The rockefeller university

We performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For the majority of these families, no copy-number variant (CNV) or candidate de novo gene-disruptive single-nucleotide variant (SNV) had been detected by microarray or whole-exome sequencing (WES). We integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. We report that compared to control individuals, probands showed a significant (p = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). This effect was only observed within 50 kb of genes that have been previously associated with autism risk, including genes where dosage sensitivity has already been established by recurrent disruptive de novo protein-coding mutations (ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM). In addition, we provide evidence of gene-disruptive CNVs (in DISCI, WNT7A, RBFOX1, and MBD5), as well as smaller de novo CNVs and exon-specific SNVs missed by exome sequencing in neurodevelopmental genes (e.g., CANX, SAE1, and PIK3CA). Our results suggest that the detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism.

We assessed the prevalence of six biocide resistance genes among 82 methicillin-resistant Staphylococcus aureus (MRSA) and 219 methicillin-susceptible S. aureus (MSSA) isolates from three African countries; the prevalence was very high for sepA (95.3%), mepA (89.4%), and norA (86.4%), intermediate for lmrS (60.8%) and qac(40.5%), and low for smr (3.7%). A significant association between biocide resistance genes and antibiotic resistance was observed, and a new cutoff MIC of >= 1 mg/liter for chlorhexidine nonsusceptibility was defined.

Objective: The objective was to validate the reliability and efficiency of alternative cutoff values on the abbreviated six-item Posttraumatic Stress Disorder (PTSD) Checklist (PCL-6) [1] for underserved, largely minority patients in primary care settings of Federally Qualified Health Centers (FQHCs). Method: Using a sample of 760 patients recruited from six FQHCs in the New York City and New Jersey metropolitan area from June 2010 to April 2013, we compared the PCL-6 with the Clinician Administered PTSD Scale (CAPS) for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. We used reliability statistics for single cutoff values on PCL-6 scores. We examined the relationship between probabilities of meeting CAPS diagnostic criteria and PCL-6 scores by nonparametric regression. Results: PCL-6 scores range between 6 and 30. Reliability and efficiency statistics for cutoff between 12 and 26 were reported. There is a strong monotonic relationship between PCL-6 scores and the probability of meeting CAPS diagnostic criteria. Conclusion: No single cutoff on PCL-6 scores has acceptable reliability on both false positive and false negative simultaneously. An ordinal decision rule (low risk: 12 or less, medium risk: 13 to 16, high risk: 17 to 25 and very high risk: 26 and above) can differentiate the risk of PTSD. A single cutoff (17 or higher as positive) may be suitable for identifying those with the greatest need for care given limited mental health capacity in FQHC settings. (C) 2016 Elsevier Inc. All rights reserved.

Genetically encoded small-molecule sensors are important tools for revealing the dynamics of metabolites and other small molecules in live cells over time. We recently developed RNA-based sensors that exhibit fluorescence in proportion to a small-molecule ligand. One class of these RNA-based sensors are termed Spinach riboswitches. These are RNAs that are based on naturally occurring riboswitches, but have been fused to the Spinach aptamer. The resulting RNA is a fluorogenic riboswitch, producing fluorescence upon binding the cognate small-molecule analyte. Here, we describe how to design and optimize these sensors by adjusting critical sequence elements, guided by structural insights from the Spinach aptamer. We provide a stepwise imaging of metabolites. Spinach riboswitch sensors offer a simple method for fluorescence measurement of a wide range of metabolites for which riboswitches exist, including nucleotides and their derivatives, amino acids, cofactors, cations, and anions.

We show the first unified description of some of the oldest known geometries such as the Pappus' theorem with more modern ones like Desargues' theorem, Monge's theorem and Ceva's theorem, through octonions, the highest normed division algebra in eight dimensions. We also show important applications in hadronic physics, giving a full description of the algebra of color applicable to quark physics, and comment on further applications.

