Activity-directed expansion of a series of antibacterial agents

The feasibility of using activity-directed synthesis to drive antibacterial discovery was investigated. An array of 220 Pd-catalysed microscale reactions was executed, and the crude product mixtures were evaluated for activity against Staphylococcus aureus. Scale-up of the hit reactions, purification and evaluation, enabled expansion of a class of antibacterial quinazolinones. The novel antibacterials had MICs from 0.016 μg mL−1 (i.e. 38 nM) to 2–4 μg mL−1 against S. aureus ATCC29213

A Microfacies Analysis of Arid Continental Carbonates from the Cedar Mesa Sandstone Formation, Utah, USA

Arid continental environments are typically dominated by siliciclastic aeolian, alluvial and fluvial deposits. Despite their common recognition within these environments, carbonate deposits are often overlooked, yet they can provide vital insight into the depositional history, climate, and tectonic controls of a sedimentary basin. This work presents a detailed microfacies analysis of the carbonates found within the Cedar Mesa Sandstone Formation of the Western USA. The Cedar Mesa Sandstone Formation is an early Permian, predominantly aeolian succession, exposed across much of the Colorado Plateau of southern Utah and northern Arizona. The formation is dominantly clastic erg deposits, that grade into a mixed carbonate/clastic sedimentary succession interbedded with carbonate and evaporitic units, interpreted to represent sabkha or sabkha‐like deposits. Whilst many authors have worked within the aeolian dominated facies and have proposed various facies schemes for the siliciclastic components, comparatively little attention has been paid to the mixed evaporitic/clastic/carbonate aeolian‐sabkha transition zone. In this work the microfacies of the carbonates present within the Cedar Mesa Sandstone are analysed, in order to: (i) develop a record of, and interpret carbonate components, (ii) propose depositional mechanisms and (iii) identify evolutionary trends that stand alongside the formation's clastic depositional story. Six microfacies are presented: MF1) Clastic Influenced Carbonate Wackestone; MF2) Laminated Carbonate Wackestone/Packstone; MF3) Microbial Laminated Fenestral Bindstone; MF4) Rounded Mudclast Wackestone; MF5) Laminated Bioclastic‐Ostracod‐Carbonate Wackestone and MF6) Microcrystalline Quartz. The microfacies have been interpreted to document the development of carbonate interdune, lacustrine and continental sabkha environments influenced by localised fault control juxtaposed across a wetting and drying climate cycle and provide useful comparisons for other mixed evaporite/carbonate and clastic sequences

Affinity of IDPs to their targets is modulated by ion-specific changes in kinetics and residual structure

Intrinsically disordered proteins (IDPs) are characterized by a lack of defined structure. Instead, they populate ensembles of rapidly interconverting conformations with marginal structural stabilities. Changes in solution conditions such as temperature and crowding agents consequently affect IDPs more than their folded counterparts. Here we reveal that the residual structure content of IDPs is modulated both by ionic strength and by the type of ions present in solution. We show that these ion-specific structural changes result in binding affinity shifts of up to sixfold, which happen through alteration of both association and dissociation rates. These effects follow the Hofmeister series, but unlike the well-established effects on the stability of folded proteins, they already occur at low, hypotonic concentrations of salt. We attribute this sensitivity to the marginal stability of IDPs, which could have physiological implications given the role of IDPs in signaling, the asymmetric ion profiles of different cellular compartments, and the role of ions in biology.This work was supported by Wellcome Trust Grant WT095195. J.C. is a Wellcome Trust Senior Research Fellow. B.I.M.W. is supported by a Cambridge Trust Scholarship

Review of research literature about the use of lesson study and lesson study-related practices relevant to the field of special needs and inclusive education

