bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger
Authors: Römling Ute , Galperin Michael Y. , Gomelsky Mark 
Published: March 2013

SUMMARYTwenty-five years have passed since the discovery of cyclic dimeric (3′→5′) GMP (cyclic di-GMP or c-di-GMP). From the relative obscurity of an allosteric activator of a bacterial cellulose synthase, c-di-GMP has emerged as one of the most common and important bacterial second messengers. Cyclic di-GMP has been shown to regulate biofilm formation, motility, virulence, the cell cycle, differentiation, and other processes. Most c-di-GMP-dependent signaling pathways control the ability of bacteria to interact with abiotic surfaces or with other bacterial and eukaryotic cells. Cyclic di-GMP plays key roles in lifestyle changes of many bacteria, including transition from the motile to the sessile state, which aids in the establishment of multicellular biofilm communities, and from the virulent state in acute infections to the less virulent but more resilient state characteristic of chronic infectious diseases. From a practical standpoint, modulating c-di-GMP signaling pathways in bacteria could represent a new way of controlling formation and dispersal of biofilms in medical and industrial settings. Cyclic di-GMP participates in interkingdom signaling. It is recognized by mammalian immune systems as a uniquely bacterial molecule and therefore is considered a promising vaccine adjuvant. The purpose of this review is not to overview the whole body of data in the burgeoning field of c-di-GMP-dependent signaling. Instead, we provide a historic perspective on the development of the field, emphasize common trends, and illustrate them with the best available examples. We also identify unresolved questions and highlight new directions in c-di-GMP research that will give us a deeper understanding of this truly universal bacterial second messenger.
Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense
Authors: Vasu Kommireddy , Nagaraja Valakunja 
Published: March 2013

SUMMARY
Restriction-modification (R-M) systems are ubiquitous and are often considered primitive immune systems in bacteria. Their diversity and prevalence across the prokaryotic kingdom are an indication of their success as a defense mechanism against invading genomes. However, their cellular defense function does not adequately explain the basis for their immaculate specificity in sequence recognition and nonuniform distribution, ranging from none to too many, in diverse species. The present review deals with new developments which provide insights into the roles of these enzymes in other aspects of cellular function. In this review, emphasis is placed on novel hypotheses and various findings that have not yet been dealt with in a critical review. Emerging studies indicate their role in various cellular processes other than host defense, virulence, and even controlling the rate of evolution of the organism. We also discuss how R-M systems could have successfully evolved and be involved in additional cellular portfolios, thereby increasing the relative fitness of their hosts in the population.
Exploiting Quorum Sensing To Confuse Bacterial Pathogens
Authors: LaSarre Breah , Federle Michael J. 
Published: March 2013

SUMMARY
Cell-cell communication, or quorum sensing, is a widespread phenomenon in bacteria that is used to coordinate gene expression among local populations. Its use by bacterial pathogens to regulate genes that promote invasion, defense, and spread has been particularly well documented. With the ongoing emergence of antibiotic-resistant pathogens, there is a current need for development of alternative therapeutic strategies. An antivirulence approach by which quorum sensing is impeded has caught on as a viable means to manipulate bacterial processes, especially pathogenic traits that are harmful to human and animal health and agricultural productivity. The identification and development of chemical compounds and enzymes that facilitate quorum-sensing inhibition (QSI) by targeting signaling molecules, signal biogenesis, or signal detection are reviewed here. Overall, the evidence suggests that QSI therapy may be efficacious against some, but not necessarily all, bacterial pathogens, and several failures and ongoing concerns that may steer future studies in productive directions are discussed. Nevertheless, various QSI successes have rightfully perpetuated excitement surrounding new potential therapies, and this review highlights promising QSI leads in disrupting pathogenesis in both plants and animals.
Molecular Regulation of Antibiotic Biosynthesis in Streptomyces
Authors: Liu Gang , Chater Keith F. , Chandra Govind , Niu Guoqing , Tan Huarong 
Published: March 2013

