that human thrombomodulin (hTBM) has complement regulatory effects as well as anticoagulant effects. To further investigate the mechanisms of complement regulation by hTBM, we deleted the EGF5, 6 domains that are involved in thrombin generation or the lectin‐like domain involved in inflammation of TBM and functional tests were performed using these modified forms. We showed that the EGF5, 6 domain of TBM principally inhibits complement activation rather than the lectin domain.ConclusionThe EGF5, 6 domains of TBM appear to be the major domains for down‐regulating the complement system rather than the lectin‐like domain during xenogenic stimuli. The role of EGF5, 6 domains of hTBM may be due to inhibition of thrombin as thrombin can cleave C3a and C5a directly and hTBM may also be involved in complement regulation. Clearly then human TBM has complement regulatory effects as well as anticoagulant effects in xeno‐immune response, and it is a promising target for attenuating xenograft rejection.
Guidelines to Classify Female Subject Groups in Sport-Science Research
Authors: Decroix Lieselot , De Pauw Kevin , Foster Carl , Meeusen Romain 
Published: July 2015

Aim:To review current cycling-related sport-science literature to formulate guidelines to classify female subject groups and to compare this classification system for female subject groups with the classification system for male subject groups.Methods:A database of 82 papers that described female subject groups containing information on preexperimental maximal cycle-protocol designs, terminology, biometrical and physiological parameters, and cycling experience was analyzed. Subject groups were divided into performance levels (PLs), according to the nomenclature. Body mass, body-mass index, maximal oxygen consumption (VO2max), peak power output (PPO), and training status were compared between PLs and between female and male PLs.Results:Five female PLs were defined, representing untrained, active, trained, well-trained, and professional female subjects. VO2max and PPO significantly increased with PL, except for PL3 and PL4 (P < .01). For each PL, significant differences were observed in absolute and relative VO2max and PPO between male and female subject groups. Relative VO2max is the most cited parameter for female subject groups and is proposed as the principal parameter to classify the groups.Conclusion:This systematic review shows the large variety in the description of female subject groups in the existing literature. The authors propose a standardized preexperimental testing protocol and guidelines to classify female subject groups into 5 PLs based on relative VO2max, relative PPO, training status, absolute VO2max, and absolute PPO.
Cross-sectional and Longitudinal Associations Between Parents’ and Preschoolers’ Physical Activity and Television Viewing: The HAPPY Study
Authors: Abbott Gavin , Hnatiuk Jill , Timperio Anna , Salmon Jo , Best Keren , Hesketh Kylie D. 
Published: July 2015

Background:Parental modeling has been shown to be important for school-aged children’s physical activity (PA) and television (TV) viewing, yet little is known about its impact for younger children. This study examined cross-sectional and 3-year longitudinal associations between PA and TV viewing behaviors of parents and their preschool children.Methods:In 2008–2009 (T1), parents in the Healthy Active Preschool and Primary Years (HAPPY) cohort study (n = 450) in Melbourne, Australia, self-reported their weekly PA and TV viewing and proxy-reported their partner’s PA and TV viewing and their 3- to 5-year-old preschool child’s TV viewing. Children’s PA was assessed via accelerometers. Repeat data collection occurred in 2011–2012 (T2).Results:Mothers’ and fathers’ PAs were associated with PA among preschool girls at T1, but not boys. Parents’ TV viewing times were significant correlates of girls’ and boys’ TV viewing at T1. Longitudinally, mothers’ PA at baseline predicted boys’ PA at T2, whereas sex-specific associations were found for TV viewing, with mothers’ and fathers’ TV viewing at T1 associated with girls’ and boys’ TV viewing respectively at T2.Conclusions:The PA and TV viewing of both parents are significantly associated with these behaviors in preschool children. The influence of the sex-matched parent appears to be important longitudinally for children’s TV viewing.
Effects of Klebsiella pneumoniae Carbapenemase Subtypes, Extended-Spectrum β-Lactamases, and Porin Mutations on the
In Vitro
Activity of Ceftazidime-Avibactam against Carbapenem-Resistant K. pneumoniae
Authors: Shields Ryan K. , Clancy Cornelius J. , Hao Binghua , Chen Liang , Press Ellen G. , Iovine Nicole M. , Kreiswirth Barry N. , Nguyen M. Hong 
Published: July 2015