This is the author accepted manuscript. The final version is available from Taylor & Francis via the DOI in this recordThere are practical questions about how inclusive schools can enable quality teaching and teachers’ professional development that are relevant to students with special educational needs (SEN). In moves towards inclusive education, teachers are confronted with issues about their knowledge, skills and perceived efficacy to adopt inclusive teaching approaches. Based on an explicit approach to inclusive teaching, this paper illustrates how Lesson Study (LS) and Lesson Study related professional development practices embody the values of inclusive teaching and reflective practice. Peer-reviewed academic papers about LS and LS related practices were reviewed. This found that these practices were predominantly used in continuing professional development and evaluated with a focus on their contexts, processes and outcomes in ordinary and specialist settings. The extent to which LS and LS related practices have been evaluated in these settings with different kinds of SEN is also examined. Based on this review increased use and evaluation of lesson study and lesson study related practices are recommended

Working with cancer: health and employment among cancer survivors.

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Available online 4 August 2015PURPOSE: Cancer affects a growing proportion of US workers. Factors contributing to whether they continue or return to work after cancer diagnosis include: age, physical and mental health, health insurance, education, and cancer site. The purpose of this study was to assess the complex relationships between health indicators and employment status for adult cancer survivors. METHODS: We analyzed pooled data from the 1997-2012 US National Health Interview Survey (NHIS). Our sample included adults with a self-reported physician diagnosis of cancer (n = 24,810) and adults with no cancer history (n = 382,837). Using structural equation modeling (SEM), we evaluated the relationship between sociodemographic factors, cancer site, and physical and mental health indicators on the overall health and employment status among adults with a cancer history. RESULTS: The overall model for cancer survivors fit the data well (χ(2) (374) = 3654.7, P < .001; comparative fit index = 0.98; root mean square error of approximation = 0.04). Although black cancer survivors were less likely to report good-to-excellent health, along with Hispanic survivors, they were more likely to continue to work after diagnosis compared with their white counterparts. Health insurance status and educational level were strongly and positively associated with health status and current employment. Age and time since diagnosis were not significantly associated with health status or employment, but there were significant differences by cancer site. CONCLUSIONS: A proportion of cancer survivors may continue to work because of employment-based health insurance despite reporting poor health and significant physical and mental health limitations. Acute and long-term health and social support are essential for the continued productive employment and quality of life of all cancer survivors.The work was supported in part by a National Cancer Institute (NCI) fellowship at the National Institutes of Health (1F31CA153937); the National Institute for Occupational Safety and Health (NIOSH R01 OH03915); and the European Regional Development Fund Programme and European Social Fund Convergence Programme for Cornwall and the Isles of Scilly (the University of Exeter Medical School)

Working with cancer: Health and employment among cancer survivors

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Purpose: Cancer affects a growing proportion of US workers. Factors contributing to whether they continue or return to work after cancer diagnosis include: age, physical and mental health, health insurance, education, and cancer site. The purpose of this study was to assess the complex relationships between health indicators and employment status for adult cancer survivors. Methods: We analyzed pooled data from the 1997-2012 US National Health Interview Survey (NHIS). Our sample included adults with a self-reported physician diagnosis of cancer (n = 24,810) and adults with no cancer history (n = 382,837). Using structural equation modeling (SEM), we evaluated the relationship between sociodemographic factors, cancer site, and physical and mental health indicators on the overall health and employment status among adults with a cancer history. Results: The overall model for cancer survivors fit the data well (χ2 (374) = 3654.7, P < .001; comparative fit index = 0.98; root mean square error of approximation = 0.04). Although black cancer survivors were less likely to report good-to-excellent health, along with Hispanic survivors, they were more likely to continue to work after diagnosis compared with their white counterparts. Health insurance status and educational level were strongly and positively associated with health status and current employment. Age and time since diagnosis were not significantly associated with health status or employment, but there were significant differences by cancer site. Conclusions: A proportion of cancer survivors may continue to work because of employment-based health insurance despite reporting poor health and significant physical and mental health limitations. Acute and long-term health and social support are essential for the continued productive employment and quality of life of all cancer survivors.The work was supported in part by a National Cancer Institute (NCI) fellowship at the National Institutes of Health (1F31CA153937); the National Institute for Occupational Safety and Health (NIOSH R01 OH03915); and the European Regional Development Fund Programme and European Social Fund Convergence Programme for Cornwall and the Isles of Scilly (the University of Exeter Medical School)