SUMMARYStreptomycetes are the most abundant source of antibiotics. Typically, each species produces several antibiotics, with the profile being species specific.Streptomyces coelicolor, the model species, produces at least five different antibiotics. We review the regulation of antibiotic biosynthesis inS. coelicolorand other, nonmodel streptomycetes in the light of recent studies. The biosynthesis of each antibiotic is specified by a large gene cluster, usually including regulatory genes (cluster-situated regulators [CSRs]). These are the main point of connection with a plethora of generally conserved regulatory systems that monitor the organism's physiology, developmental state, population density, and environment to determine the onset and level of production of each antibiotic. Some CSRs may also be sensitive to the levels of different kinds of ligands, including products of the pathway itself, products of other antibiotic pathways in the same organism, and specialized regulatory small molecules such as gamma-butyrolactones. These interactions can result in self-reinforcing feed-forward circuitry and complex cross talk between pathways. The physiological signals and regulatory mechanisms may be of practical importance for the activation of the many cryptic secondary metabolic gene cluster pathways revealed by recent sequencing of numerousStreptomycesgenomes.
Ocular Tropism of Respiratory Viruses
Authors: Belser Jessica A. , Rota Paul A. , Tumpey Terrence M. 
Published: March 2013

SUMMARYRespiratory viruses (including adenovirus, influenza virus, respiratory syncytial virus, coronavirus, and rhinovirus) cause a broad spectrum of disease in humans, ranging from mild influenza-like symptoms to acute respiratory failure. While species D adenoviruses and subtype H7 influenza viruses are known to possess an ocular tropism, documented human ocular disease has been reported following infection with all principal respiratory viruses. In this review, we describe the anatomical proximity and cellular receptor distribution between ocular and respiratory tissues. All major respiratory viruses and their association with human ocular disease are discussed. Research utilizingin vitroandin vivomodels to study the ability of respiratory viruses to use the eye as a portal of entry as well as a primary site of virus replication is highlighted. Identification of shared receptor-binding preferences, host responses, and laboratory modeling protocols among these viruses provides a needed bridge between clinical and laboratory studies of virus tropism.
Physical exercise and executive functions in preadolescent children, adolescents and young adults: a meta-analysis
Authors: Verburgh Lot , Königs Marsh , Scherder Erik J A , Oosterlaan Jaap 
Published: March 2013

PurposeThe goal of this meta-analysis was to aggregate available empirical studies on the effects of physical exercise on executive functions in preadolescent children (6–12 years of age), adolescents (13–17 years of age) and young adults (18–35 years of age).MethodThe electronic databases PubMed, EMBASE and SPORTDiscus were searched for relevant studies reporting on the effects of physical exercise on executive functions. Nineteen studies were selected.ResultsThere was a significant overall effect ofacutephysical exercise on executive functions (d=0.52, 95% CI 0.29 to 0.76, p<0.001). There were no significant differences between the three age groups (Q (2)=0.13, p=0.94). Furthermore, no significant overall effect ofchronicphysical exercise (d=0.14, 95%CI −0.04 to 0.32, p=0.19) on executive functions (Q (1)=5.08, p<0.05) was found. Meta-analytic effect sizes were calculated for the effects of acute physical exercise on the domain's inhibition/interference control (d=0.46, 95% CI 0.33 to 0.60, p<0.001) and working memory (d=0.05, 95% CI  −0.51 to 0.61, p=0.86) as well as for the effects ofchronicphysical exercise on planning (d=0.16, 95% CI 0.18 to 0.89, p=0.18).ConclusionsResults suggest thatacutephysical exercise enhances executive functioning. The number of studies onchronicphysical exercise is limited and it should be investigated whetherchronicphysical exercise shows effects on executive functions comparable toacutephysical exercise. This is highly relevant in preadolescent children and adolescents, given the importance of well-developed executive functions for daily life functioning and the current increase in sedentary behaviour in these age groups.
A novel model-based meta-analysis to indirectly estimate the comparative efficacy of two medications: an example using DPP-4 inhibitors, sitagliptin and linagliptin, in treatment of type 2 diabetes mellitus
Authors: Gross Jorge Luiz , Rogers James , Polhamus Daniel , Gillespie William , Friedrich Christian , Gong Yan , Monz Brigitta Ursula , Patel Sanjay , Staab Alexander , Retlich Silke 
Published: March 2013

