The fork protection complex recruits FACT to reorganize nucleosomes during replication

Chromosome replication depends on efficient removal of nucleosomes by accessory factors to ensure rapid access to genomic information. Here, we show this process requires recruitment of the nucleosome reorganization activity of the histone chaperone FACT. Using single-molecule FRET, we demonstrate that reorganization of nucleosomal DNA by FACT requires coordinated engagement by the middle and C-terminal domains of Spt16 and Pob3 but does not require the N-terminus of Spt16. Using structure-guided pulldowns, we demonstrate instead that the N-terminal region is critical for recruitment by the fork protection complex subunit Tof1. Using in vitro chromatin replication assays, we confirm the importance of these interactions for robust replication. Our findings support a mechanism in which nucleosomes are removed through the coordinated engagement of multiple FACT domains positioned at the replication fork by the fork protection complex

Is there a positive effect of participation on a clinical trial for patients with advanced non-small cell lung cancer?

Background: There is general belief that patients who enrolled on a clinical trial have better outcomes compared to those who are treated outside of a trial. We analyzed if there was a \u2032trial effect\u2032 for patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy. Materials and methods: A retrospective analysis of cohorts of patients with advanced NSCLC who received chemotherapy inside and outside of a clinical trial were analyzed for response rates (RR), progression free survival (PFS), overall survival (OS), 1 and 2 year survival. Results: There were 194 patients who received chemotherapy of which, 54 were on a clinical trial and 140 outside of it. For the whole group, the RR, median PFS, OS, one and two-year survivals were 35.4%, six months (range, 2-70), seven months (range, 2-72), 29.8% and 9.7% respectively. The differences in RR and PFS of patients who were treated inside and outside of a clinical trial were not significant (P=0.6164, 0.0881). The differences in median OS and one-year survivals between the groups were significant (P=0.0052, 0.022). For the whole group, patients who received II line chemotherapy had better OS (P\ua30.0001). More patients in the trial group received II line chemotherapy (P=0.0004).The difference in the median OS between the groups continued to be significant even after patients who received II line chemotherapy were censored (P=0.0437). Conclusion: Patients with advanced NSCLC who were treated inside of a clinical trial had better OS compared to those who were treated outside of it

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Monte Carlo and molecular dynamics simulation of argon clusters and n-alkanes in the confined regions of zeolites

Geometry and energy of argon clusters confined in zeolite NaCaA are compared with those of free clusters. Results indicate the possible existence of magic numbers among the confined clusters. Spectra obtained from instantaneous normal mode analysis of free and confined clusters give a larger percentage of imaginary frequencies for the latter indicating that the confined cluster atoms populate the saddle points of the potential energy surface significantly. The variation of the percentage of imaginary frequencies with temperature during melting is akin to the variation of other properties. It is shown that confined clusters might exhibit inverse surface melting, unlike medium-to-large-sized free clusters that exhibit surface melting. Configurational-bias Monte Carlo (CBMC) simulations of n-alkanes in zeolites Y and A are reported. CBMC method gives reliable estimates of the properties relating to the conformation of molecules. Changes in the conformational properties of n-butane and other longer n alkanes such as n-hexane and n-heptane when they are confined in different zeolites are presented. The changes in the conformational properties of n-butane and n-hexane with temperature and concentration is discussed. In general, in zeolite Y as well as A, there is significant enhancement of the gauche population as compared to the pure unconfined fluid

Adaptive Super Twisting Controller for a Quadrotor UAV

In this paper we present a robust quadrotor controller for tracking a reference trajectory in presence of uncertainties and disturbances. A Super Twisting controller is implemented using the recently proposed gain adaptation law [1], [2], which has the advantage of not requiring the knowledge of the upper bound of the lumped uncertainties. The controller design is based on the regular form of the quadrotor dynamics, without separation in two nested control loops for position and attitude. The controller is further extended by a feedforward dynamic inversion control that reduces the effort of the sliding mode controller. The higher order quadrotor dynamic model and proposed controller are validated using a SimMechanics physical simulation with initial error, parameter uncertainties, noisy measurements and external perturbations

