The rockefeller university

The dementia of Alzheimer's disease (AD) results primarily from degeneration of neurons that furnish glutamatergic corticocortical connections that subserve cognition. Although neuron death is minimal in the absence of AD, age-related cognitive decline does occur in animals as well as humans, and it decreases quality of life for elderly people. Age-related cognitive decline has been linked to synapse loss and/or alterations of synaptic proteins that impair function in regions such as the hippocampus and prefrontal cortex. These synaptic alterations are likely reversible, such that maintenance of synaptic health in the face of aging is a critically important therapeutic goal. Here, we show that riluzole can protect against some of the synaptic alterations in hippocampus that are linked to age-related memory loss in rats. Riluzole increases glutamate uptake through glial transporters and is thought to decrease glutamate spillover to extrasynaptic NMDA receptors while increasing synaptic glutamatergic activity. Treated aged rats were protected against age-related cognitive decline displayed in nontreated aged animals. Memory performance correlated with density of thin spines on apical dendrites in CA1, although not with mushroom spines. Furthermore, riluzole-treated rats had an increase in clustering of thin spines that correlated with memory performance and was specific to the apical, but not the basilar, dendrites of CA1. Clustering of synaptic inputs is thought to allow nonlinear summation of synaptic strength. These findings further elucidate neuroplastic changes in glutamatergic circuits with aging and advance therapeutic development to prevent and treat agerelated cognitive decline.

Posttranscriptional gene regulation by miRNAs and RNA binding proteins (RBP) is important in development, physiology, and disease. To examine the interplay between miRNAs and the RBP ELAVL1 (HuR), we mapped miRNA binding sites at the transcriptome-wide scale in wild-type and Elavl1 knockout murine bone-marrow-derived macrophages. Proximity of ELAVL1 binding sites attenuated miRNA binding to transcripts and promoted gene expression. Transcripts that regulate angiogenesis and macrophage/endothelial crosstalk were preferentially targeted by miRNAs, suggesting that ELAVL1 promotes angiogenesis, at least in part by antagonism of miRNA function. We found that ELAVL1 antagonized binding of miR-27 to the 3' UTR of Zfp36 mRNA and alleviated miR-27-mediated suppression of the RBP ZFP36 (Tristetraprolin). Thus, the miR-27-regulated mechanism synchronizes the expression of ELAVL1 and ZFP36. This study provides a resource for systems-level interrogation of posttranscriptional gene regulation in macrophages, a key cell type in inflammation, angiogenesis, and tissue homeostasis.

Telomeres have evolved to protect the ends of linear chromosomes from the myriad of threats posed by the cellular DNA damage signaling and repair pathways. Mammalian telomeres have to block nonhomologous end joining (NHEJ), thus preventing chromosome fusions; they need to control homologous recombination (HR), which could change telomere lengths; they have to avoid activating the ATM (ataxia telangiectasia mutated) and ATR (ATM- and RAD3-related) kinase pathways, which could induce cell cycle arrest; and they have to protect chromosome ends from hyperresection. Recent studies of telomeres have provided insights into the mechanisms of NHEJ and HR, how these double-strand break (DSB) repair pathways can be thwarted, and how telomeres have co-opted DNA repair factors to help in the protection of chromosome ends. These aspects of telomere biology are reviewed here with particular emphasis on recombination, the main focus of this collection.

Extending our previous analyses to the most recently described monoclonal broadly neutralizing antibodies (bNAbs), we confirmed a drift of HIV-1 clade B variants over 2 decades toward higher resistance to bNAbs targeting almost all the identified gp120-neutralizing epitopes. In contrast, the sensitivity to bNAbs targeting the gp41 membrane-proximal external region remained stable, suggesting a selective pressure on gp120 preferentially. Despite this evolution, selected combinations of bNAbs remain capable of neutralizing efficiently most of the circulating variants.

The International Psoriasis Council, a global nonprofit organization dedicated to advancing psoriasis research and treatment, led an initiative to better define the association of various cardiometabolic comorbidities with psoriasis. In November 2013, a workshop was held in Boston, Mass. By assembling a panel of global dermatology, immunology, and cardiovascular experts, the objective was to better define the current status of the science that explains the association of psoriasis with various cardiometabolic-related comorbidities. The International Psoriasis Council has played a historical role in associating psoriasis with various comorbidities by integrating multidisciplinary expertise to advance the scientific and clinical knowledge through publications and clinical trials. This report synthesizes the current understanding of psoriasis with various cardiometabolic risk factors by exploring the potential shared pathogenic mechanisms and genetic connectivity. Published by Elsevier Inc.

We report a measurement of the indirect CP-violating asymmetries (A(Gamma)) between effective lifetimes of anticharm and charm mesons reconstructed in D-0 --> K+K- and D-0 --> pi(+)pi(-) decays. We use the full data set of proton-antiproton collisions collected by the Collider Detector at Fermilab experiment and corresponding to 9.7 fb(-1) of integrated luminosity. The strong-interaction decay D*(+) --> D-0 pi(+) is used to identify the meson at production as D-0 or (D) over bar (0). We statistically subtract D-0 and (D) over bar (0) mesons originating from b-hadron decays and measure the yield asymmetry between anticharm and charm decays as a function of decay time. We measure A(Gamma)(K+K- ) = (-0.19 +/- 0.15(stat) +/- 0.04(syst))% and A(Gamma)(pi(+)pi(-)) = (- 0.01 +/- 0.18(stat) +/- 0.03(syst)%. The results are consistent with the hypothesis of CP symmetry and their combination yields A(Gamma) = (- 0.12 +/- 0.12)%.