ObjectivesTo develop a longitudinal statistical model to indirectly estimate the comparative efficacies of two drugs, using model-based meta-analysis (MBMA). Comparison of two oral dipeptidyl peptidase (DPP)-4 inhibitors, sitagliptin and linagliptin, for type 2 diabetes mellitus (T2DM) treatment was used as an example.DesignSystematic review with MBMA.Data sourcesMEDLINE, EMBASE,http://www.ClinicalTrials.gov, Cochrane review of DPP-4 inhibitors for T2DM, sitagliptin trials on Food and Drug Administration website to December 2011 and linagliptin data from the manufacturer.Eligibility criteria for selecting studiesDouble-blind, randomised controlled clinical trials, ≥12 weeks’ duration, that analysed sitagliptin or linagliptin efficacies as changes in glycated haemoglobin (HbA1c) levels, in adults with T2DM and HbA1c >7%, irrespective of background medication.Model development and applicationA Bayesian model was fitted (Markov Chain Monte Carlo method). The final model described HbA1c levels as function of time, dose, baseline HbA1c, washout status/duration and ethnicity. Other covariates showed no major impact on model parameters and were not included. For the indirect comparison, a population of 1000 patients was simulated from the model with a racial composition reflecting the average racial distribution of the linagliptin trials, and baseline HbA1c of 8%.ResultsThe model was developed using longitudinal data from 11 234 patients (10 linagliptin, 15 sitagliptin trials), and assessed by internal evaluation techniques, demonstrating that the model adequately described the observations. Simulations showed both linagliptin 5 mg and sitagliptin 100 mg reduced HbA1c by 0.81% (placebo-adjusted) at week 24. Credible intervals for participants without washout were −0.88 to −0.75 (linagliptin) and −0.89 to −0.73 (sitagliptin), and for those with washout, −0.91 to −0.76 (linagliptin) and −0.91 to −0.75 (sitagliptin).ConclusionsThis study demonstrates the use of longitudinal MBMA in the field of diabetes treatment. Based on an example evaluating HbA1c reduction with linagliptin versus sitagliptin, the model used seems a valid approach for indirect drug comparisons.
Addressing challenges in 4 F and 5 F arterial access for neurointerventional procedures in infants and young children
Authors: Gross Bradley A , Orbach Darren B 
Published: March 2013

BackgroundAmong the technical challenges involved in safely performing neuroendovascular procedures in infants are limitations on the size of femoral arterial access catheters. Restricting groin access to 4 F and 5 F systems constrains the range of procedures that can potentially be performed.Methods and ResultsWe present here a consecutive series of transfemoral angiographic procedures in children with no permanent and one transient case of groin morbidity related to femoral access. We illustrate two strategies for using 4 F and 5 F systems for interventions in a manner that enables such techniques as balloon assisted coil embolization and the deployment of triaxial catheter systems to be used.ConclusionsExtremely low groin morbidity is achievable using rigorous parameters around femoral catheterization in children. With creative approaches to working within the limitations of the access vessel size, complex endovascular neurointerventions are possible, even in the youngest infants.
Predictive value of flat-panel CT for haemorrhagic transformations in patients with acute stroke treated with thrombectomy
Authors: Rouchaud Aymeric , Pistocchi Silvia , Blanc Raphaël , Engrand Nicolas , Bartolini Bruno , Piotin Michel 
Published: March 2013

IntroductionHaemorrhagic transformations are pejorative for patients with acute ischaemic stroke (AIS). We estimated flat-panel CT performances to detect brain parenchymal hyperdense lesions immediately after mechanical thrombectomy directly on the angiography table in patients with AIS, and its ability to predict haemorrhagic transformation. We also evaluated an easy-reading protocol for post-procedure flat-panel CT evaluation by clinicians to enable them to determine the potential risk of haemorrhage.MethodsTwo neuroradiologists retrospectively reviewed post-procedural flat-panel CT and 24 h follow-up imaging. We evaluated hyperdense lesions on flat-panel CT to predict the occurrence of haemorrhagic transformation within 24 h detected with conventional imaging.ResultsOf 63 patients, 60.3% presented post-procedural parenchymal hyperdensity and 54.0% had haemorrhagic transformation. Significantly more patients with hyperdense lesions on post-thrombectomy flat-panel CT presented haemorrhagic transformation (84.2% vs 8.0%; p<0.0001). No significant haemorrhagic transformations were detected for patients without parenchymal hyperdensity. Sensitivity and specificity of hyperdense lesions on flat-panel CT for the prediction of haemorrhagic transformation were 94.1% (80.3–99.3%) and 79.3% (60.3–92.0%), respectively. The positive and negative predictive values for the occurrence of haemorrhage were 84.2% (68.8–94.0%) and 92.0% (74.0–99.0%), respectively. For significant parenchymal haemorrhage type 2, sensitivity and negative predictive values were 100%. We observed good homogeneity between the different readers. Hyperdensity on post-procedural flat-panel CT was associated with a tendency for higher risk of death and lower risk of good clinical outcome.ConclusionsFlat-panel CT appears to be a good tool to detect brain parenchymal hyperdensities after mechanical thrombectomy in patients with AIS and to predict haemorrhagic transformation.
Angiopoietin-2: An Attractive Target for Improved Antiangiogenic Tumor Therapy
Authors: Gerald Damien , Chintharlapalli Sudhakar , Augustin Hellmut G. , Benjamin Laura E. 
Published: March 2013

