Automated Structure Solution with the PHENIX Suite

Significant time and effort are often required to solve and complete a macromolecular crystal structure. The development of automated computational methods for the analysis, solution and completion of crystallographic structures has the potential to produce minimally biased models in a short time without the need for manual intervention. The PHENIX software suite is a highly automated system for macromolecular structure determination that can rapidly arrive at an initial partial model of a structure without significant human intervention, given moderate resolution and good quality data. This achievement has been made possible by the development of new algorithms for structure determination, maximum-likelihood molecular replacement (PHASER), heavy-atom search (HySS), template and pattern-based automated model-building (RESOLVE, TEXTAL), automated macromolecular refinement (phenix.refine), and iterative model-building, density modification and refinement that can operate at moderate resolution (RESOLVE, AutoBuild). These algorithms are based on a highly integrated and comprehensive set of crystallographic libraries that have been built and made available to the community. The algorithms are tightly linked and made easily accessible to users through the PHENIX Wizards and the PHENIX GUI

Public Duty and Private Prejudice: Sexualities, Equalities and Local Government

Rather than critiquing social institutions and practices that have historically excluded lesbians and gay men, as did earlier social movements in the 1960s and 1970s, since the 1990s the politics of sexuality has increasingly been about demanding equal rights of citizenship. These citizenship demands have, at least to a degree, been answered via a raft of recent legislation in the UK including the Adoption and Children Act 2002, Employment Equality (Sexual Orientation) Regulations 2003, Gender Recognition Act 2004 and the Civil Partnership Act 2004, and by associated changes in policy making and practice that emphasize ‘Equality and Diversity’. In this article we consider how the implementation of sexualities equalities policies is related to processes of privatization and individualization. This is illustrated by using sexualities equalities work in local government as a case study to indicate how processes of change and resistance are aided by these processes. The article draws on findings from a study of lesbian, gay, bisexual and transgender (LGBT) equalities initiatives in local government in England, Wales and Northern Ireland, which examined the views of those who now have a public duty to implement recent legislative and policy shifts and are obliged to develop equalities initiatives concerning ‘sexual orientation' and ‘gender reassignment’

The separateness of social and emotional loneliness in childhood

Much of the childhood loneliness research is misleading because it confounds objective and subjective measures of loneliness. The overall aim of this research was to examine the relationship between social isolation and emotional loneliness. Method: Three extreme groups were identified in a sample of 640 4-9-year-old children. There were two ('rejected' [Nˆ60] and 'lonely' [Nˆ146]) in which social and emotional loneliness were unrelated. The first were socially isolated (rejected) but they did not feel lonely. The second group felt lonely but they were not socially isolated. The third group ('rejected/ lonely') consisted of 61 children who were rejected and also felt lonely. Results: Felt loneliness and social rejection were experienced together by 61 children, but 206 children experienced either one or the other, but not both. The fourth and largest group [Nˆ374] were neither rejected nor lonely. Differences between the groups were found on direct observation measures of solitariness, sociability, and aggression; peer reports of shyness, aggression, prosocial behaviour, disruptive behaviour and inability to take teasing; self-reports of self-worth and competence, self-reports of supportive relationships; and measures of language use

Enhanced cardiac phosphoinositide 3-kinase (p110α) using gene therapy attenuates cardiac remodeling in type 2 diabetic mice

Diabetic cardiomyopathy is a distinct form of heart disease that represents a major cause of death and disability in diabetic patients, particularly the more prevalent type-2 diabetic population. In the current study, we investigated administration of recombinant adeno-associated viral vectors carrying a constitutively-active PI3K(p110α) construct (rAAV6-caPI3K) at a clinically-relevant time point attenuates diabetic cardiomyopathy in a pre-clinical type-2 diabetes (T2D) model. T2D was induced by a combination of high-fat diet and low-dose streptozotocin, and confirmed by increased body weight, hyperglycemia, and impaired glucose tolerance. After 18 weeks of untreated diabetes, impaired left ventricular (LV) systolic dysfunction was evident, as confirmed by echocardiography. A single tail vein injection of rAAV6-caPI3K gene therapy was then administered. Mice were followed for an additional 8 weeks before end-point. Administration of cardiac targeted rAAV6-caPI3K attenuates diabetes-induced cardiac remodeling by limiting cardiac fibrosis and cardiomyocyte hypertrophy. The diabetes-induced LV systolic dysfunction was reversed with rAAV6-caPI3K as demonstrated by improved fractional shortening and velocity of circumferential fiber shortening. This cardioprotection occurred in combination with reduced LV ROS levels and an associated decrease in markers of endoplasmic reticulum stress. Together, the findings demonstrate that cardiac-selective increases in PI3K(p110α), via rAAV6-caPI3K, attenuates diabetic cardiomyopathy in a mouse model of T2D.Darnel Prakoso, Miles J. De Blasio, Mitchel Tate, Helen Kiriazis, Daniel G. Donner, Hongwei Qian ... et al