Measurements of the velocity distribution for granular flow in a Couette cell

© 2018 American Physical Society. In this paper, magnetic resonance velocimetry is used to measure the spatially resolved velocity and velocity fluctuations for granular flow in a Couette cell for four different particle sizes. The largest particles studied (dp=1.7mm) showed significant slip at the inner wall. The remaining particles showed no slip and all exhibit the same behavior in the profiles of the mean velocity and variance of velocity. The measurements demonstrate that the velocity and variance in velocity scale with the inner wall velocity U; the variance does not scale with U2. The experimental data were compared with a kinetic theory based model of granular flow and a hydrodynamic model. It was found that the shear rate scales with an exponent of 1.5-2.0 with respect to the velocity fluctuations (uy2), compared with the value of 1.0 expected from kinetic theory. The difference in the exponent is consistent with the effect of collective dynamics as described by the hydrodynamic model

Role of Non-Native Electrostatic Interactions in the Coupled Folding and Binding of PUMA with Mcl-1

PUMA, which belongs to the BH3-only protein family, is an intrinsically disordered protein (IDP). It binds to its cellular partner Mcl-1 through its BH3 motif, which folds upon binding into an α helix. We have applied a structure-based coarse-grained model, with an explicit Debye-Hückel charge model, to probe the importance of electrostatic interactions both in the early and the later stages of this model coupled folding and binding process. This model was carefully calibrated with the experimental data on helical content and affinity, and shown to be consistent with previously published experimental data on binding rate changes with respect to ion strength. We find that intramolecular electrostatic interactions influence the unbound states of PUMA only marginally. Our results further suggest that intermolecular electrostatic interactions, and in particular non-native electrostatic interactions, are involved in formation of the initial encounter complex. We are able to reveal the binding mechanism in more detail than is possible using experimental data alone however, and in particular we uncover the role of non-native electrostatic interactions. We highlight the potential importance of such electrostatic interactions for describing the binding reactions of IDPs. Such approaches could be used to provide predictions for the results of mutational studies.This work was supported by grants to JW from the National Science Foundation (NSF-MCB-0947767 and NSF-PHY-76066, website: www.nsf.gov/), the National Natural Science Foundation of China (91430217, website: www.nsfc.gov.cn/publish/portal1/), and Ministry of Science and Technology of China (2016YFA0203200 and 2013YQ170585, website: http://www.most.gov.cn/eng/); WTC from the National Natural Science Foundation of China (21603217, website: www.nsfc.gov.cn/publish/portal1/), and China Postdoctoral Science Foundation (2016M590268, website: jj.chinapostdoctor.org.cn/V1/Program3/Default.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Lung adenocarcinoma originates from retrovirus infection of proliferating type 2 pneumocytes during pulmonary post-natal development or tissue repair

Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer

Subbarrel patterns in somatosensory cortical barrels can emerge from local dynamic instabilities

Complex spatial patterning, common in the brain as well as in other biological systems, can emerge as a result of dynamic interactions that occur locally within developing structures. In the rodent somatosensory cortex, groups of neurons called "barrels" correspond to individual whiskers on the contralateral face. Barrels themselves often contain subbarrels organized into one of a few characteristic patterns. Here we demonstrate that similar patterns can be simulated by means of local growth-promoting and growth-retarding interactions within the circular domains of single barrels. The model correctly predicts that larger barrels contain more spatially complex subbarrel patterns, suggesting that the development of barrels and of the patterns within them may be understood in terms of some relatively simple dynamic processes. We also simulate the full nonlinear equations to demonstrate the predictive value of our linear analysis. Finally, we show that the pattern formation is robust with respect to the geometry of the barrel by simulating patterns on a realistically shaped barrel domain. This work shows how simple pattern forming mechanisms can explain neural wiring both qualitatively and quantitatively even in complex and irregular domains. © 2009 Ermentrout et al