The first structure of polarity suppression protein, Psu from enterobacteria phage P4, reveals a novel fold and a knotted dimer

Psu is a capsid decoration protein of bacteriophage P4 and acts as an antiterminator of Rho-dependent transcription termination in bacteria. So far, no structures have been reported for the Psu protein or its homologues. Here, we report the first structure of Psu solved by the Hg2+ single wavelength anomalous dispersion method, which reveals that Psu exists as a knotted homodimer and is first of its kind in nature. Each monomer of Psu attains a novel fold around a tight coiled-coil motif. CD spectroscopy and the structure of an engineered disulfide-bridged Psu derivative reveal that the protein folds reversibly and reassembles by itself into the knotted dimeric conformation without the requirement of any chaperone. This structure would help to explain the functional properties of the protein and can be used as a template to design a minimal peptide fragment that can be used as a drug against Rho-dependent transcription termination in bacteria

Functional connexin35 increased in the myopic chicken retina.

Our previous research showed that increased phosphorylation of connexin (Cx)36 indicated extended  coupling of AII amacrine cells (ACs) in the rod-dominant mouse myopic retina. This research will determine whether phosphorylation at serine 276 of Cx35-containing gap junctions increased in the myopic chicken, whose retina is cone-dominant. Refractive errors and ocular biometric dimensions of 7-days-old chickens were determined following 12 h and 7 days induction of myopia by a -10D lens. The expression pattern and size of Cx35-positive plaques were examined in the early (12 h) and compensated stages (7 days) of lens-induced myopia (LIM). At the same time, phosphorylation at serine 276 (functional assay) of Cx35 in strata 5 (S5) of the inner plexiform layer was investigated. The axial length of the 7 days LIM eyes was significantly longer than that of non-LIM controls (P < 0.05). Anti-phospho-Ser276 (Ser276-P)-labeled plaques were significantly increased in LIM retinas at both 12 h and 7 days. The density of Ser276-P of Cx35 was observed to increase after 12 h LIM. In the meanwhile, the areas of existing Cx35 plaques did not change. As there was more phosphorylation of connexin35 at Ser276 at both the early and late stages (12 h) and 7 days of LIM chicken retinal activity, the coupling with ACs could be increased in myopia development of the cone-dominated chicken retina

Increased Connexin36 Phosphorylation in AII Amacrine Cell Coupling of the Mouse Myopic Retina.

Myopia is a substantial public health problem worldwide. In the myopic retina, distant images are focused in front of the photoreceptors. The cells and mechanisms for retinal signaling that account either for emmetropization (i.e., normal refraction) or for refractive errors have remained elusive. Gap junctions play a key component in enhancement of signal transmission in visual pathways. AII amacrine cells (ACs), coupled by connexin36, segregate signals into ON and OFF pathways. Coupling between AII ACs is actively modulated through phosphorylation at serine 293 via dopamine in the mouse retina. In this study, form deprivation mouse myopia models were used to evaluate the expression patterns of connexin36-positive plaques (structural assay) and the state of connexin36 phosphorylation (functional assay) in AII ACs, which was green fluorescent protein-expressing in the Fam81a mouse line. Single-cell RNA sequencing showed dopaminergic synapse and gap junction pathways of AII ACs were downregulated in the myopic retina, although Gjd2 mRNA expression remained the same. Compared with the normal refractive eye, phosphorylation of connexin36 was increased in the myopic retina, but expression of connexin36 remained unchanged. This increased phosphorylation of Cx36 could indicate increased functional gap junction coupling of AII ACs in the myopic retina, a possible adaptation to adjust to the altered noisy signaling status

phase 2 study evaluating intermittent and continuous linsitinib and weekly paclitaxel in patients with recurrent platinum resistant ovarian epithelial cancer

