Singularly Perturbed Monotone Systems and an Application to Double Phosphorylation Cycles

The theory of monotone dynamical systems has been found very useful in the modeling of some gene, protein, and signaling networks. In monotone systems, every net feedback loop is positive. On the other hand, negative feedback loops are important features of many systems, since they are required for adaptation and precision. This paper shows that, provided that these negative loops act at a comparatively fast time scale, the main dynamical property of (strongly) monotone systems, convergence to steady states, is still valid. An application is worked out to a double-phosphorylation ``futile cycle'' motif which plays a central role in eukaryotic cell signaling.Comment: 21 pages, 3 figures, corrected typos, references remove

Bs,d→ππ,πK,KKB_{s,d} \to \pi\pi,\pi K, KK: Status and Prospects

Several years ago, it was pointed out that the U-spin-related decays $B_d\to\pi^+\pi^-$, $B_s\to K^+K^-$ and $B_d\to\pi^\mp K^\pm$, $B_s\to \pi^\pm K^\mp$ offer interesting strategies for the extraction of the angle gamma of the unitarity triangle. Using the first results from the Tevatron on the $B_s$ decays and the B-factory data on $B_{u,d}$ modes, we compare the determinations of gamma from both strategies, study the sensitivity on U-spin-breaking effects, discuss the resolution of discrete ambiguities, predict observables that were not yet measured but will be accessible at LHCb, explore the extraction of the width difference $\Delta\Gamma_s$ from untagged $B_s\to K^+K^-$ rates, and address the impact of new physics. The data for the $B_d\to\pi^+\pi^-$, $B_s\to K^+K^-$ system favour the BaBar measurement of direct CP violation in $B_d\to\pi^+\pi^-$, which will be used in the numerical analysis, and result in a fortunate situation, yielding $\gamma=(66.6^{+4.3+4.0}_{-5.0-3.0})^\circ$, where the latter errors correspond to a generous estimate of U-spin-breaking effects. On the other hand, the $B_d\to\pi^\mp K^\pm$, $B_s\to \pi^\pm K^\mp$ analysis leaves us with $26^\circ\leq\gamma\leq70^\circ$, and points to a value of the $B_s\to \pi^\pm K^\mp$ branching ratio that is larger than the current Tevatron result. An important further step will be the measurement of mixing-induced CP violation in $B_s\to K^+K^-$, which will also allow us to extract the $B^0_s$--$\bar B^0_s$ mixing phase unambiguously with the help of $B_s\to J/\psi \phi$ at the LHC. Finally, the measurement of direct CP violation in $B_s\to K^+K^-$ will make the full exploitation of the physics potential of the $B_{s,d}\to \pi\pi, \pi K, KK$ modes possible.Comment: 28 pages, 10 figure

Screening for Syphilis Infection in Nonpregnant Adults and Adolescents: US Preventive Services Task Force Recommendation Statement

