The rockefeller university

Clamp loaders are pentameric ATPases of the AAA+ family that operate to ensure processive DNA replication. They do so by loading onto DNA the ring-shaped sliding clamps that tether the polymerase to the DNA. Structural and biochemical analysis of clamp loaders has shown how, despite differences in composition across different branches of life, all clamp loaders undergo the same concerted conformational transformations, which generate a binding surface for the open clamp and an internal spiral chamber into which the DNA at the replication fork can slide, triggering ATP hydrolysis, release of the clamp loader, and closure of the clamp round the DNA. We review here the current understanding of the clamp loader mechanism and discuss the implications of the differences between clamp loaders from the different branches of life.

Objectives: To evaluate the surgical management of vitreoretinal pathology in patients with a permanent Boston Type 1 keratoprosthesis (hereafter referred to as a KPro) in the era of small-gauge vitrectomy techniques. Methods: Retrospective review of 23 small-gauge vitreoretinal surgical procedures during or after Dohlman-Doane KPro placement in 14 eyes. Results: Established and innovative techniques were used, including sutureless small-gauge vitrectomy, temporal positioning of surgeon, long-term tamponades, and exploratory endoscopy. Retro-KPro membranes formed less frequently when vitrectomy was performed during KPro placement. Anatomical goals were achieved, and no serious complications directly resulted from these techniques. Visual acuity, frequently limited by preexisting pathology, improved in most cases. Conclusions: Modern posterior segment surgical techniques, including small-gauge sutureless vitrectomy, can be effectively used for patients with a permanent KPro. Vitrectomy and glaucoma tube revision by a team of subspecialists at the time of KPro placement may reduce subsequent complications.

Ovariectomized females were given an infusion in the medial preoptic area (MPOA) of a viral vector carrying either a shRNA directed against the estrogen receptor a (ERet) or luciferase. The females were subjected to a test for sexual incentive motivation immediately followed by a test for receptivity and proceptive behaviors. Two weeks later they were tested in the light/dark choice procedure, and after another 2 weeks they were subjected to a test in a brightly lit open field. Finally, the females were given free access to a running wheel for 88 h. The females were treated with estradiol benzoate (EB), 18 or 1.5 mu g/kg, in randomized order 52 h before each test except the running wheel. In that experiment, they were given EB 48 h after introduction into the wheel cage. They were given progesterone, 1 mg/rat, about 4 h before all tests, except the running wheel. The shRNA reduced the number of ER alpha with 83%. Females with few ER alpha in the MPOA showed increased lordosis quotient after the 1.5 mu g/kg dose of EB. There was no effect on proceptive behaviors or on rejections. When given the 18 mu g/kg EB dose, there was no difference between females with few preoptic ER alpha and controls. In the test for sexual incentive motivation, females with few preoptic ER alpha approached the castrated male incentive more than controls, regardless of EB dose. They also moved a shorter distance. In the light/dark choice test as well as in the open field, females with few ER alpha in the MPOA showed signs of reduced fear/anxiety, since they spent more time in the light part of the dark/light box and in the center of the open field. Finally, the data from the running wheel showed that females with few preoptic ER alpha failed to show enhanced activity after treatment with EB. These data show that the preoptic ER alpha inhibits lordosis in females with an intermediate level of receptivity while it fails to do so in fully receptive females. The ER alpha in the MPOA seems to be necessary for selective approach to a sexual incentive. Finally, activation of this receptor appears to have anxiogenic effects in the procedures employed here. A hypothesis for how all these actions of the preoptic ER alpha contributes to efficient reproductive behavior is outlined. (C) 2012 Elsevier B.V. All rights reserved.

The inclusive b-jet production cross section in pp collisions at a center-of-mass energy of 7TeV is measured using data collected by the CMS experiment at the LHC. The cross section is presented as a function of the jet transverse momentum in the range 18 < p(T) < 200 GeV for several rapidity intervals. The results are also given as the ratio of the b-jet production cross section to the inclusive jet production cross section. The measurement is performed with two different analyses, which differ in their trigger selection and b-jet identification: a jet analysis that selects events with a b jet using a sample corresponding to an integrated luminosity of 34 pb(-1), and a muon analysis requiring a b jet with a muon based on an integrated luminosity of 3 pb(-1). In both approaches the b jets are identified by requiring a secondary vertex. The results from the two methods are in agreement with each other and with next-to-leading order calculations, as well as with predictions based on the PYTHIA event generator.

Hepatitis C virus (HCV) infects similar to 2% of the world's population. It is estimated that there are more than 500,000 new infections annually in Egypt, the country with the highest HCV prevalence. An effective vaccine would help control this expanding global health burden. HCV is highly variable, and an effective vaccine should target conserved T- and B-cell epitopes of the virus. Conserved B-cell epitopes overlapping the CD81 receptor-binding site (CD81bs) on the E2 viral envelope glycoprotein have been reported previously and provide promising vaccine targets. In this study, we isolated 73 human mAbs recognizing five distinct antigenic regions on the virus envelope glycoprotein complex E1E2 from an HCV-immune phage-display antibody library by using an exhaustive-panning strategy. Many of these mAbs were broadly neutralizing. In particular, the mAb AR4A, recognizing a discontinuous epitope outside the CD81bs on the E1E2 complex, has an exceptionally broad neutralizing activity toward diverse HCV genotypes and protects against heterologous HCV challenge in a small animal model. The mAb panel will be useful for the design and development of vaccine candidates to elicit broadly neutralizing antibodies to HCV.

