The rockefeller university

Leprosy is caused by infection with Mycobacterium leprae and is classified clinically into paucibacillary (PB) or multibacillary (MB) subtypes based on the number of skin lesions and the bacillary index detected in skin smears. We previously identified a major PB susceptibility locus on chromosome region 10p13 in Vietnamese families by linkage analysis. In the current study, we conducted high-density association mapping of the 9.5 Mb linkage peak on chromosome region 10p13 covering 39 genes. Using leprosy per se and leprosy subtypes as phenotypes, we employed 294 nuclear families (303 leprosy cases, 63 % MB, 37 % PB) as a discovery sample and 192 nuclear families (192 cases, 55 % MB, 45 % PB) as a replication sample. Replicated significant association signals were revealed in the genes for cubilin (CUBN) and nebulette (NEBL). In the combined sample, the C allele (frequency 0.26) at CUBN SNP rs10904831 showed association [p = 1 x 10(-5); OR 0.52 (0.38-0.7)] with MB leprosy only. Likewise, allele T (frequency 0.42) at NEBL SNP rs11012461 showed association [p = 4.2 x 10(-5); OR 2.51 (1.6-4)] with MB leprosy only. These associations remained valid for the CUBN signal when taking into account the effective number of tests performed (type I error significance threshold = 2.4 x 10(-5)). We used the results of our analyses to propose a new model for the genetic control of polarization of clinical leprosy.

Background Buruli ulcer, caused by Mycobacterium ulcerans, was identified as a neglected emerging infectious disease by WHO in 1998. Although Buruli ulcer is the third most common mycobacterial disease worldwide, understanding of the disease is incomplete. We analysed a large cohort of laboratory-confirmed cases of Buruli ulcer from Pob, Benin, to provide a comprehensive description of the clinical presentation of the disease, its variation with age and sex, and its effect on the occurrence of permanent functional sequelae. Methods Between Jan 1, 2005, and Dec 31, 2011, we prospectively collected clinical and laboratory data from all patients with Buruli ulcer diagnosed at the Centre de Depistage et de Traitement de l'Ulcere de Buruli in Pob, Benin. We followed up patients to assess the frequency of permanent functional sequelae. All analyses were done on cases that were laboratory confirmed. Findings 1227 cases of laboratory-confirmed Buruli ulcer were included in the analysis. Typically, patients with Buruli ulcer were children (median age at diagnosis 12 years) presenting with a unique (1172 [96%]) large (>= 15 cm, 444 [36%]) ulcerative (805 [66%]) lesion of the lower limb (733 [60%]). Atypical clinical presentation of Buruli ulcer included Buruli ulcer osteomyelitis with no identifiable present or past Buruli ulcer skin lesions, which was recorded in at least 14 patients. The sex ratio of Buruli ulcer widely varied with age, with male patients accounting for 57% (n= 427) of patients aged 15 years and younger, but only 33% (n=158) of those older than 15 years (odds ratio [OR] 2.59, 95% CI 2.04-3.30). Clinical presentation of Buruli ulcer was significantly dependent on age and sex. 54 (9%) male patients had Buruli ulcer osteomyelitis, whereas only 28 (4%) of female patients did (OR 2.21, 95% CI 1.39-3.59). 1 year after treatment, 229 (22% of 1043 with follow-up information) patients presented with permanent functional sequelae. Presentation with oedema, osteomyelitis, or large (>= 15 cm in diameter), or multifocal lesions was significantly associated with occurrence of permanent functional sequelae (OR 7.64, 95% CI 5.29-11.31) and operationally defines severe Buruli ulcer. Interpretation Our findings have important clinical implications for daily practice, including enhanced surveillance for early detection of osteomyelitis in boys; systematic search for M ulcerans in osteomyelitis cases of non-specific aspect in areas endemic for Buruli ulcer; and specific disability prevention for patients presenting with osteomyelitis, oedema, or multifocal or large lesions. Our findings also suggest a crucial underestimation of the burden of Buruli ulcer in Africa and raise key questions about the contribution of environmental and physiopathological factors to the recorded heterogeneity of the clinical presentation of Buruli ulcer.