Abstract
Anti-VEGF pathway therapies primarily target immature blood vessels in tumors. However, emerging approaches to combine with targeted therapies impacting the later stages of remodeling and vessel maturation are expected to improve clinical efficacy by expanding the target vessel population. The angiopoietin/Tie ligand/receptor system is a prototypic regulator of vessel remodeling and maturation. Angiopoietin-2 (Ang2) appears to be a particularly attractive therapeutic target. In fact, the experimental proof-of-concept showing improved efficacy when VEGF and Ang2-targeting therapies are combined has been solidly established in preclinical models, and several Ang2-targeting drugs are in clinical trials. However, rational development of these second-generation combination therapies is hampered by a limited understanding of the biological complexity that is generated from agonistic and antagonistic Ang/Tie signaling. This review discusses recent mechanistic advances in angiopoietin signaling, particularly in light of the recent study published on REGN910 and summarizes the status quo of Ang2-targeting therapies. In light of the clarified partial agonist function of Ang2, we propose that clarity on the expression profile of the angiopoietin ligands and Tie1 and Tie2 receptors in subsets of cancer vessels and cancer cells will provide clearer hypotheses for more focused rational clinical trials to exploit this seminal pathway and improve current antiangiogenic therapies. Cancer Res; 73(6); 1649–57. ©2013 AACR.
Targeting CXCR2 Enhances Chemotherapeutic Response, Inhibits Mammary Tumor Growth, Angiogenesis, and Lung Metastasis
Authors: Sharma Bhawna , Nawandar Dhananjay M. , Nannuru Kalyan C. , Varney Michelle L. , Singh Rakesh K. 
Published: March 2013

AbstractBreast cancer is one of the leading causes of cancer deaths among females. Many challenges exist in the current management of advanced stage breast cancer as there are fewer recognized therapeutic strategies, often because of therapy resistance. How breast cancer cells evade chemotherapy and the underlying mechanism remains unclear. We and others have observed that malignant cells that survive initial chemo- and radiation therapy express higher levels of CXCR2 ligands, which may provide a survival benefit leading to therapy resistance. In this report, we test the hypothesis that CXCR2-dependent signaling in malignant cells may be critical for chemotherapy resistance and targeting this signaling axis may enhance the antitumor and antimetastatic activity of chemotherapeutic drugs and limit their toxicity. We used Cl66-wt, 4T1-wt, Cl66sh-CXCR2, and 4T1sh-CXCR2 cells expressing differential levels of the CXCR2 receptor to evaluate the role of targeting CXCR2 on chemotherapeutic responses. Knockdown of CXCR2 enhances paclitaxel and doxorubicin-mediated toxicity at suboptimal doses. Moreover, we observed an increase in the expression of CXCL1, a CXCR2 ligand in paclitaxel and doxorubicin-treated mammary tumor cells, which were inhibited following CXCR2 knockdown. Knockdown of CXCR2 enhanced antitumor activity of paclitaxel in an in vivo mammary tumor model. We observed significant inhibition of spontaneous lung metastases in animals bearing CXCR2 knockdown tumors and treated with paclitaxel as compared with the control group. Our data suggest the novel role of CXCR2 and its ligands in maintaining chemotherapy resistance and provide evidence that targeting CXCR2 signaling in an adjuvant setting will help circumvent chemotherapy resistance. Mol Cancer Ther; 12(5); 799–808. ©2013 AACR.
Both NF-κB and c-Jun/AP-1 involved in anti-β2GPI/β2GPI-induced tissue factor expression in monocytes
Authors: Xia Longfei , Hu Lichao , Xie Hongxiang , Wang Ting , Xu Ya , Liu Jingjing , Zhang Xiaolei , Yan Jinchuan , Zhou Hong 
Published: March 2013