Abstract Background Linsitinib, an oral, dual inhibitor of insulin-like growth factor-1 receptor and insulin receptor, in combination with weekly paclitaxel, may improve clinical outcomes compared with paclitaxel alone in patients with refractory or platinum-resistant ovarian cancer. Patients and methods This open-label phase 1/2 clinical trial (NCT00889382) randomized patients with refractory or platinum-resistant ovarian cancer (1:1:1) to receive either oral intermittent linsitinib (600mg once daily on Days 1–3 per week) combined with paclitaxel (80mg/m 2 on Days 1, 8, and 15; Arm A) or continuous linsitinib (150mg twice daily) in combination with paclitaxel (Arm B), or paclitaxel alone (Arm C). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety/tolerability. Results A total of 152 women were randomized to treatment (n=51 Arm A; n=51 Arm B, n=50 Arm C). In combination with paclitaxel, neither intermittent linsitinib (median PFS 2.8months; 95% confidence interval [CI]:2.5–4.4) nor continuous linsitinib (median PFS 4.2months; 95% CI:2.8–5.1) improved PFS over weekly paclitaxel alone (median PFS 5.6months; 95% CI:3.2–6.9). No improvement in ORR, DCR, or OS in either linsitinib dosing schedule was observed compared with paclitaxel alone. Adverse event (AE) rates, including all-grade and grade 3/4 treatment-related AEs, and treatment-related AEs leading to discontinuation, were higher among patients receiving intermittent linsitinib compared with the other treatment arms. Conclusion Addition of intermittent or continuous linsitinib with paclitaxel did not improve outcomes in patients with platinum-resistant/refractory ovarian cancer compared with paclitaxel alone

Fifteen-year incidence rate and risk factors of pterygium in the Southern Indian state of Andhra Pradesh.

PURPOSE: To report 15-year incidence rate and associated risk factors of pterygium among people aged 30 years and above at baseline in the rural clusters of longitudinal Andhra Pradesh Eye Disease Study (APEDS III). METHODS: The baseline APEDS I included 7771 participants of which 6447 (83%) were traced and 5395 (83.7%) were re-examined in APEDS III. To estimate the incidence of pterygium, we selected participants who were 30 years and above at baseline (4188), of which 2976 were traced and 2627 (88.3%) were examined, and based on inclusion criteria, 2290 participants were included in the study. The incidence rate of pterygium was defined as the proportion of people free of pterygium at baseline who had developed the condition at 15-year follow-up (range 13-17 years). Univariate and multivariable analyses for risk factors were undertaken. RESULTS: The sex-adjusted incidence rate of pterygium was 25.2 per 100 person-years (95% CI 24.8 to 25.7) which was significantly higher for men than women (26.3 per 100 person-years (95% CI 25.6 to 27.0) and 24.7 (95% CI 24.1 to 25.3) respectively). At the multivariable analysis, male gender (RR: 1.35, 95% CI 1.0 to 1.83), no formal education (RR: 2.46, 95% CI 1.22 to 4.93), outdoor occupation (RR: 1.47, 95% CI 1.14 to 1.9) and lower body mass index (BMI) (<18.5) (RR: 1.25, 95% CI 1.02 to 1.55) were associated with increased risk of pterygium. CONCLUSIONS: The overall incidence rate of pterygium was high in this rural population, especially in men and those engaged in outdoor activities, lack of formal education and with lower BMI. It is likely that greater exposure to ultraviolet light is a major contributing factor, thus warranting preventive strategies

Calorimetry Task Force Report

In this note we summarize the studies and recommendations of the calorimeter simulation task force (CaloTF). The CaloTF was established in February 2008 in order to understand and reconcile the discrepancies observed between the CMS calorimetry simulation and the test beam data recorded during 2004 and 2006. As the result of studies by the CaloTF a new version of Geant4 was developed and introduced in the CMS detector simulation leading to significanly better agreement with test beam data. Fast and flexible parameterizations describing showering in the calorimeter are introduced both in the Full Simulation (with a Gflash-like approach) and in the Fast Simulation. The CaloTF has developed a strategy to rapidly tune the CMS calorimeter simulation using the first LHC collision data when it becomes available. The improvements delivered by the CaloTF have been implemented in the software release CMSSW 2.1.0