Background: N-cadherin is a cell-cell adhesion molecule and deletion of N-cadherin in mice is embryonic lethal. During the secretory stage of enamel development, E-cadherin is down-regulated and N-cadherin is specifically up-regulated in ameloblasts when groups of ameloblasts slide by one another to form the rodent decussating enamel rod pattern. Since N-cadherin promotes cell migration, we asked if N-cadherin is essential for ameloblast cell movement during enamel development. Methodology/Principal Findings: The enamel organ, including its ameloblasts, is an epithelial tissue and for this study a mouse strain with N-cadherin ablated from epithelium was generated. Enamel from wild-type (WT) and N-cadherin conditional knockout (cKO) mice was analyzed. mu CT and scanning electron microscopy showed that thickness, surface structure, and prism pattern of the cKO enamel looked identical to WT. No significant difference in hardness was observed between WT and cKO enamel. Interestingly, immunohistochemistry revealed the WT and N-cadherin cKO secretory stage ameloblasts expressed approximately equal amounts of total cadherins. Strikingly, E-cadherin was not normally down-regulated during the secretory stage in the cKO mice suggesting that E-cadherin can compensate for the loss of N-cadherin. Previously it was demonstrated that bone morphogenetic protein-2 (BMP2) induces E- and N-cadherin expression in human calvaria osteoblasts and we show that the N-cadherin cKO enamel organ expressed significantly more BMP2 and significantly less of the BMP antagonist Noggin than did WT enamel organ. Conclusions/Significance: The E- to N-cadherin switch at the secretory stage is not essential for enamel development or for forming the decussating enamel rod pattern. E- cadherin can substitute for N-cadherin during these developmental processes. Bmp2 expression may compensate for the loss of N-cadherin by inducing or maintaining E-cadherin expression when E- cadherin is normally down-regulated. Notably, this is the first demonstration of a natural endogenous increase in E-cadherin expression due to N-cadherin ablation in a healthy developing tissue.

We perform a search for new physics using final states consisting of three leptons and a large imbalance in transverse momentum resulting from proton-antiproton collisions at 1.96 TeV center-of-mass energy. We use data corresponding to 5.8 fb(-1) of integrated luminosity recorded by the CDF II detector at the Tevatron collider. Our main objective is to investigate possible new low-momentum (down to 5 GeV/c) multi-leptonic final states not investigated by LHC experiments. Relative to previous CDF analyses, we expand the geometric and kinematic coverage of electrons and muons and utilize tau leptons that decay hadronically. Inclusion of tau leptons is particularly important for supersymmetry (SUSY) searches. The results are consistent with standard-model predictions within 1.85 sigma. By optimizing our event selection to increase sensitivity to the minimal supergravity (mSUGRA) SUSY model, we set limits on the associated production of chargino and next-to-lightest neutralino, the SUSY partners of the electroweak gauge bosons. We exclude cross sections up to 0.1 pb and chargino masses up to 168 GeV/c(2) at 95% C.L., for a suitable set of mSUGRA parameters. We also exclude a region of the two-dimensional space of the masses of the neutralino and the supersymmetric partner of the tau lepton, not previously excluded at the Tevatron.

ProNGF and p75(NTR) are upregulated and induce cell death following status epilepticus (SE) in rats. However, less is known about the proneurotrophin response to SE in mice, a more genetically tractable species where mechanisms can be more readily dissected. We evaluated the temporal- and cell-specific induction of the proneurotrophins and their receptors, including p75(NTR), sortilin, and sorCS2, following mild SE induced with kainic acid (KA) or severe SE induced by pilocarpine. We found that mature NGF, p75(NTR), and proBDNF were upregulated following SE, while proNGF was not altered, indicating potential mechanistic differences between rats and mice. ProBDNF was localized to mossy fibers and microglia following SE. p75(NTR) was transiently induced primarily in axons and axon terminals following SE, as well as in neuron and astrocyte cell bodies. ProBDNF and p75(NTR) increased independently of cell death and their localization was different depending on the severity of SE. We also examined the expression of proneurotrophin co-receptors, sortilin and sorCS2. Following severe SE, sorCS2, but not sortilin, was elevated in neurons and astrocytes. These data indicate that important differences exist between rat and mouse in the proneurotrophin response following SE. Moreover, the proBDNF and p75(NTR) increase after seizures in the absence of significant cell death suggests that proneurotrophin signaling may play other roles following SE.

Tetherin/BST-2 is a host restriction factor that could directly inhibit retroviral particle release by tethering nascent virions to the plasma membrane. However, the immunological impact of Tetherin during retrovirus infection remains unknown. We now show that Tetherin influences antiretroviral cell-mediated immune responses. In contrast to the direct antiviral effects of Tetherin, which are dependent on cell surface expression, the immunomodulatory effects are linked to the endocytosis of the molecule. Mice encoding endocytosis-competent C57BL/6 Tetherin exhibited lower viremia and pathology at 7 d postinfection with Friend retrovirus (FV) compared with mice encoding endocytosis-defective NZW/LacJ Tetherin. Notably, antiretroviral protection correlated with stronger NK cell responses. In addition, Friend retrovirus infection levels were significantly lower in wild-type C57BL/6 mice than in Tetherin knockout mice at 2 wk postinfection, and antiretroviral protection correlated with stronger NK cell and virus-specific CD8(+) T cell responses. The results demonstrate that Tetherin acts as a modulator of the cell-mediated immune response against retrovirus infection in vivo.