Antibodies (Abs) specific for the V3 loop of the HIV-1 gp120 envelope neutralize most tier 1 and many tier 2 viruses and are present in essentially all HIV-infected individuals as well as immunized humans and animals. Vaccine-induced V3 Abs are associated with reduced HIV infection rates in humans and affect the nature of transmitted viruses in infected vaccinees, despite the fact that V3 is often occluded in the envelope trimer. Here, we link structural and experimental data showing how conformational alterations of the envelope trimer render viruses exceptionally sensitive to V3 Abs. The experiments interrogated the neutralization sensitivity of pseudoviruses with single amino acid mutations in various regions of gp120 that were predicted to alter packing of the V3 loop in the Env trimer. The results indicate that the V3 loop is metastable in the envelope trimer on the virion surface, flickering between states in which V3 is either occluded or available for binding to chemokine receptors (leading to infection) and to V3 Abs (leading to virus neutralization). The spring-loaded V3 in the envelope trimer is easily released by disruption of the stability of the V3 pocket in the unliganded trimer or disruption of favorable V3/pocket interactions. Formation of the V3 pocket requires appropriate positioning of the V1V2 domain, which is, in turn, dependent on the conformation of the bridging sheet and on the stability of the V1V2 B-C strand-connecting loop. IMPORTANCE The levels of antibodies to the third variable region (V3) of the HIV envelope protein correlate with reduced HIV infection rates. Previous studies showed that V3 is often occluded, as it sits in a pocket of the envelope trimer on the surface of virions; however, the trimer is flexible, allowing occluded portions of the envelope (like V3) to flicker into an exposed position that binds antibodies. Here we provide a systematic interrogation of mechanisms by which single amino acid changes in various regions of gp120 (i) render viruses sensitive to neutralization by V3 antibodies, (ii) result in altered packing of the V3 loop, and (iii) activate an open conformation that exposes V3 to the effects of V3 Abs. Taken together, these and previous studies explain how V3 antibodies can protect against HIV-1 infection and why they should be one of the targets of vaccine-induced antibodies.

The mammalian skin epidermis and its hair and sweat gland appendages provide a protective barrier that retains essential body fluids, guards against invasion by harmful microbes, and regulates body temperature through the ability to sweat. At the interface between the external environment and the body, skin is constantly subjected to physical trauma and must also be primed to repair wounds in response to injury. In adults, the skin maintains epidermal homeostasis, hair regeneration, and wound repair through the use of its stem cells. This essay focuses on when stem cells become established during skin development and where these cells reside in adult epithelial tissues of the skin. I explore how skin stem cells maintain tissue homeostasis and repair wounds and how they regulate the delicate balance between proliferation and differentiation. Finally, I tackle the relation between skin cancer and mutations that perturb the regulation of stem cells.

Altered abundance of phosphatidyl inositides (PIs) is a feature of cancer. Various PIs mark the identity of diverse membranes in normal and malignant cells. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2) resides predominantly in the plasma membrane, where it regulates cellular processes by recruiting, activating, or inhibiting proteins at the plasma membrane. We find that PTPRN2 and PLC beta 1 enzymatically reduce plasma membrane PI(4,5)P-2 levels in metastatic breast cancer cells through two independent mechanisms. These genes are upregulated in highly metastatic breast cancer cells, and their increased expression associates with human metastatic relapse. Reduction in plasma membrane PI(4,5)P-2 abundance by these enzymes releases the PI(4,5)P-2-binding protein cofilin from its inactive membrane-associated state into the cytoplasm where it mediates actin turnover dynamics, thereby enhancing cellular migration and metastatic capacity. Our findings reveal an enzymatic network that regulates metastatic cell migration through lipid-dependent sequestration of an actin-remodeling factor.

Although the nosocomial prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in Angola is over 60% and one of the highest in Africa, the extent of MRSA in the community is unknown. To fill this gap, we conducted a hospital-based study in which 158 children attending the emergency ward and ambulatory services of a pediatric hospital in Luanda, the capital of Angola, were screened for S. aureus nasal colonization. Overall, 70 (44.3%) individuals were colonized with S. aureus, of which 20 (28.6%) carried MRSA, resulting in a prevalence of 12.7% (20/158) of MRSA in the population screened. Molecular characterization by pulsed-field gel electrophoresis (PFGE), spa typing, multilocus sequence typing, and SCCmec typing distributed the isolates into two major MRSA clones and one dominant methicillin-susceptible S. aureus (MSSA) lineage, corresponding to the main clones circulating in hospitals in Luanda. The MRSA isolates mainly belonged to clones A (PFGE type A, spa type t105, ST5-IVa-65%) and B (PFGE B, t3869, ST88-IVa-30%), while MSSA isolates mainly belonged to clone L (PFGE type L, t861, ST508-42%). S. aureus isolates showed resistance to penicillin (96%), rifampin (87%), and trimethoprim-sulfamethoxazole (21%). In conclusion, the prevalence of MRSA among children in the community in Luanda is high and seems to originate from hospitals, warranting continuous monitoring and implementation of additional infection control measures.

This paper describes the algorithms used by the CMS experiment to reconstruct and identify tau -> hadrons + nu(tau) decays during Run 1 of the LHC. The performance of the algorithms is studied in proton-proton collisions recorded at a centre-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 19.7 fb(-1). The algorithms achieve an identification efficiency of 50-60%, with misidentification rates for quark and gluon jets, electrons, and muons between per mille and per cent levels.