Clinical Review & Education US Preventive Services Task Force | RECOMMENDATION STATEMENT Screening for Syphilis Infection in Nonpregnant Adults and Adolescents US Preventive Services Task Force Recommendation Statement US Preventive Services Task Force (USPSTF) Editorial page 2281 IMPORTANCE In 2014, 19 999 cases of syphilis were reported in the United States. Left untreated, syphilis can progress to late-stage disease in about 15% of persons who are infected. Late-stage syphilis can lead to development of inflammatory lesions throughout the body, which can lead to cardiovascular or organ dysfunction. Syphilis infection also increases the risk for acquiring or transmitting HIV infection. OBJECTIVE To update the 2004 US Preventive Services Task Force (USPSTF) recommendation on screening for syphilis infection in nonpregnant adults. Screening for syphilis in pregnant women was updated in a separate recommendation statement in 2009 (A recommendation). EVIDENCE REVIEW The USPSTF reviewed the evidence on screening for syphilis infection in asymptomatic, nonpregnant adults and adolescents, including patients coinfected with other sexually transmitted infections (such as HIV). Author Audio Interview at jama.com Related article page 2328 and JAMA Patient Page page 2367 CME Quiz at jamanetworkcme.com and CME Questions page 2342 Related articles at jamadermatology.com, jamaneurology.com, jamapediatrics.com FINDINGS The USPSTF found convincing evidence that screening for syphilis infection in asymptomatic, nonpregnant persons at increased risk for infection provides substantial benefit. Accurate screening tests are available to identify syphilis infection in populations at increased risk. Effective treatment with antibiotics can prevent progression to late-stage disease, with small associated harms, providing an overall substantial health benefit. CONCLUSIONS AND RECOMMENDATION The USPSTF recommends screening for syphilis infection in persons who are at increased risk for infection. (A recommendation) Authors/Group Information: The USPSTF members are listed at the end of the article. JAMA. 2016;315(21):2321-2327. doi:10.1001/jama.2016.5824 Corresponding Author: Kirsten Bibbins-Domingo, PhD, MD, MAS ([email protected]). T he US Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without obvious related signs or symptoms. It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the bal- ance. The USPSTF does not consider the costs of providing a ser- vice in this assessment. The USPSTF recognizes that clinical decisions involve more con- siderations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clini- cal benefits and harms. Summary of Recommendation and Evidence The USPSTF recommends screening for syphilis infection in per- sons who are at increased risk for infection. (A recommendation) (Figure 1) jama.com See the Clinical Considerations section later in this article for in- formation on risk factors for infection. Rationale Importance The number of cases of primary and secondary syphilis have been in- creasing since 2000. In 2014, 19 999 cases (6.3 cases per 100 000 persons)ofprimaryandsecondarysyphiliswerereportedintheUnited States. 1 Left untreated, syphilis can progress to late-stage disease in approximately 15% of persons who are infected. 2 Consequences of late-stage syphilis include development of inflammatory lesions throughout the body (eg, aortitis, gummatous lesions, and osteitis), which can lead to cardiovascular or organ dysfunction. Syphilis in- fection of the central nervous system (neurosyphilis) can occur at any stage of disease and can result in blindness, paresis, tabes dor- salis, and dementia. Syphilis infection also increases the risk for ac- quiring or transmitting HIV infection. The USPSTF addresses screening for syphilis in pregnant women in a separate recommendation statement. 3 (Reprinted) JAMA June 7, 2016 Volume 315, Number 21 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/ by a University of California - Los Angeles User on 09/21/201

T-odd correlation in the K+ ->pi l nu gamma decays beyond Standard Model

The dependence of the T-odd correlation on the effective Lagrangian parameters in the $K^+ \to \pi l \nu \gamma, l=e, \mu$ decays is analyzed. It is shown that the introduced observable is perspective in a search for new physics in the vector and pseudovector sector of the Lagrangian. As for scalar and pseudoscalar sectors, the T-odd correlation studies will not allow one to improve current restrictions on parameters of models beyond SM.Comment: 18 pages, 1 figur

Probing exotic phenomena at the interface of nuclear and particle physics with the electric dipole moments of diamagnetic atoms: A unique window to hadronic and semi-leptonic CP violation

The current status of electric dipole moments of diamagnetic atoms which involves the synergy between atomic experiments and three different theoretical areas -- particle, nuclear and atomic is reviewed. Various models of particle physics that predict CP violation, which is necessary for the existence of such electric dipole moments, are presented. These include the standard model of particle physics and various extensions of it. Effective hadron level combined charge conjugation (C) and parity (P) symmetry violating interactions are derived taking into consideration different ways in which a nucleon interacts with other nucleons as well as with electrons. Nuclear structure calculations of the CP-odd nuclear Schiff moment are discussed using the shell model and other theoretical approaches. Results of the calculations of atomic electric dipole moments due to the interaction of the nuclear Schiff moment with the electrons and the P and time-reversal (T) symmetry violating tensor-pseudotensor electron-nucleus are elucidated using different relativistic many-body theories. The principles of the measurement of the electric dipole moments of diamagnetic atoms are outlined. Upper limits for the nuclear Schiff moment and tensor-pseudotensor coupling constant are obtained combining the results of atomic experiments and relativistic many-body theories. The coefficients for the different sources of CP violation have been estimated at the elementary particle level for all the diamagnetic atoms of current experimental interest and their implications for physics beyond the standard model is discussed. Possible improvements of the current results of the measurements as well as quantum chromodynamics, nuclear and atomic calculations are suggested.Comment: 46 pages, 19 tables and 16 figures. A review article accepted for EPJ