Vancomycin is a glycopeptide antibiotic used for the treatment of Gram-positive bacterial infections. Traditionally, it has been used as a drug of last resort; however, clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) strains with decreased susceptibility to vancomycin (vancomycin intermediate-resistant S. aureus [VISA]) and more recently with high-level vancomycin resistance (vancomycin-resistant S. aureus [VRSA]) have been described in the clinical literature. The rare VRSA strains carry transposon Tn1546, acquired from vancomycin-resistant Enterococcus faecalis, which is known to alter cell wall structure and metabolism, but the resistance mechanisms in VISA isolates are less well defmed. Herein, we review selected mechanistic aspects of resistance in VISA and summarize biochemical studies on cell wall synthesis in a VRSA strain. Finally, we recapitulate a model that integrates common mechanistic features of VRSA and VISA strains and is consistent with the mode of action of vancomycin.

Background: Female sexual receptivity offers an excellent model for complex behavioral decisions. The female must parse her own reproductive state, the external environment, and male sensory cues to decide whether to copulate. In the fly Drosophila melanogaster, virgin female receptivity has received relatively little attention, and its neural circuitry and individual behavioral components remain unmapped. Using a genome-wide neuronal RNAi screen, we identify a subpopulation of neurons responsible for pausing, a novel behavioral aspect of virgin female receptivity characterized in this study. Results: We show that Abdominal-B (Abd-B), a homeobox transcription factor, is required in developing neurons for high levels of virgin female receptivity. Silencing adult Abd-B neurons significantly decreased receptivity. We characterize two components of receptivity that are elicited in sexually mature females by male courtship: pausing and vaginal plate opening. Silencing Abd-B neurons decreased pausing but did not affect vaginal plate opening, demonstrating that these two components of female sexual behavior are functionally separable. Synthetic activation of Abd-B neurons increased pausing, but male courtship song alone was not sufficient to elicit this behavior. Conclusions: Our results provide an entry point to the neural circuit controlling virgin female receptivity. The female integrates multiple sensory cues from the male to execute discrete motor programs prior to copulation. Abd-B neurons control pausing, a key aspect of female sexual receptivity, in response to male courtship.

Recent studies implicated the RNA-binding protein with multiple splicing (RBPMS) family of proteins in oocyte, retinal ganglion cell, heart, and gastrointestinal smooth muscle development. These RNA-binding proteins contain a single RNA recognition motif (RRM), and their targets and molecular function have not yet been identified. We defined transcriptome-wide RNA targets using photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) in HEK293 cells, revealing exonic mature and intronic pre-mRNA binding sites, in agreement with the nuclear and cytoplasmic localization of the proteins. Computational and biochemical approaches defined the RNA recognition element (RRE) as a tandem CAC trinucleotide motif separated by a variable spacer region. Similar to other mRNA-binding proteins, RBPMS family of proteins relocalized to cytoplasmic stress granules under oxidative stress conditions suggestive of a support function for mRNA localization in large and/or multinucleated cells where it is preferentially expressed.

Posttraumatic stress disorder (PTSD) is a common problem in primary care. Although effective treatments are available, little is known about whether such treatments are effective within the context of Federally Qualified Health Centers (FQHCs) that serve as national "safety nets" for providing primary care for low income and underinsured patients. The Violence and Stress Assessment (ViStA) study is the first randomized controlled trial (RCT) to test the impact of a care management intervention for treating PTSD in FQHCs. To develop a PTSD management intervention appropriate for lower resource FQHCs and the predominantly Latino patients they serve, formative work was conducted through a collaborative effort between researchers and an FQHC practice-based research network. This article describes how FQHC stakeholders were convened to review, assess, and prioritize evidence-based strategies for addressing patient, clinician, and system-level barriers to care. This multi-component care management intervention incorporates diagnosis with feedback, patient education and activation; navigation and linkage to community resources; clinician education and medication guidance; and structured cross-disciplinary communication and continuity of care, all facilitated by care managers with FQHC experience. We also describe the evaluation design of this five-year RCT and the characteristics of the 404 English or Spanish speaking patients enrolled in the study and randomized to either the intervention or to usual care. Patients are assessed at baseline, six months, and 12 months to examine intervention effectiveness on PTSD, other mental health symptoms, health-related quality-of-life, health care service use; and perceived barriers to care and satisfaction with care. (C) 2014 Elsevier Inc. All rights reserved.