Objective: To assess the prevalence of vulvovaginitis, enuresis and encopresis in children who were referred for allegations of sexual abuse. Subjects: A retrospective chart review of 1280 children presenting for non-acute examination after allegations of sexual abuse during a 15-year time span. Interview documentation, physical examination documentation, urinalysis, urine and vaginal cultures were reviewed. Results: Of the 1280 children, 73.3% were female and 26.7% male. The ages of the children ranged from 6 months to 18 years (median age was 6 years). Interviews revealed that fondling contact was the most common allegation, followed by oral, vaginal, and anal penetration. Interviews also disclosed lower urinary tract symptoms, UTI, constipation, encopresis and enuresis. Physical examination revealed no abnormal genital findings in 44.7% of cases. Examinations of the vagina noted: erythema (18.1%); hymenal notching (posterior 16.8%, anterior 4.4%); vuvlovaginitis (14.0%); laceration or transection (0.6%); and bruising (0.4%). Examination of the anus noted: anal fissure/tear (14.9%); loss of anal tone (10.6%); reflex anal dilatation (9.2%); venous congestion (3.8%); and proctitis (0.9%). Vulvovaginitis was noted in 14% (131/936) and encopresis in 2.3% (21/936). Enuresis according to age was reported in 13% of 5-9 year olds, 14.7% of 10-16 year olds and 18.2% of 17-18 year olds suspected of being abused. Conclusion: Prevalence of vulvovaginitis and enuresis were increased, and encopresis was decreased in children with allegations of sexual abuse when compared to the general pediatric population. Physicians should continue to be aware of the possibility of the presence of these conditions in children who have been sexually abused, and offer appropriate treatment. (C) 2014 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

IRAK-4 and MyD88 deficiencies impair interleukin 1 receptor and Toll-like receptor (TLR) signaling and lead to heightened susceptibility to invasive bacterial infections. Individuals with these primary immunodeficiencies have fewer immunoglobulin M (IgM)(+)IgD(+)CD27(+) B cells, a population that resembles murine splenic marginal zone B cells that mount T-independent antibody responses against bacterial antigens. However, the significance of this B-cell subset in humans is poorly understood. Using both a 610 carbohydrate array and enzyme-linked immunosorbent assay, we found that patients with IRAK-4 and MyD88 deficiencies have reduced serum IgM, but not IgG antibody, recognizing T-independent bacterial antigens. Moreover, the quantity of specific IgM correlated with IgM(+)IgD(+)CD27(+) B-cell frequencies. As with mouse marginal zone B cells, human IgM(+)CD27(+) B cells activated by TLR7 or TLR9 agonists produced phosphorylcholine-specific IgM. Further linking splenic IgM(+)IgD(+)CD27(+) B cells with production of T-independent IgM, serum from splenectomized subjects, who also have few IgM(+)IgD(+)CD27(+) B cells, had reduced antibacterial IgM. IRAK-4 and MyD88 deficiencies impaired TLR-induced proliferation of this B-cell subset, suggesting a means by which loss of this activation pathway leads to reduced cell numbers. Thus, by bolstering the IgM(+)IgD(+)CD27(+) B-cell subset, IRAK-4 and MyD88 promote optimal T-independent IgM antibody responses against bacteria in humans.

Fanconi anemia (FA) is the most common of the inherited bone marrow failure syndromes with an incidence of approximately 1/100,000 to 1/200,000 live births. FA is a genetically complex and phenotypically heterogeneous condition involving birth defects, bone marrow failure, and cancer predisposition. This rare disease became well known in the genetic counseling community in 2002, when it was identified that biallelic mutations in BRCA2 can cause FA. Knowledge gained from the growing association between FA and breast cancer pathways has brought even more light to the complex genetic issues that arise when counseling families affected by this disease. Genetic counseling issues surrounding a diagnosis of FA affect many different disciplines. This review will serve as a way to cross-link the various topics important to genetic counselors that arise throughout the life of a patient with FA. Issues covered will include: an overview of FA, phenotypic presentation, management and treatment, the genetics and inheritance of FA, cytogenetic and molecular testing options, and the risks to family members of an individual with FA.

The evolutionarily conserved Mediator complex is a critical coactivator for RNA polymerase II (Pol II)-mediated transcription. Here we report the reconstitution of a functional 15-subunit human core Mediator complex and its characterization by functional assays and chemical cross-linking coupled to MS (CX-MS). Whereas the reconstituted head and middle modules can stably associate, basal and coactivator functions are acquired only after incorporation of MED14 into the bimodular complex. This results from a dramatically enhanced ability of MED14-containing complexes to associate with Pol II. Altogether, our analyses identify MED14 as both an architectural and a functional backbone of the Mediator complex. We further establish a conditional requirement for metazoan-specific MED26 that becomes evident in the presence of heterologous nuclear factors. This general approach paves the way for systematic dissection of the multiple layers of functionality associated with the Mediator complex.