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A major goal of modern protein chemistry is to create new proteins with different functions. One approach is to amalgamate secondary and tertiary structures from different proteins. This is difficult for several reasons, not the least of which is the fact that the junctions between secondary and tertiary structures are not degenerate and usually affect the function and folding of the entire complex. Here, we offer a solution to this problem by coupling a large combinatorial library of about 10 7 different N- and C-terminal junctions to a powerful system that selects for function. Using this approach, the entire Leptin and follicle-stimulating hormone (FSH) were inserted into an antibody. Complexes with full retention of function in vivo and in vitro, although rare, were found easily by using an autocrine selection system to search for hormonal activity. Such large diversity systems, when coupled to robust selection systems, should enable construction of novel therapeutic proteins.

In November 2011, The Rockefeller University Center for Clinical and Translational Science (CCTS), the Laboratory of Microbiology and Infectious Diseases, and Clinical Directors Network (CDN) launched a research and learning collaborative project with six community health centers in the New York City metropolitan area to determine the nature (clonal type) of community-acquired Staphylococcus aureus strains causing skin and soft tissue infections (SSTIs). Between November 2011 and March 2013, wound and nasal samples from 129 patients with active SSTIs suspicious for S. aureus were collected and characterized by molecular typing techniques. In 63 of 129 patients, the skin wounds were infected by S. aureus: methicillin-resistant S. aureus (MRSA) was recovered from 39 wounds and methicillin-sensitive S. aureus (MSSA) was recovered from 24. Most-46 of the 63-wound isolates belonged to the CC8/Panton-Valentine leukocidin-positive (PVL+) group of S. aureus clone USA300: 34 of these strains were MRSA and 12 were MSSA. Of the 63 patients with S. aureus infections, 30 were also colonized by S. aureus in the nares: 16 of the colonizing isolates were MRSA, and 14 were MSSA, and the majority of the colonizing isolates belonged to the USA300 clonal group. In most cases (70%), the colonizing isolate belonged to the same clonal type as the strain involved with the infection. In three of the patients, the identity of invasive and colonizing MRSA isolates was further documented by whole-genome sequencing.

BackgroundIt is essential to track the careers and accomplishments of the graduates of translational research training programs to assess the impact of the programs and to improve them. The major obstacle is the lack of a convenient method to collect the information in a comprehensive and standardized manner. MethodsWe have developed a Web-based electronic Graduate Tracking Survey System (GTSS) that prepopulates the graduate's information on publications, grants, patents, and clinical trials from public data sources, thus insuring a uniform data format, facilitating survey completion, and facilitating the aggregation of data at individual or multiple sites. GTSS questions are designed to assess whether trainees make important contributions that improve human health, and to track related surrogate career development indicators of likely future success. ResultsThe GTSS has been in use at Rockefeller University since 2011 and has been adopted by 21 other Clinical and Translational Science Award programs. ConclusionsThe GTSS provides an efficient and convenient mechanism to track the graduates of a wide variety of training programs. It has the potential to aggregate standardized data across institutions, thus providing benchmarks for the assessment of individual training programs and data for program improvement.

We measure the particle-level forward-backward production asymmetry in b (b) over bar pairs with masses (m(b (b) over bar)) larger than 150 GeV/c(2), using events with hadronic jets and employing jet charge to distinguish b from (b) over bar. The measurement uses 9.5 fb(-1) of p (p) over bar collisions at a center-of-mass energy of 1.96 TeV recorded by the CDF II detector. The asymmetry as a function of m(b (b) over bar) is consistent with zero, as well as with the predictions of the standard model. The measurement disfavors a simple model including an axigluon with a mass of 200 GeV/c(2), whereas a model containing a heavier 345 GeV/c(2) axigluon is not excluded.