ABSTRACT

Avibactam is a novel β-lactamase inhibitor with affinity for
Klebsiella pneumoniae
carbapenemases (KPCs). In combination with ceftazidime, the agent demonstrates activity against KPC-producing
K. pneumoniae
(KPC-Kp). KPC-Kp strains are genetically diverse and harbor multiple resistance determinants, including defects in outer membrane proteins and extended-spectrum β-lactamases (ESBLs). Mutations in porin gene
ompK36
confer high-level carbapenem resistance to KPC-Kp strains. Whether specific mechanisms of antimicrobial resistance also influence the activity of ceftazidime-avibactam is unknown. We defined the effects of ceftazidime-avibactam against 72 KPC-Kp strains with diverse mechanisms of resistance, including various combinations of KPC subtypes and ESBL and
ompK36
mutations. Ceftazidime MICs ranged from 64 to 4,096 μg/ml and were lowered by a median of 512-fold with the addition of avibactam. All strains exhibited ceftazidime-avibactam MICs at or below the CLSI breakpoint for ceftazidime (≤4 μg/ml; range, 0.25 to 4). However, the MICs were within two 2-fold dilutions of the CLSI breakpoint against 24% of the strains, and those strains would be classified as nonsusceptible to ceftazidime by EUCAST criteria (MIC > 1 μg/ml). Median ceftazidime-avibactam MICs were higher against KPC-3 than KPC-2 variants (
P
= 0.02). Among KPC-2-Kp strains, the presence of both ESBL and porin mutations was associated with higher drug MICs compared to those seen with either factor alone (
P
= 0.003 and
P
= 0.02, respectively). In conclusion, ceftazidime-avibactam displays activity against genetically diverse KPC-Kp strains. Strains with higher-level drug MICs provide a reason for caution. Judicious use of ceftazidime-avibactam alone or in combination with other agents will be important to prevent the emergence of resistance.
Influence of the
yjiL-mdtM
Gene Cluster on the Antibacterial Activity of Proline-Rich Antimicrobial Peptides Overcoming Escherichia coli Resistance Induced by the Missing SbmA Transporter System
Authors: Krizsan Andor , Knappe Daniel , Hoffmann Ralf 
Published: July 2015

ABSTRACT

In view of increasing health threats from multiresistant pathogens, antimicrobial peptides (AMPs) and, specifically, proline-rich AMPs (PrAMPs) have been investigated in animal models. PrAMPs enter bacteria via the ABC transporter SbmA and inhibit intracellular targets. We used phage transduction (Tn
10
insertion) to screen by random mutagenesis for alternative uptake mechanisms for analogs of apidaecin 1b, a honeybee-derived PrAMP. All 24 apidaecin-resistant mutants had the Tn
10
insertion in the
sbmA
gene. These
sbmA
::Tn
10
insertion mutants and the
Escherichia coli
BW25113 Δ
sbmA
(JW0368) strain were still susceptible to the bactenecin PrAMP Bac7(1-35) and oncocin PrAMPs Onc18 and Onc112, as well as to Chex1-Arg20, despite significantly reduced internalizations. In a second round of random mutagenesis, the remaining susceptibility was linked to the
yjiL-mdtM
gene cluster.
E. coli
BW25113 and its Δ
yjiL
null mutant (JW5785) were equally susceptible to all PrAMPs tested, whereas the BW25113 Δ
mdtM
mutant was less susceptible to oncocins. The JW0368
yjiL
::Tn
10
transposon mutant (BS2) was resistant to all short PrAMPs and susceptible only to full-length Bac7 and A3-APO. Interestingly, PrAMPs appear to enter bacteria via MdtM, a multidrug resistance transporter (drug/H
+
antiporter) of the major facilitator superfamily (MFS) that can efflux antibiotics, biocides, and bile salts. In conclusion, PrAMPs enter bacteria via ABC and MFS transporters that efflux antibiotics and cytotoxic compounds from the cytoplasm to the periplasm.
Reversible Conformational Change in the Plasmodium falciparum Circumsporozoite Protein Masks Its Adhesion Domains
Authors: Herrera Raul , Anderson Charles , Kumar Krishan , Molina-Cruz Alvaro , Nguyen Vu , Burkhardt Martin , Reiter Karine , Shimp Richard , Howard Randall F. , Srinivasan Prakash , Nold Michael J. , Ragheb Daniel , Shi Lirong , DeCotiis Mark , Aebig Joan , Lambert Lynn , Rausch Kelly M. , Muratova Olga , Jin Albert , Reed Steven G. , Sinnis Photini , Barillas-Mury Carolina , Duffy Patrick E. , MacDonald Nicholas J. , Narum David L. 
Published: July 2015