Cosmological Applications of Gravitational Lensing

The last decade has seen an enormous increase of activity in the field of gravitational lensing, mainly driven by improvements of observational capabilities. I will review the basics of gravitational lens theory, just enough to understand the rest of this contribution, and will then concentrate on several of the main applications in cosmology. Cluster lensing, and weak lensing, will constitute the main part of this review.Comment: 26 pages, including 2 figures (a third figure can be obtained from the author by request) gziped and uuencoded postscript file; to be published in Proceedings of the Laredo Advanced Summer School, Sept. 9

Biologics Delay Progression of Crohn's Disease, but Not Early Surgery, in Children

Background & Aims: Up to 30% of patients with Crohn's disease (CD) require surgery within the first 5 years from diagnosis. We investigated the recent risk of bowel surgery in an inception cohort of pediatric patients with CD and whether early use of biologics (tumor necrosis factor antagonists) alters later disease course. Methods: We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group registry on 1442 children (age, ó16 y) diagnosed with CD from January 2002 through December 2014. Data were collected at diagnosis, 30 days following diagnosis, and then quarterly and during hospitalizations for up to 12 years. Our primary aim was to determine the 10-year risk for surgery in children with CD. Our secondary aim was to determine whether early use of biologics (<3 mo of diagnosis) affected risk of disease progression. Results: The 10-year risk of first bowel surgery was 26%. The 5-year risk of bowel surgery did not change from 2002 through 2014, and remained between 13% and 14%. Most surgeries occurred within 3 years from diagnosis. The only predictor of surgery was disease behavior at diagnosis. CD with inflammatory behavior had the lowest risk of surgery compared to stricturing disease, penetrating disease, or both. We associated slowing of disease progression to stricturing or penetrating disease (but not surgery) with early use of biologics, but this effect only became evident after 5 years of disease. Our results indicate that biologics slow disease progression over time (hazard ratio, 0.85; 95% CI, 0.76?0.95). Conclusions: In an analysis of data from a registry of pediatric patients with CD, we found that among those with significant and progressing disease at or shortly after presentation, early surgery is difficult to prevent, even with early use of biologics. Early use of biologics (<3 mo of diagnosis) can delay later disease progression to stricturing and/or penetrating disease, but this affect could become evident only years after initial management decisions are made

A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data

Background: Rare variants have gathered increasing attention as a possible alternative source of missing heritability. Since next generation sequencing technology is not yet cost-effective for large-scale genomic studies, a widely used alternative approach is imputation. However, the imputation approach may be limited by the low accuracy of the imputed rare variants. To improve imputation accuracy of rare variants, various approaches have been suggested, including increasing the sample size of the reference panel, using sequencing data from study-specific samples (i.e., specific populations), and using local reference panels by genotyping or sequencing a subset of study samples. While these approaches mainly utilize reference panels, imputation accuracy of rare variants can also be increased by using exome chips containing rare variants. The exome chip contains 250 K rare variants selected from the discovered variants of about 12,000 sequenced samples. If exome chip data are available for previously genotyped samples, the combined approach using a genotype panel of merged data, including exome chips and SNP chips, should increase the imputation accuracy of rare variants. Results: In this study, we describe a combined imputation which uses both exome chip and SNP chip data simultaneously as a genotype panel. The effectiveness and performance of the combined approach was demonstrated using a reference panel of 848 samples constructed using exome sequencing data from the T2D-GENES consortium and 5,349 sample genotype panels consisting of an exome chip and SNP chip. As a result, the combined approach increased imputation quality up to 11 %, and genomic coverage for rare variants up to 117.7 % (MAF < 1 %), compared to imputation using the SNP chip alone. Also, we investigated the systematic effect of reference panels on imputation quality using five reference panels and three genotype panels. The best performing approach was the combination of the study specific reference panel and the genotype panel of combined data. Conclusions: Our study demonstrates that combined datasets, including SNP chips and exome chips, enhances both the imputation quality and genomic coverage of rare variants