The CMS Outer Hadron Calorimeter

The CMS hadron calorimeter is a sampling calorimeter with brass absorber and plastic scintillator tiles with wavelength shifting fibres for carrying the light to the readout device. The barrel hadron calorimeter is complemented with a outer calorimeter to ensure high energy shower containment in CMS and thus working as a tail catcher. Fabrication, testing and calibrations of the outer hadron calorimeter are carried out keeping in mind its importance in the energy measurement of jets in view of linearity and resolution. It will provide a net improvement in missing \et measurements at LHC energies. The outer hadron calorimeter has a very good signal to background ratio even for a minimum ionising particle and can hence be used in coincidence with the Resistive Plate Chambers of the CMS detector for the muon trigger

Incidence, Incident Causes, and Risk Factors of Visual Impairment and Blindness in a Rural Population in India: 15-Year Follow-up of the Andhra Pradesh Eye Disease Study.

PURPOSE: To report 15-year incidence rate of visual loss (blindness and visual impairment [VI]), causes, and risk factors for participants in Andhra Pradesh Eye Disease Study III (APEDS III). DESIGN: Population-based cohort study. METHODS: From 2012 to 2016, all rural participants were interviewed and underwent a comprehensive eye examination, including dilated fundus examination and imaging. Presenting visual acuity (PVA) and best-corrected visual acuity (BCVA) were measured using a standard logarithm of Minimum Angle of Resolution chart at 3 meters. World Health Organization (WHO) and United States of America (USA) categories of VI and blindness were used. Incident visual loss was defined as the development of or worsening of visual loss of one or more categories. RESULTS: In APEDS I, 7,771 rural participants were examined using stratified, random-cluster systematic sampling; in APEDS III, 5,395 participants (69.4% of rural or 52.4% of total participants) were re-examined. Using WHO categories, the crude incidence rate of any visual loss based on PVA and BCVA were 14.6 (95% confidence interval [CI]:13.6-15.7) and 6.3 (95% CI: 6.1-6.4) per 100 person-years, respectively. Using USA criteria, the values were 22.6 (95% CI: 22.3-23.0) and 10.6 (95% CI: 10.3-10.8) per 100 person-years, respectively. More than 90% of visual loss was attributable to cataract and uncorrected refractive error. Using WHO categories, significant independent risk factors for the incident visual loss were increasing age, female gender, illiteracy, past or current smoker, and current use of alcohol. Using the USA definition, an additional risk factor was lower level of education. CONCLUSIONS: The high incidence likely reflects poor access to eye care in this population, which needs to be taken into account when planning eye care programs

Fifteen-Year Incidence Rate of Primary Angle Closure Disease in the Andhra Pradesh Eye Disease Study.

PURPOSE: To report on the 15-year incidence of primary angle closure disease (PACD) among participants aged ≥40 years in rural southern India DESIGN: Population-based longitudinal incidence rate study METHODS: Setting: 3 rural study centres. STUDY POPULATION: Phakic participants aged ≥40 years who participated in both examination time points. OBSERVATION PROCEDURES: All participants at the baseline and at the mean 15-year follow-up visit underwent a detailed interview, anthropometry, blood pressure measurement, and comprehensive eye examination. Automated perimetry was attempted based on predefined criteria. Main outcome measures included development of any form of PACD, as defined by the International Society for Geographical and Epidemiological Ophthalmology (ISGEO), during the follow-up period in phakic participants, who did not have the disease at baseline. RESULTS: We analyzed data obtained from 1,197 (81.4% out of available 1,470) participants to calculate the incidence of the disease. The mean age (standard deviation) of the study participants at the baseline was 50.2 (8.1) years, with 670 male (45.5%) and 800 female (54.4%) participants. The incidence rate per 100 person-years (95% confidence interval) for primary angle closure suspect, primary angle closure, and primary angle closure glaucoma was 8.8 (8.4, 9.2), 6.2 (5.9, 6.6), and 1.6 (1.4, 1.8), respectively. Thus, the incidence of all forms of PACD was 16.4 (15.9, 17) per 100 person-years. On logistic regression analysis, female gender was a significant risk factor whereas presence of myopia was protective. CONCLUSIONS: This study reports long-term incidence of PACD from rural India. It has implications for eye health care policies, strategies, and planning