Deciphering interplay between Salmonella invasion effectors

Bacterial pathogens have evolved a specialized type III secretion system (T3SS) to translocate virulence effector proteins directly into eukaryotic target cells. Salmonellae deploy effectors that trigger localized actin reorganization to force their own entry into non-phagocytic host cells. Six effectors (SipC, SipA, SopE/2, SopB, SptP) can individually manipulate actin dynamics at the plasma membrane, which acts as a ‘signaling hub’ during Salmonella invasion. The extent of crosstalk between these spatially coincident effectors remains unknown. Here we describe trans and cis binary entry effector interplay (BENEFIT) screens that systematically examine functional associations between effectors following their delivery into the host cell. The results reveal extensive ordered synergistic and antagonistic relationships and their relative potency, and illuminate an unexpectedly sophisticated signaling network evolved through longstanding pathogen–host interaction

CCAAT-enhancer-binding protein-beta expression in vivo is associated with muscle strength

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Declining muscle strength is a core feature of aging. Several mechanisms have been postulated, including CCAAT/enhancer-binding protein-beta (C/EBP-β)-triggered macrophage-mediated muscle fiber regeneration after micro-injury, evidenced in a mouse model. We aimed to identify in vivo circulating leukocyte gene expression changes associated with muscle strength in the human adult population. We undertook a genome-wide expression microarray screen, using peripheral blood RNA samples from InCHIANTI study participants (aged 30 and 104). Logged expression intensities were regressed with muscle strength using models adjusted for multiple confounders. Key results were validated by real-time PCR. The Short Physical Performance Battery (SPPB) score tested walk speed, chair stand, and balance. CEBPB expression levels were associated with muscle strength (β coefficient = 0.20560, P = 1.03*10(-6), false discovery rate q = 0.014). The estimated handgrip strength in 70-year-old men in the lowest CEBPB expression tertile was 35.2 kg compared with 41.2 kg in the top tertile. CEBPB expression was also associated with hip, knee, ankle, and shoulder strength and the SPPB score (P = 0.018). Near-study-wide associations were also noted for TGF-β3 (P = 3.4*10(-5) , q = 0.12) and CEBPD expression (P = 9.7*10(-5) , q = 0.18) but not for CEBPA expression. We report here a novel finding that raised CEBPB expression in circulating leukocyte-derived RNA samples in vivo is associated with greater muscle strength and better physical performance in humans. This association may be consistent with mouse model evidence of CEBPB-triggered muscle repair: if this mechanism is confirmed, it may provide a target for intervention to protect and enhance aging muscle

Changes in ponderal index and body mass index across childhood and their associations with fat mass and cardiovascular risk factors at age 15

Background: Little is known about whether associations between childhood adiposity and later adverse cardiovascular health outcomes are driven by tracking of overweight from childhood to adulthood and/or by vascular and metabolic changes from childhood overweight that persist into adulthood. Our objective is to characterise associations between trajectories of adiposity across childhood and a wide range of cardiovascular risk factors measured in adolescence, and explore the extent to which these are mediated by fat mass at age 15. Methods and Findings: Using data from the Avon Longitudinal Study of Parents and Children, we estimated individual trajectories of ponderal index (PI) from 0-2 years and BMI from 2-10 years using random-effects linear spline models (N = 4601). We explored associations between PI/BMI trajectories and DXA-determined total-body fat-mass and cardiovascular risk factors at 15 years (systolic and diastolic blood pressure, fasting LDL-and HDL-cholesterol, triglycerides, C-reactive protein, glucose, insulin) with and without adjustment for confounders. Changes in PI/BMI during all periods of infancy and childhood were associated with greater DXA-determined fat-mass at age 15. BMI changes in childhood, but not PI changes from 0-2 years, were associated with most cardiovascular risk factors in adolescence; associations tended to be strongest for BMI changes in later childhood (ages 8.5-10), and were largely mediated by fat mass at age 15. Conclusion: Changes in PI/BMI from 0-10 years were associated with greater fat-mass at age 15. Greater increases in BMI from age 8.5-10 years are most strongly associated with cardiovascular risk factors at age 15, with much of these associations mediated by fat-mass at this age. We found little evidence supporting previous reports that rapid PI changes in infancy are associated with future cardiovascular risk. This study suggests that associations between early overweight and subsequent adverse cardiovascular health are largely due to overweight children tending to remain overweight

Gene expression drives the evolution of dominance.

Dominance is a fundamental concept in molecular genetics and has implications for understanding patterns of genetic variation, evolution, and complex traits. However, despite its importance, the degree of dominance in natural populations is poorly quantified. Here, we leverage multiple mating systems in natural populations of Arabidopsis to co-estimate the distribution of fitness effects and dominance coefficients of new amino acid changing mutations. We find that more deleterious mutations are more likely to be recessive than less deleterious mutations. Further, this pattern holds across gene categories, but varies with the connectivity and expression patterns of genes. Our work argues that dominance arises as a consequence of the functional importance of genes and their optimal expression levels