ABSTRACT

The extended rod-like
Plasmodium falciparum
circumsporozoite protein (CSP) is comprised of three primary domains: a charged N terminus that binds heparan sulfate proteoglycans, a central NANP repeat domain, and a C terminus containing a thrombospondin-like type I repeat (TSR) domain. Only the last two domains are incorporated in RTS,S, the leading malaria vaccine in phase 3 trials that, to date, protects about 50% of vaccinated children against clinical disease. A seroepidemiological study indicated that the N-terminal domain might improve the efficacy of a new CSP vaccine. Using a panel of CSP-specific monoclonal antibodies, well-characterized recombinant CSPs, label-free quantitative proteomics, and
in vitro
inhibition of sporozoite invasion, we show that native CSP is N-terminally processed in the mosquito host and undergoes a reversible conformational change to mask some epitopes in the N- and C-terminal domains until the sporozoite interacts with the liver hepatocyte. Our findings show the importance of understanding processing and the biophysical change in conformation, possibly due to a mechanical or molecular signal, and may aid in the development of a new CSP vaccine.
The Global Transcription Factor Lrp Controls Virulence Modulation in Xenorhabdus nematophila
Authors: Hussa Elizabeth A. , Casanova-Torres Ángel M. , Goodrich-Blair Heidi 
Published: July 2015

ABSTRACT

The bacterium
Xenorhabdus nematophila
engages in phenotypic variation with respect to pathogenicity against insect larvae, yielding both virulent and attenuated subpopulations of cells from an isogenic culture. The global regulatory protein Lrp is necessary for
X. nematophila
virulence and immunosuppression in insects, as well as colonization of the mutualistic host nematode
Steinernema carpocapsae
, and mediates expression of numerous genes implicated in each of these phenotypes. Given the central role of Lrp in
X. nematophila
host associations, as well as its involvement in regulating phenotypic variation pathways in other bacteria, we assessed its function in virulence modulation. We discovered that expression of
lrp
varies within an isogenic population, in a manner that correlates with modulation of virulence. Unexpectedly, although Lrp is necessary for optimal virulence and immunosuppression, cells expressing high levels of
lrp
were attenuated in these processes relative to those with low to intermediate
lrp
expression. Furthermore, fixed expression of
lrp
at high and low levels resulted in attenuated and normal virulence and immunosuppression, respectively, and eliminated population variability of these phenotypes. These data suggest that fluctuating
lrp
expression levels are sufficient to drive phenotypic variation in
X. nematophila
.