Deep brain stimulation (DBS) has shown promise in the treatment of many neurological and psychiatric disorders as well as a disorder of consciousness, the minimally conscious state (MCS). In the clinic. DBS is always monotonic standard pulses; however, we have hypothesized that temporally patterned pulses might be more efficient in achieving desired behavioral responses. Here we present two experiments on DBS of the central thalamus to increase arousal, as measured by motor activity, and to affect the electroencephalogram (EEG). In the first, we optimized amplitude and frequency in standard stimulation of the central thalamus in intact mice. In the second, the optimized fixed frequency was compared to two alternative temporal patterns, chaotic and random, which were physically identical to each other and fixed frequency in all ways except temporal pattern. In both experiments and with all types of stimulation, DBS of the central thalamus increased arousal as measured by motor activity. These data also revealed that temporal patterning of pulses can modulate response to stimulation. That temporal patterns in DBS of the central thalamus were found to alter motor activity response implies possible usefulness of temporal patterns in DBS of other contexts. More investigation into exactly how temporally patterned stimulation may affect neuronal circuit dynamics is necessary. (C) 2012 Elsevier B.V. All rights reserved.

The vast majority of bacteria present in environmental samples have never been cultured and therefore have not been exploited for the ability to produce useful biocatalysts or collections of biocatalysts generating interesting small molecules. Metagenomic libraries constructed using DNA extracted directly from natural bacterial communities offer access to the genetic information present in the genomes of these as yet uncultured bacteria. This review highlights recent efforts to recover both discrete enzymes and small molecules from metagenomic libraries.

Objective: To evaluate the complication rate for adenotonsillectomy in children younger than 3 years, without a diagnosis of severe obstructive sleep apnea, to assess the necessity for postoperative inpatient admission. Design: Retrospective medical record review (January 1, 2003, through October 31, 2009). Setting: Tertiary care academic medical center. Patients: Retrospective medical record review of 105 patients younger than 3 years who underwent adenotonsillectomy performed by a single surgeon. Nineteen patients were excluded from our review because of incomplete medical records or severe underlying disease, leaving a total of 86 patients with medical records available for inclusion in our study. Patient medical records were deidentified and reviewed for age, sex, indications for surgery, intraoperative and perioperative interventions, and postoperative complications. One child with a diagnosis of severe obstructive sleep apnea was excluded from the study. Main Outcome Measures: Complications, including bleeding, dehydration requiring admission, and airway intervention, during the intraoperative or perioperative period were recorded. Results: The mean age of the study population was approximately 27.5 months (range, 13-35 months), with most children (76.5%) between 23 and 31 months of age. Among the patients whose records were reviewed, 80 (93.0%) did not experience any intraoperative or postoperative complications. Dehydration was the most common complication and was the cause of all documented readmissions (4.7%) in our patients who ranged in age from 14 to 30 months. Two patients had other complications, reactive airway disease (n = 1) and postoperative fever (n = 1), which were identified and treated in the post-anesthesia care unit, resulting in same-day discharge. No airway complications were noted in our study. Conclusions: Our study reveals a low complication rate in children younger than 3 years. The recommendations for mandatory admission for children younger than 3 years should be reexamined. Criteria for inpatient admission for children younger than 3 years should be based on preoperative and postoperative clinical evaluation of the patient and an evaluation of the family resources for adequately caring for young children at home in the postoperative period. These recommendations apply only to otherwise healthy children (American Society of Anesthesiologists classifications I and II) without a diagnosis of severe obstructive sleep apnea syndrome.

The angular distributions of muons from gamma(1S, 2S, 3S) -> mu(+)mu(-) decays are measured using data from p (p) over bar collisions at root s = 1.96 TeV corresponding to an integrated luminosity of 6.7 fb(-1) and collected with the CDF II detector at the Fermilab Tevatron. This analysis is the first to report the full angular distributions as functions of transverse momentum p(T) for gamma mesons in both the Collins-Soper and s-channel helicity frames. This is also the first measurement of the spin alignment of gamma(3S) mesons. Within the kinematic range of gamma rapidity vertical bar y vertical bar < 0.6 and p(T) up to 40 GeV/c, the angular distributions are found to be nearly isotropic.

T helper 17 (Th17) cells are characterized by the secretion of IL-17, a proinflammatory cytokine. They represent a newly described T helper subpopulation that is distinct from Th1 and Th2 lineages. Because of their pleiotropic activity on fibroblasts, keratinocytes, endothelial cells, neutrophils and memory T cells, Th17 cells are thought to be crucial in mediating tissue inflammation and autoimmunity. Autoimmune diseases were classically considered as Th1-mediated disorders such as rheumatoid arthritis or 'mixed' Th1/Th2 diseases such as inflammatory bowel diseases, systemic lupus erythematosus, bullous diseases, but new evidence suggests the deep involvement of Th17 cells in their pathogenesis that, potentially, may address a selective therapeutic approach targeting the IL23/Th17 pathway. This review summarizes the current knowledge of the pathogenic contribution of Th17 cells in select cutaneous autoimmune disorders, including lupus erythematosus, scleroderma, dermatomyositis, bullous pemphigoid and pemphigus vulgaris.