Adjusting for multiple prognostic factors in the analysis of randomised trials

Background: When multiple prognostic factors are adjusted for in the analysis of a randomised trial, it is unclear (1) whether it is necessary to account for each of the strata, formed by all combinations of the prognostic factors (stratified analysis), when randomisation has been balanced within each stratum (stratified randomisation), or whether adjusting for the main effects alone will suffice, and (2) the best method of adjustment in terms of type I error rate and power, irrespective of the randomisation method. Methods: We used simulation to (1) determine if a stratified analysis is necessary after stratified randomisation, and (2) to compare different methods of adjustment in terms of power and type I error rate. We considered the following methods of analysis: adjusting for covariates in a regression model, adjusting for each stratum using either fixed or random effects, and Mantel-Haenszel or a stratified Cox model depending on outcome. Results: Stratified analysis is required after stratified randomisation to maintain correct type I error rates when (a) there are strong interactions between prognostic factors, and (b) there are approximately equal number of patients in each stratum. However, simulations based on real trial data found that type I error rates were unaffected by the method of analysis (stratified vs unstratified), indicating these conditions were not met in real datasets. Comparison of different analysis methods found that with small sample sizes and a binary or time-to-event outcome, most analysis methods lead to either inflated type I error rates or a reduction in power; the lone exception was a stratified analysis using random effects for strata, which gave nominal type I error rates and adequate power. Conclusions: It is unlikely that a stratified analysis is necessary after stratified randomisation except in extreme scenarios. Therefore, the method of analysis (accounting for the strata, or adjusting only for the covariates) will not generally need to depend on the method of randomisation used. Most methods of analysis work well with large sample sizes, however treating strata as random effects should be the analysis method of choice with binary or time-to-event outcomes and a small sample size

Spinning strings and integrable spin chains in the AdS/CFT correspondence

In this introductory review we discuss dynamical tests of the AdS_5 x S^5 string/N=4 super Yang-Mills duality. After a brief introduction to AdS/CFT we argue that semiclassical string energies yield information on the quantum spectrum of the string in the limit of large angular momenta on the S^5. The energies of the folded and circular spinning string solutions rotating on a S^3 within the S^5 are derived, which yield all loop predictions for the dual gauge theory scaling dimensions. These follow from the eigenvalues of the dilatation operator of N=4 super Yang-Mills in a minimal SU(2) subsector and we display its reformulation in terms of a Heisenberg s=1/2 spin chain along with the coordinate Bethe ansatz for its explicit diagonalization. In order to make contact to the spinning string energies we then study the thermodynamic limit of the one-loop gauge theory Bethe equations and demonstrate the matching with the folded and closed string result at this loop order. Finally the known gauge theory results at higher-loop orders are reviewed and the associated long-range spin chain Bethe ansatz is introduced, leading to an asymptotic all-loop conjecture for the gauge theory Bethe equations. This uncovers discrepancies at the three-loop order between gauge theory scaling dimensions and string theory energies and the implications of this are discussed. Along the way we comment on further developments and generalizations of the subject and point to the relevant literature.Comment: 40 pages, invited contribution to Living Reviews in Relativity. v2: improvements in the text and references adde

Genetic Polymorphisms of the TYMS Gene Are Not Associated with Congenital Cardiac Septal Defects in a Han Chinese Population

Background: Clinical research indicates that periconceptional administration of folic acid can reduce the occurrence of congenital cardiac septal defects (CCSDs). The vital roles of folate exhibits in three ways: the unique methyl donor for DNA expression regulation, the de novo biosynthesis of purine and pyrimidine for DNA construction, and the serum homocysteine removal. Thymidylate synthase (TYMS) is the solo catalysis enzyme for the de novo synthesis of dTMP, which is the essential precursor of DNA biosynthesis and repair process. To examine the role of TYMS in Congenital Cardiac Septal Defects (CCSDs) risk, we investigated whether genetic polymorphisms in the TYMS gene associated with the CCSDs in a Han Chinese population. Method: Polymorphisms in the noncoding region of TYMS were identified via direct sequencing in 32 unrelated individuals composed of half CCSDs and half control subjects. Nine SNPs and two insertion/deletion polymorphisms were genotyped from two independent case-control studies involving a total of 529 CCSDs patients and 876 healthy control participants. The associations were examined by both single polymorphism and haplotype tests using logistic regression. Result: We found that TYMS polymorphisms were not related to the altered CCSDs risk, and even to the changed risk of VSDs subgroup, when tested in both studied groups separately or in combination. In the haplotype analysis, there were no haplotypes significantly associated with risks for CCSDs either. Conclusion: Our results show no association between common genetic polymorphisms of the regulatory region of th

The risks and rewards of covariate adjustment in randomized trials: an assessment of 12 outcomes from 8 studies

Adjustment for prognostic covariates can lead to increased power in the analysis of randomized trials. However, adjusted analyses are not often performed in practice

Double-logs, Gribov-Lipatov reciprocity and wrapping

We study analytical properties of the five-loop anomalous dimension of twist-2 operators at negative even values of Lorentz spin. Following L. N. Lipatov and A. I. Onishchenko, we have found two possible generalizations of double-logarithmic equation, which allow to predict a lot of poles of anomalous dimension of twist-2 operators at all orders of perturbative theory from the known results. Second generalization is related with the reciprocity-respecting function, which is a single-logarithmic function in this case. We have found, that the knowledge of first orders of the reciprocity-respecting function gives all-loop predictions for the highest poles. Obtained predictions can be used for the reconstruction of a general form of the wrapping corrections for twist-2 operators.Comment: 17 pages, references adde

Six-Loop Anomalous Dimension of Twist-Three Operators in N=4 SYM

The result for the six-loop anomalous dimension of twist-three operators in the planar N=4 SYM theory is presented. The calculations were performed along the paper arXiv:0912.1624. This result provides a new data for testing the proposed spectral equations for planar AdS/CFT correspondence.Comment: 19 pages, typos corrected, details adde