IMPORTANCE
Many bacteria use cell-to-cell phenotypic variation, characterized by distinct phenotypic subpopulations within an isogenic population, to cope with environmental change. Pathogenic bacteria utilize this strategy to vary antigen or virulence factor expression. Our work establishes that the global transcription factor Lrp regulates phenotypic variation in the insect pathogen
Xenorhabdus nematophila
, leading to attenuation of virulence and immunosuppression in insect hosts. Unexpectedly, we found an inverse correlation between Lrp expression levels and virulence: high levels of expression of Lrp-dependent putative virulence genes are detrimental for virulence but may have an adaptive advantage in other aspects of the life cycle. Investigation of
X. nematophila
phenotypic variation facilitates dissection of this phenomenon in the context of a naturally occurring symbiosis.
CodY Regulates SigD Levels and Activity by Binding to Three Sites in the
fla
/
che
Operon
Authors: Ababneh Qutaiba O. , Herman Jennifer K. 
Published: July 2015

ABSTRACT

Exponentially growing cultures of
Bacillus subtilis
(PY79) are composed primarily of nonmotile, chained cells. The alternative sigma factor, SigD, promotes the phenotypic switch from nonmotile, chained cells to unchained, motile cells. In the present work, we investigated the role of the GTP-sensing protein CodY in the regulation of SigD. Deletion of
codY
resulted in a significant increase in SigD accumulation and activity and shifted the proportion of unchained cells up from ∼15% to ∼75%, suggesting that CodY is an important regulator of SigD. CodY was previously shown to bind to the P

D3

and P

fla
/
che

promoters located upstream of the first gene in the
sigD
-containing
fla
/
che
operon. Using electrophoretic mobility shift assays, we found that CodY also binds to two other previously uncharacterized sites within the
fla
/
che
operon. Mutations in any one of the three binding sites resulted in SigD levels similar to those seen with the Δ
codY
mutant, suggesting that each site is sufficient to tip cells toward a maximal level of CodY-dependent SigD accumulation. However, mutations in all three sites were required to phenocopy the Δ
codY
mutant's reduced level of cell chaining, consistent with the idea that CodY binding in the
fla
/
che
operon is also important for posttranslational control of SigD activity.

IMPORTANCE
One way that bacteria adapt quickly and efficiently to changes in environmental quality is to employ global transcriptional regulators capable of responding allosterically to key cellular metabolites. In this study, we found that the conserved GTP-sensing protein CodY directly regulates cell motility and chaining in
B. subtilis
by controlling expression and activity of SigD. Our results suggest that
B. subtilis
becomes poised for cell dispersal as intracellular GTP levels are depleted.
Age correction in monitoring audiometry: method to update OSHA age-correction tables to include older workers
Authors: Dobie Robert A , Wojcik Nancy C 
Published: July 2015

ObjectivesThe US Occupational Safety and Health Administration (OSHA) Noise Standard provides the option for employers to apply age corrections to employee audiograms to consider the contribution of ageing when determining whether a standard threshold shift has occurred. Current OSHA age-correction tables are based on 40-year-old data, with small samples and an upper age limit of 60 years. By comparison, recent data (1999–2006) show that hearing thresholds in the US population have improved. Because hearing thresholds have improved, and because older people are increasingly represented in noisy occupations, the OSHA tables no longer represent the current US workforce. This paper presents 2 options for updating the age-correction tables and extending values to age 75 years using recent population-based hearing survey data from the US National Health and Nutrition Examination Survey (NHANES). Both options provide scientifically derived age-correction values that can be easily adopted by OSHA to expand their regulatory guidance to include older workers.MethodsRegression analysis was used to derive new age-correction values using audiometric data from the 1999–2006 US NHANES. Using the NHANES median, better-ear thresholds fit to simple polynomial equations, new age-correction values were generated for both men and women for ages 20–75 years.ResultsThe new age-correction values are presented as 2 options. The preferred option is to replace the current OSHA tables with the values derived from the NHANES median better-ear thresholds for ages 20–75 years. The alternative option is to retain the current OSHA age-correction values up to age 60 years and use the NHANES-based values for ages 61–75 years.ConclusionsRecent NHANES data offer a simple solution to the need for updated, population-based, age-correction tables for OSHA. The options presented here provide scientifically valid and relevant age-correction values which can be easily adopted by OSHA to expand their regulatory guidance to include older workers.
The inactive–active phase transition in the noisy additive (exclusive-or) probabilistic cellular automaton
Authors: Mendonça J. Ricardo G. 
Published: July 2015

