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We present a measurement of the CP-violating parameter beta(J/psi phi)(s) using approximately 6500 B-s(0) -> J/psi phi decays reconstructed with the CDF II detector in a sample of p (p) over bar collisions at root s = 1.96 TeV corresponding to 5.2 fb(-1) integrated luminosity produced by the Tevatron collider at Fermilab. We find the CP-violating phase to be within the range beta(J/psi phi)(s) is an element of [0.02, 0.52] boolean OR [1.08, 1.55] at 68% confidence level where the coverage property of the quoted interval is guaranteed using a frequentist statistical analysis. This result is in agreement with the standard model expectation at the level of about one Gaussian standard deviation. We consider the inclusion of a potential S-wave contribution to the B-s(0) -> J/psi K+K- final state which is found to be negligible over the mass interval 1.009 < m(K+K-) < 1.028 GeV/c(2). Assuming the standard model prediction for the CP-violating phase beta(J/psi phi)(s), we find the B-s(0) decay width difference to be Delta Gamma(s) = 0.075 +/- 0.035(stat) +/- 0.006(syst) ps(-1). We also present the most precise measurements of the B-s(0) mean lifetime tau(B-s(0)) = 1.529 +/- 0.025(stat) +/- 0.012(syst) ps, the polarization fractions vertical bar A(0)(0)vertical bar(2) = 0.524 +/- 0.013(stat) +/- 0.015(syst) and vertical bar A(parallel to)(0)vertical bar(2) = 0.231 +/- 0.014(stat) +/- 0.015(syst), as well as the strong phase delta(perpendicular to) = 2.95 +/- 0.64(stat) +/- 0.07(syst) rad. In addition, we report an alternative Bayesian analysis that gives results consistent with the frequentist approach.

Medicine is rapidly applying exome and genome sequencing to the diagnosis and management of human disease. Somatic mosaicism, however, is not readily detectable by these means, and yet it accounts for a significant portion of undiagnosed disease. We present a rapid and sensitive method, the Continuous Distribution Function as applied to single nucleotide polymorphism (SNP) array data, to quantify somatic mosaic-ism throughout the genome. We also demonstrate application of the method to novel diseases and mechanisms. Published by Elsevier Inc.

Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.

The vast majority of bacteria present in environmental samples have never been cultured and therefore have not been exploited for the ability to produce useful biocatalysts or collections of biocatalysts generating interesting small molecules. Metagenomic libraries constructed using DNA extracted directly from natural bacterial communities offer access to the genetic information present in the genomes of these as yet uncultured bacteria. This review highlights recent efforts to recover both discrete enzymes and small molecules from metagenomic libraries.

COMMUNITY ENGAGEMENT IS INCREASINGLY becoming an integral part of research. "Community-engaged research" (CEnR) introduces new stakeholders as well as unique challenges to the protection of participants and the integrity of the research process. We a group of representatives of CTSA-funded institutions and others who share expertise in research ethics and CEnR have identified gaps in the literature regarding (1) ethical issues unique to CEnR; (2) the particular instructional needs of academic investigators, community research partners, and IRB members; and (3) best practices for teaching research ethics. This paper presents what we know, as well as what we still need to learn, in order to develop quality research ethics educational materials tailored to the full range of stakeholder groups in CEnR.

Objective: To evaluate the complication rate for adenotonsillectomy in children younger than 3 years, without a diagnosis of severe obstructive sleep apnea, to assess the necessity for postoperative inpatient admission. Design: Retrospective medical record review (January 1, 2003, through October 31, 2009). Setting: Tertiary care academic medical center. Patients: Retrospective medical record review of 105 patients younger than 3 years who underwent adenotonsillectomy performed by a single surgeon. Nineteen patients were excluded from our review because of incomplete medical records or severe underlying disease, leaving a total of 86 patients with medical records available for inclusion in our study. Patient medical records were deidentified and reviewed for age, sex, indications for surgery, intraoperative and perioperative interventions, and postoperative complications. One child with a diagnosis of severe obstructive sleep apnea was excluded from the study. Main Outcome Measures: Complications, including bleeding, dehydration requiring admission, and airway intervention, during the intraoperative or perioperative period were recorded. Results: The mean age of the study population was approximately 27.5 months (range, 13-35 months), with most children (76.5%) between 23 and 31 months of age. Among the patients whose records were reviewed, 80 (93.0%) did not experience any intraoperative or postoperative complications. Dehydration was the most common complication and was the cause of all documented readmissions (4.7%) in our patients who ranged in age from 14 to 30 months. Two patients had other complications, reactive airway disease (n = 1) and postoperative fever (n = 1), which were identified and treated in the post-anesthesia care unit, resulting in same-day discharge. No airway complications were noted in our study. Conclusions: Our study reveals a low complication rate in children younger than 3 years. The recommendations for mandatory admission for children younger than 3 years should be reexamined. Criteria for inpatient admission for children younger than 3 years should be based on preoperative and postoperative clinical evaluation of the patient and an evaluation of the family resources for adequately caring for young children at home in the postoperative period. These recommendations apply only to otherwise healthy children (American Society of Anesthesiologists classifications I and II) without a diagnosis of severe obstructive sleep apnea syndrome.

