The rockefeller university

Viruses specifically infecting bacteria, or bacteriophages, are the most common biological entity in the biosphere. As such, they greatly influence bacteria, both in terms of enhancing their virulence and in terms of killing them. Since the first identification of bacteriophages in the beginning of the 20th century, researchers have been fascinated by these microorganisms and their ability to eradicate bacteria. In this review, we will cover the history of the Propionibacterium acnes bacteriophage research and point out how bacteriophage research has been an important part of the research on P. acnes itself. We will further discuss recent findings from phage genome sequencing and the identification of phage sequence signatures in clustered regularly interspaced short palindromic repeats (CRISPRs). Finally, the potential to use P. acnes bacteriophages as a therapeutic strategy to combat P. acnes-associated diseases will be discussed.

Background Glutamate (GLUT) in the lateral hypothalamus (LH) has been suggested to mediate reward behaviors and may promote the ingestion of drugs of abuse. This study tested the hypothesis that GLUT in the LH stimulates consumption of ethanol ( EtOH ) and that this effect occurs, in part, via its interaction with local peptides, hypocretin/orexin (OX), and melanin-concentrating hormone (MCH). Methods In Experiments 1 and 2, male Sprague-Dawley rats, after being trained to drink 9% EtOH , were microinjected in the LH with N-methyl-d-aspartate (NMDA) or its antagonist, D-AP5, or with alpha-amino-5-methyl-3-hydroxy-4-isoxazole propionic acid (AMPA) or its antagonist, CNQX-ds. Consumption of EtOH , chow, and water was then measured. To provide an anatomical control, a separate set of rats was injected 2 mm dorsal to the LH. In Experiment 3, the effect of LH injection of NMDA and AMPA on the expression of OX and MCH was measured using radiolabeled in situ hybridization (ISH) !

Aspergillus fumigatus causes life-threatening pneumonia in immunocompromised patients. Conidia, the infectious form of the organism, are handled in a biologic safety cabinet under BSL2 conditions. However because germinated conidia form noninfectious hyphae in tissue, we hypothesized that rabbits inoculated intratracheally would grow A. fumigatus in their lungs but that the environment would remain free of this fungus, potentially permitting maintenance of infected animals under ABSL1 conditions. We performed a surveillance study for the presence of A. fumigatus in the environment before proceeding with antifungal therapy studies of experimental pulmonary aspergillosis. The expected outcome included absence of A. fumigatus in the environment, stool, and blood and presence in rabbit lungs. Female SPF New Zealand white rabbits were immunosuppressed and inoculated intratracheally (n = 4) or intraesophageally (n = 2) with 1.25 * 10(8) conidia of A. fumigatus. Feces, pan liners, and walls were sampled daily during the 11-d experiment, and blood was sampled on days 2, 6, and 8 after inoculation. Samples were cultured on 5% Sabouraud glucose agar plates. Lungs were weighed and scored for hemorrhagic infarcts and homogenized for culture on 5% Sabouraud glucose agar and trypticase soy agar plates. Blood cultures, rabbit stool, and environmental swabs were all negative for A. fumigatus whereas the lungs inoculated intratracheally demonstrated 4.5 * 10(2) 0.8 * 10(2) CFU/g of A. fumigatus. Therefore, neutropenic rabbits with experimental invasive pulmonary aspergillosis do not shed conidia of A. fumigatus and can be safely housed under ABSL1 conditions after inoculation.

Tissue growth is the multifaceted outcome of a cell's intrinsic capabilities and its interactions with the surrounding environment. Decoding these complexities is essential for understanding human development and tumorigenesis. Here we tackle this problem by carrying out the first genome-wide RNA-interference-mediated screens in mice. Focusing on skin development and oncogenic (Hras(G12V)-induced) hyperplasia, our screens uncover previously unknown as well as anticipated regulators of embryonic epidermal growth. Among the top oncogenic screen hits are Mllt6 and the Wnt effector beta-catenin, which maintain Hras(G12V)-dependent hyperproliferation. We also expose beta-catenin as an unanticipated antagonist of normal epidermal growth, functioning through Wnt-independent intercellular adhesion. Finally, we validate functional significance in mouse and human cancers, thereby establishing the feasibility of in vivo mammalian genome-wide investigations to dissect tissue development and tumorigenesis. By documenting some oncogenic growth regulators, we pave the way for future investigations of other hits and raise promise for unearthing new targets for cancer therapies.

The lifetime of the B-c(-) meson is measured using 272 exclusive B-c(-) -> J/psi (-> mu(+) mu(-))pi(-) decays reconstructed in data from proton-antiproton collisions corresponding to an integrated luminosity of 6.7 fb(-1) recorded by the CDF II detector at the Fermilab Tevatron. The lifetime of the B-c(-) meson is measured to be tau(B-c(-)) = 0.452 +/- 0.048(stat) +/- 0.027(syst) ps. This is the first measurement of the B-c(-) meson lifetime in a fully reconstructed hadronic channel, and it agrees with previous results and has comparable precision. DOI: 10.1103/PhysRevD.87.011101