Assessment of knowledge, attitude, and practices regarding biomedical waste management among operation room personnel in a tertiary care center

Background and Aims: Biomedical waste management is an important issue of concern to all healthcare personnel as inappropriate management has the potential for serious infections and noninfectious injury to patients and care providers. Operation room is a department in the hospital wherein large amounts of waste are generated on a daily basis. This study aims to evaluate the knowledge, attitude, and practice regarding biomedical waste among operation room personnel. Material and Methods: This is a cross-sectional study done among various strata of operation room personnel with a questionnaire to evaluate the knowledge, attitude, and practice with respect to biomedical waste management. Results: This study revealed gaps in knowledge and practices among all strata of operation room personnel regarding biomedical waste management. Conclusion: This study highlights the need for appropriate training of all operation room personnel about appropriate waste management practices

Adaptive super twisting controller for a quadrotor UAV

In this paper we present a robust quadrotor controller for tracking a reference trajectory in presence of uncertainties and disturbances. A Super Twisting controller is implemented using the recently proposed gain adaptation law [1], [2], which has the advantage of not requiring the knowledge of the upper bound of the lumped uncertainties. The controller design is based on the regular form of the quadrotor dynamics, without separation in two nested control loops for position and attitude. The controller is further extended by a feedforward dynamic inversion control that reduces the effort of the sliding mode controller. The higher order quadrotor dynamic model and proposed controller are validated using a SimMechanics physical simulation with initial error, parameter uncertainties, noisy measurements and external perturbations

Transient brachial monoparesis following epidural anesthesia for cesarean section

Monoparesis following lumbar epidural block is a rare occurrence, with few cases reported in the literature. We report development of transient brachial monoparesis following epidural anesthesia in a parturient for cesarean section. The patient received a mixture of 15 mL of 2% lignocaine with 50 mcg fentanyl epidurally to achieve a blockade up to T6 level. She remained hemodynamically stable throughout the procedure, with no respiratory distress or desaturation. However, near the end of surgery, she developed weakness in the right upper limb. The weakness lasted for 90 min, followed by complete neurological recovery. Subsequent hospital stay was uneventful

Cervical dilatation in parturient receiving neuraxial analgesia: Comparison of epidural analgesia alone with combined spinal epidural analgesia

Background: Both epidural analgesia and combined spinal epidural analgesia (CSEA) are employed for pain relief during labor because they provide reliable analgesia compared to other modalities. Studies are equivocal with respect to their effect on the rate of cervical dilatation, duration of labor, and labor outcome. The primary outcome of the present study was to compare the effect of epidural analgesia alone with CSEA with respect to the rate of cervical dilatation. Materials and Methods: One hundred and twenty parturients with an initial cervical dilatation of <4 cm were randomized to receive CSEA or epidural analgesia alone for pain relief during labor. The rate of cervical dilatation, onset of effective analgesia, number of epidural top-ups requested, labor outcome, and the quality of analgesia was assessed in both the study groups. Statistical Analysis: Mann–Whitney and Chi-square tests were performed where applicable to compare the data between the two groups. Results: The results of the study showed that the rate of cervical dilatation was rapid with CSEA compared to epidural analgesia alone [median (interquartile range) 2 (1.2,3) v/s 1.16 (1,2)]. The onset of analgesia was earlier with combined spinal epidural (CSE v/s EA, 3.7 ± 1.3 min v/s 23.8 ± 5.8 min). Labor outcome and quality of analgesia was similar between the two groups. The incidence of pruritus was higher with CSEA than with epidural analgesia alone. Conclusion: CSEA is associated with more rapid cervical dilatation and shorter duration of first stage of labor when compared with epidural analgesia alone