Fanconi anemia (FA) nuclear core complex is a multiprotein complex required for the functional integrity of the FA-BRCA pathway regulating DNA repair. This pathway is inactivated in FA, a devastating genetic disease, which leads to hematologic defects and cancer in patients. Here we report the isolation and characterization of a novel 20-kDa FANCA-associated protein (FAAP20). We show that FAAP20 is an integral component of the FA nuclear core complex. We identify a region on FANCA that physically interacts with FAAP20, and show that FANCA regulates stability of this protein. FAAP20 contains a conserved ubiquitin-binding zinc-finger domain (UBZ), and binds K-63-linked ubiquitin chains in vitro. The FAAP20-UBZ domain is not required for interaction with FANCA, but is required for DNA-damage-induced chromatin loading of FANCA and the functional integrity of the FA pathway. These findings reveal critical roles for FAAP20 in the FA-BRCA pathway of DNA damage repair and genome maintenance. (Blood. 2012; 119(14): 3285-3294)

Dendritic cells (DC) are specialized antigen-presenting cells, responsible for peripheral immune responses. Recently, resident brain dendritic cells (bDC) were identified and functionally characterized in the young adult Itgax (CD11c) EYFP+ transgenic mouse brain. In the present study, we describe changes in number, phenotype, and source of bDC in the aging mouse brain. Immunohistochemistry and fluorescent activated cell sorting (FACS) analysis revealed an age-related increase in bDC with a concomitant rise in the expression of immune activation markers MHCII, CD80, and CD86. Quantification of immunolabeled bDC in the cortex, corpus callosum, and cerebellum of the aged brain revealed a 2- to 5-fold increase. In contrast, either no change or a decrease in bDC was noted in regions of adult neurogenesis. Chimeras (wild type host/EYFP+ bone marrow) suggest that the increase of EYFP+ cells in the aging brain is in part due to an accumulation of peripherally derived cells. Collectively, the numerical and phenotypic changes in bDC indicate these cells may serve as an important immune component in the functional and anatomic alterations associated with aging. (C) 2012 Elsevier Inc. All rights reserved.

The formation of the National Center for Advancing Translational Sciences (NCATS) brings new promise for moving basic science discoveries to clinical practice, ultimately improving the health of the nation. The Clinical and Translational Science Award (CTSA) sites, now housed with NCATS, are organized and prepared to support in this endeavor. The CTSAs provide a foundation for capitalizing on such promise through provision of a disease-agnostic infrastructure devoted to clinical and translational (C&T) science, maintenance of training programs designed for C&T investigators of the future, by incentivizing institutional reorganization and by cultivating institutional support. Clin Trans Sci 2012; Volume #: 19

Small RNA-mediated gene regulation during development causes long-lasting changes in cellular phenotypes. To determine whether small RNAs of the adult brain can regulate memory storage, a process that requires stable and long-lasting changes in the functional state of neurons, we generated small RNA libraries from the Aplysia CNS. In these libraries, we discovered an unexpectedly abundant expression of a 28 nucleotide sized class of piRNAs in brain, which had been thought to be germline specific. These piRNAs have unique biogenesis patterns, predominant nuclear localization, and robust sensitivity to serotonin, a modulatory transmitter that is important for memory. We find that the Piwi/piRNA complex facilitates serotonin-dependent methylation of a conserved CpG island in the promoter of CREB2, the major inhibitory constraint of memory in Aplysia, leading to enhanced long-term synaptic facilitation. These findings provide a small RNA-mediated gene regulatory mechanism for establishing stable long-term changes in neurons for the persistence of memory.