SummaryOur previous data has demonstrated that Toll-like receptor 4 (TLR4) and its signalling pathway can contribute to anti-β2-glycoprotein I/β2-glycoprotein I (anti-β2GPI/β2GPI) -induced tissue factor (TF) expression in human blood monocytes and acute monocytic leukaemia cell line THP-1. However, its downstream nuclear transcription factors have not been well explored. In the current study, we further investigated whether nuclear factor kappa B (NF-κB) and activator protein (AP-1) were activated and their roles in anti-β2GPI/β2GPI complex stimulating TF expression. The results showed that treatment of the cells with anti-β2GPI (10 µg/ml)/β2GPI (100 mg/ml) complex could markedly increase the levels of phosphorylated NF-κB (p-NF-κB p65) and c-Jun/AP-1 (p-c-Jun), as well as TF expression. Both NF-κB inhibitor PDTC (20 µM) and AP-1 inhibitor curcumin (25 mM) could attenuate TF expression induced by anti-β2GPI/β2GPI or APS-IgG/β2GPI complex. Combination of any two inhibitors of MAPKs (SB203580/U0126 or SB203580/SP600125 or U0126/SP600125) could decrease activation of NF-κB. SB203580/SP600125 or U0126/SP600125, but not SB203580/U0126, could reduce the phosphorylation of c-Jun/AP-1. Neither NF-κB nor c-Jun/AP-1 activation caused by anti-β2GPI/β2GPI complex could be affected by TLR4 inhibitor TAK-242. In conclusion, our results indicate that both NF-κB and c-Jun/AP-1 can be activated and play important roles in the process of anti-β2GPI/β2GPI-induced TF expression in monocytes, thereby contributing to the pathological processes of antiphospholipid syndrome.
Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding
Authors: Paré Guillaume , Eriksson Niclas , Lehr Thorsten , Connolly Stuart , Eikelboom John , Ezekowitz Michael D. , Axelsson Tomas , Haertter Sebastian , Oldgren Jonas , Reilly Paul , Siegbahn Agneta , Syvanen Ann-Christine , Wadelius Claes , Wadelius Mia , Zimdahl-Gelling Heike , Yusuf Salim , Wallentin Lars 
Published: March 2013

Background—
Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in the prevention of stroke in atrial fibrillation patients compared with warfarin. We hypothesized that genetic variants could contribute to interindividual variability in blood concentrations of the active metabolite of dabigatran etexilate and influence the safety and efficacy of dabigatran.

Methods and Results—

We successfully conducted a genome-wide association study in 2944 Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) participants. The
CES1
single-nucleotide polymorphism rs2244613 was associated with trough concentrations, and the
ABCB1
single-nucleotide polymorphism rs4148738 and the
CES1
single-nucleotide polymorphism rs8192935 were associated with peak concentrations at genome-wide significance (
P
<9×10
−8
) with a gene-dose effect. Each minor allele of the
CES1
single-nucleotide polymorphism rs2244613 was associated with lower trough concentrations (15% decrease per allele; 95% confidence interval, 10–19;
P
=1.2×10
−8
) and a lower risk of any bleeding (odds ratio, 0.67; 95% confidence interval, 0.55–0.82;
P
=7×10
−5
) in dabigatran-treated participants, with a consistent but nonsignificant lower risk of major bleeding (odds ratio, 0.66; 95% confidence interval, 0.43–1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (
P
=0.002), with carriers having less bleeding with dabigatran than warfarin (hazard ratio, 0.59; 95% confidence interval, 0.46–0.76;
P
=5.2×10
−
5) in contrast to no difference in noncarriers (hazard ratio, 0.96; 95% confidence interval, 0.81–1.14;
P
=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events.

Conclusions—

Genome-wide association analysis identified that carriage of the
CES1
rs2244613 minor allele occurred in 32.8% of patients in RE-LY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00262600.