General arousal has been operationally defined as an enhanced motor activity and enhanced intensity of response to sensory stimuli. Even though the effects of gonadal hormones on mating behavior have been much studied, their potential effect on generalized arousal, as defined above, has never been evaluated. In the present study we employed a thoroughly validated assay of general arousal to determine the effects of estradiol (E) and testosterone (T) in gonadectomized female and male mice, respectively. The steroids were administered in three different ways: A fast-acting, water soluble preparation given intraperitoneally, an oil solution given subcutaneously, and an oil solution in a subcutaneous Silastic capsule. Motor activity and responses to sensory stimuli were recorded for 24 h, 91 h, and seven days following hormone administration, respectively. All measures of arousal varied according to the day/night cycle. The water soluble steroid preparation had no reliable effect. When the same doses of estradiol and testosterone were administered subcutaneously in an oil vehicle no effect of either treatment on arousal was observed. The subcutaneously implanted capsule containing estradiol or testosterone had a delayed effect on motor activity in females (four to seven days) but no effect in males. The long time required by the gonadal hormones for affecting arousal would be consistent with, but does not prove, a genomic action. The limited effects of E and T in our arousal assay suggest to us that the strongest actions of these hormones on arousal occur in the context of sequences of responses to sexually relevant stimuli, (C) 2015 Elsevier Inc. All rights reserved.

We present a measurement of the top-quark mass in events containing two leptons (electrons or muons) with a large transverse momentum, two or more energetic jets, and a transverse-momentum imbalance. We use the full proton-antiproton collision data set collected by the CDF experiment during the Fermilab Tevatron Run II at center-of-mass energy root s = 1.96 TeV, corresponding to an integrated luminosity of 9.1 fb(-1). A special observable is exploited for an optimal reduction of the dominant systematic uncertainty, associated with the knowledge of the absolute energy of the hadronic jets. The distribution of this observable in the selected events is compared to simulated distributions of t (t) over bar dilepton signal and background. We measure a value for the top-quark mass of 171.5 +/- 1.9 (stat) +/- 2.5 (syst) GeV/c(2).

The development and evaluation of effective therapies and vaccines for the hepatitis C virus (HCV) and the study of its interactions with the mammalian host have been hindered for a long time by the absence of suitable small animal models. Immune compromised mouse models that recapitulate the complete HCV life cycle have been useful to investigate many aspects of the HCV life cycle including antiviral interventions. However, HCV has a high propensity to establish persistence and associated histopathological manifestations such as steatosis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Better understanding of these processes requires the development of a permissive and fully immunocompetent small animal model. In this review we summarize the in vivo models that are available for the study of HCV.

Aire controls immunologic tolerance by inducing a battery of thymic transcripts encoding proteins characteristic of peripheral tissues. Its unusually broad effect is achieved by releasing RNA polymerase II paused just downstream of transcriptional start sites. We explored Aire's collaboration with the bromodomain-containing protein, Brd4, uncovering an astonishing correspondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain blocker. Aire: Brd4 binding depended on an orchestrated series of posttranslational modifications within Aire's caspase activation and recruitment domain. This interaction attracted P-TEFb, thereby mobilizing downstream transcriptional elongation and splicing machineries. Aire: Brd4 association was critical for tolerance induction, and its disruption could account for certain point mutations that provoke human autoimmune disease. Our findings evoke the possibility of unanticipated immunologic mechanisms subtending the potent antitumor effects of bromodomain blockers.

The germinal center (GC) is a microanatomical compartment wherein high-affinity antibody-producing B cells are selectively expanded. B cells proliferate and mutate their antibody genes in the dark zone (DZ) of the GC and are then selected by T cells in the light zone (LZ) on the basis of affinity. Here, we show that T cell help regulates the speed of cell cycle phase transitions and DNA replication of GC B cells. Genome sequencing and single-molecule analyses revealed that T cell help shortens S phase by regulating replication fork progression, while preserving the relative order of replication origin activation. Thus, high-affinity GC B cells are selected by a mechanism that involves prolonged dwell time in the DZ where selected cells undergo accelerated cell cycles.