We investigate the inactive–active phase transition in an array of additive (exclusive-or) cellular automata (CA) under noise. The model is closely related with the Domany-Kinzel (DK) probabilistic cellular automaton (PCA), for which there are rigorous as well as numerical estimates on the transition probabilities. Here, we characterize the critical behavior of the noisy additive cellular automaton by mean field analysis and finite-size scaling and show that its phase transition belongs to the directed percolation universality class of critical behavior. As a by-product of our analysis, we argue that the critical behavior of the noisy elementary CA 90 and 102 (in Wolfram’s enumeration scheme) must be the same. We also perform an empirical investigation of the mean field equations to assess their quality and find that away from the critical point (but not necessarily very far away) the mean field approximations provide a reasonably good description of the dynamics of the PCA.
Automated Generation of Counterterrorism Policies Using Multiexpert Input
Authors: Sawant Anshul , Dickerson John P. , Hajiaghayi Mohammad T. , Subrahmanian V. S. 
Published: July 2015

The use of game theory to model conflict has been studied by several researchers, spearheaded by Schelling. Most of these efforts assume a single payoff matrix that captures players’ utilities under different assumptions about what the players will do. Our experience in counterterrorism applications is that experts disagree on these payoffs. We leverage Shapley’s notion of vector equilibria, which formulates games where there are multiple payoff matrices, but note that they are very hard to compute in practice. To effectively enumerate large numbers of equilibria with payoffs provided by multiple experts, we propose a novel combination of vector payoffs and well-supported ϵ-approximate equilibria. We develop bounds related to computation of these equilibria for some special cases and give a quasipolynomial time approximation scheme (QPTAS) for the general case when the number of players is small (which is true in many real-world applications). Leveraging this QPTAS, we give efficient algorithms to find such equilibria and experimental results showing that they work well on simulated data.

We then built a policy recommendation engine based on vector equilibria, called
PREVE
. We use PREVE to model the terrorist group Lashkar-e-Taiba (LeT), responsible for the 2008 Mumbai attacks, as a five-player game. Specifically, we apply it to three payoff matrices provided by experts in India--Pakistan relations, analyze the equilibria generated by PREVE, and suggest counterterrorism policies that may reduce attacks by LeT. We briefly discuss these results and identify their strengths and weaknesses from a policy point of view.
Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer
Authors: Tewari Krishnansu S. , Eskander Ramez N. , Monk Bradley J. 
Published: July 2015

Abstract
The FDA approval of the PARP inhibitor olaparib for fourth-line therapy of germline BRCA1/2-mutated ovarian cancer represents the first registered indication for this class of drugs in any disease. PARP is a family of proteins involved in the repair of single-strand DNA breaks. High-grade serous ovarian carcinomas with BRCA deficiencies may be particularly vulnerable to both direct and indirect effects of PARP inhibition. This phenotype frequently arises as a consequence of defects in the repair of damaged DNA, rendering cancer cells susceptible to DNA-damaging platinum compounds and targeted therapies affecting homologous recombination repair (HRR). When cells already deficient in HRR are exposed to PARP inhibitors, apoptosis occurs by way of synthetic lethality. In this review, we trace the clinical development of olaparib for women with recurrent epithelial ovarian carcinoma harboring germline BRCA mutations, a biomarker for HRR deficiency present in 15% to 20% of cases. Clinical trials highlighted include not only those pivotal studies that have led to regulatory approval in the United States and in Europe, but also those in which olaparib was studied in novel combinations, including chemotherapy and antiangiogenesis agents. Clin Cancer Res; 21(17); 3829–35. ©2015 AACR.