Background: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression post-transcriptionally in a wide range of biological processes. The zebra finch (Taeniopygia guttata), an oscine songbird with characteristic learned vocal behavior, provides biologists a unique model system for studying vocal behavior, sexually dimorphic brain development and functions, and comparative genomics. Results: We deep sequenced small RNA libraries made from the brain, heart, liver, and muscle tissues of adult male and female zebra finches. By mapping the sequence reads to the zebra finch genome and to known miRNAs in miRBase, we annotated a total of 193 miRNAs. Among them, 29 (15%) are avian specific, including three novel zebra finch specific miRNAs. Many of the miRNAs exhibit sequence heterogeneity including length variations, untemplated terminal nucleotide additions, and internal substitution events occurring at the uridine nucleotide within a GGU motif. We also identified seven Z chromosome-encoded miRNAs. Among them, miR-2954, an avian specific miRNA, is expressed at significantly higher levels in males than in females in all tissues examined. Target prediction analysis reveals that miR-2954, but not other Z-linked miRNAs, preferentially targets Z chromosome-encoded genes, including several genes known to be expressed in a sexually dimorphic manner in the zebra f!

Circadian clocks enable organisms to adapt to a 24 h diurnal cycle and anticipate rhythmic changes in the environment. The Arabidopsis central oscillator contains three genes encoding core clock components. CIRCADIAN CLOCK ASSOCIATED 1 (CCA1)/LATE ELONGATED HYPOCOTYL (LHY) and TIMING OF CEXPRESSION 1 (TOC1) reciprocally repress genes encoding each other and are critical for the generation of circadian rhythms controlling many clock outputs. A precise regulation of transcriptional events is, therefore, essential for proper circadian function. Here, we investigated histone 3 (H3) tail modifications of CCA1, LHY and TOC1 under various conditions. We found specific association of only H3K4Me3 and H3K9/14Ac with the translational start site of these three genes. These H3 marks were enriched at circadian time points of their increased transcription at different photoperiods and under free-running conditions, suggesting circadian regulation of H3 modifications. Analysis of clock-compromised CCA1-overexpressing lines provided evidence that light/dark photoperiods signal the establishment of these chromatin changes which are gated by the clock.

Approximately 1% of those infected with HIV-1 develop broad and potent serum cross-neutralizing antibody activities. It is unknown whether or not the development of such immune responses affects the replication of the contemporaneous autologous virus. Here, we defined a pathway of autologous viral escape from contemporaneous potent and broad serum neutralizing antibodies developed by an elite HIV-1-positive (HIV-1(+)) neutralizer. These antibodies potently neutralize diverse isolates from different clades and target primarily the CD4-binding site (CD4-BS) of the viral envelope glycoprotein. Viral escape required mutations in the viral envelope glycoprotein which limited the accessibility of the CD4-binding site to the autologous broadly neutralizing anti-CD4-BS antibodies but which allowed the virus to infect cells by utilizing CD4 receptors on their surface. The acquisition of neutralization resistance, however, resulted in reduced cell entry potential and slower viral replication kinetics. Our results indicate that in vivo escape from autologous broadly neutralizing antibodies exacts fitness costs to HIV-1.

Background. MicroRNA (miRNA) alterations accompanying interstitial fibrosis and tubular atrophy (IFTA) in kidney allografts may point toward pathologic mechanisms. Small-RNA sequencing provides information on total miRNA abundance and specific miRNA expression and allows analysis of differential expression based on read counts. Methods. MiRNA expression profiles of 8 human kidney allograft biopsies (4 IFTA and 4 normal biopsies, discovery set) were characterized using barcoded deep-sequencing of a cDNA library prepared from multiplexed RNA. Statistical analysis of the sequence data guided selection of miRNAs for validation and the levels of selected miRNAs were quantified in 18 biopsies (10 IFTA and 8 normal) using real-time quantitative PCR assays (RT-QPCR). Results. Total miRNA content was 50% lower in RNA from IFTA compared with normal biopsies. Global miRNA profiles clustered in partial agreement with diagnosis. Several miRNAs, including miR-21, 142-3p, and 5p and the cluster comprising miR-506 on chromosome X had twofold to sevenfold higher expression in IFTA compared with normal biopsies, whereas miRNA miR-30b and 30c were lower in IFTA biopsies (miR-30a, -30d, -30e, and all respective star sequences showed similar trends). IFTA and normal biopsy distinction was also noted in the pattern of miRNA nucleotide sequence variations. Differentially expressed miRNAs were confirmed on the larger set of allograft biopsies using RT-QPCR, and the levels of miRNAs were found to be associated with allograft function and survival. Conclusion. Differentially expressed miRNAs and their predicted targets identified by deep sequencing are candidates for further investigation to decipher the mechanism and management of kidney allograft fibrosis.

Unraveling the intricate interactions between Trypanosoma brucei, the protozoan parasite causing African trypanosomiasis, and the tsetse (Glossina) vector remains a challenge. Metacyclic trypanosomes, which inhabit the tsetse salivary glands, transmit the disease and are produced through a complex differentiation and unknown program. By overexpressing a single RNA-binding protein, TbRBP6, in cultured noninfectious trypanosomes, we recapitulated the developmental stages that have been observed in tsetse, including the generation of infective metacyclic forms expressing the variant surface glycoprotein. Thus, events leading to acquisition of infectivity in the insect vector are now accessible to laboratory investigation, providing an opening for new intervention strategies.