Identification of oligomerization and drug-binding domains of the membrane fusion protein EmrA

Many pathogenic Gram-negative bacteria possess tripartite transporters that catalyze drug extrusion across the inner and outer membranes, thereby conferring resistance. These transporters consist of inner (IMP) and outer (OMP) membrane proteins, which are coupled by a periplasmic membrane fusion (MFP) protein. However, it is not know whether the MFP translocates the drug between the membranes, by acting as a channel, or whether it brings the IMP and OMP together, facilitating drug transfer. The MFP EmrA has an elongated periplasmic domain, which binds transported drugs, and is anchored to the inner membrane by a single -helix, which contains a leucine zipper dimerization domain. Consistent with CD and hydrodynamic analyses, the periplasmic domain is predicted to be composed of a -sheet subdomain and an -helical coiled-coil. We propose that EmrA forms a trimer in which the coiled-coils radiate across the periplasm, where they could sequester the OMP TolC. The "free" leucine zipper in the EmrA trimer might stabilize the interaction with the IMP EmrB, which also possesses leucine zipper motifs in the putative N- and C-terminal helices. The -sheet subdomain of EmrA would sit at the membrane surface adjacent to the EmrB, from which it receives the transported drug, inducing a conformational change that triggers the interaction with the OMP

Misdiagnosed and misunderstood’: Insights into rarer forms of dementia through a stepwise approach to co-constructed research poetry

This study investigated co-constructed research poetry as a way to understand the lived experiences of people affected by rarer dementia and as a means to use poetry to convey those experiences to healthcare professionals. Using mixed methods, 71 people living with rarer dementia and care-partners (stakeholders) contributed to co-constructing 27 poems with professional poets; stakeholders’ verbatim words were analysed with descriptive qualitative analysis. Stakeholders were also surveyed and interviewed about their participation. Healthcare professionals (n = 93) were surveyed to elicit their responses to learning through poetry and its acceptability as a learning tool. Poems conveyed a shared narrative of different aspects of lived experience, often owing to atypical symptoms, misunderstandings by professionals, lack of support pathways, and a continuous struggle to adapt. Stakeholder surveys indicated it was a valuable experience to both co-create and respond to the poems, whilst group interviews revealed people’s experiences of the research poetry were characterised by reflection on lived experience, curiosity and exploration. Healthcare professionals’ responses reinforced poetry’s capacity to stimulate cognitive and affective learning specific to rare dementia support and prompt both empathy and critical thinking in practice. As the largest poetry-based study that we are aware of, this novel accessible approach of creating group poems yielded substantial information about the experiences and needs of those affected by rarer dementia and how poetry can contribute to healthcare education and training

PSR J1119-6127 and the X-ray Emission from High Magnetic Field Radio Pulsars

The existence of radio pulsars having inferred magnetic elds in the magnetar regime suggests that possible transition objects could be found in the radio pulsar population. The discovery of such an object would contribute greatly to our understanding of neutron star physics. Here we report on unusual X-ray emission detected from the radio pulsar PSR J1119-6127 using XMM-Newton. The pulsar has a characteristic age of 1,700 yrs and inferred surface dipole magnetic eld strength of 4.1x10^13 G. In the 0.5-2.0 keV range, the emission shows a single, narrow pulse with an unusually high pulsed fraction of ~70%. No pulsations are detected in the 2.0-10.0 keV range, where we derive an upper limit at the 99% level for the pulsed fraction of 28%. The pulsed emission is well described by a thermal blackbody model with a high temperature of 2.4x10^6 K. While no unambiguous signature of magnetar-like emission has been found in high-magnetic-eld radio pulsars, the X-ray characteristics of PSR J1119-6127 require alternate models from those of conventional thermal emission from neutron stars. In addition, PSR J1119-6127 is now the radio pulsar with the smallest characteristic age from which thermal X-ray emission has been detected

Pulsar-wind nebulae and magnetar outflows: observations at radio, X-ray, and gamma-ray wavelengths

We review observations of several classes of neutron-star-powered outflows: pulsar-wind nebulae (PWNe) inside shell supernova remnants (SNRs), PWNe interacting directly with interstellar medium (ISM), and magnetar-powered outflows. We describe radio, X-ray, and gamma-ray observations of PWNe, focusing first on integrated spectral-energy distributions (SEDs) and global spectral properties. High-resolution X-ray imaging of PWNe shows a bewildering array of morphologies, with jets, trails, and other structures. Several of the 23 so far identified magnetars show evidence for continuous or sporadic emission of material, sometimes associated with giant flares, and a few possible "magnetar-wind nebulae" have been recently identified.Comment: 61 pages, 44 figures (reduced in quality for size reasons). Published in Space Science Reviews, "Jets and Winds in Pulsar Wind Nebulae, Gamma-ray Bursts and Blazars: Physics of Extreme Energy Release

Domestic Violence and Health Care: Opening Pandora¿s Box ¿ Challenges and Dilemmas

In this article we take a critical stance toward the rational progressive narrative surrounding the integration of domestic violence within health care. Whilst changes in recent UK policy and practice have resulted in several tangible benefits, it is argued that there may be hidden dilemmas and challenges. We suggest that the medical model of care and its discursive practices position women as individually accountable for domestic violence-related symptoms and injuries. This may not only be ineffective in terms of service provision but could also have the potential to reduce the political significance of domestic violence as an issue of concern for all women. Furthermore, it is argued that the use of specific metaphors enables practitioners to distance themselves from interactions that may prove to be less comfortable and provide less than certain outcomes. Our analysis explores the possibilities for change that might currently be available. This would appear to involve a consideration of alternative discourses and the reformulation of power relations and subject positions in health care

Reframing gender and feminist knowledge construction in marketing and consumer research: missing feminisms and the case of men and masculinities

Gender has been theorised and studied in many ways and across different disciplines. Although a number of these theorisations have been recognised and adopted in marketing and consumer research, the significance of feminism in knowledge construction has largely remained what we would call ‘unfinished’. Based on a critical reframing of gender research in marketing and consumer research, in dialogue with feminist theory, this article offers theoretical and practical suggestions for how to reinvigorate these research efforts. The analysis highlights dominant theorisations of gender, relating to gender as variable, difference and role; as fundamental difference and structuring; and as cultural and identity constructions. This reframing emphasises various neglected or ‘missing feminisms’, including queer theory; critical race, intersectional and transnational feminisms; material-discursive feminism; and critical studies on men and masculinities. A more detailed discussion of the latter, as a relatively new, growing and politically contentious area, is further developed to highlight more specifically which feminist and gender theories are mainly in use in marketing and consumer research and which are little or not used. In the light of this, it is argued that marketing and related disciplines have thus far largely neglected several key contemporary gender and feminist theorisations, particularly those that centre on gender power relations. The potential impact of these theoretical frames on transdisciplinary studies in marketing and consumer research and research agenda(s) is discussed

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors