Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13.

Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Recently, there have been several reports that predicted loss of function variants in HSD17B13 protect against the progression of steatosis to non-alcoholic steatohepatitis with fibrosis and hepatocellular carcinoma. Here we report crystal structures of full length HSD17B13 in complex with its NAD+ cofactor, and with lipid/detergent molecules and small molecule inhibitors from two distinct series in the ligand binding pocket. These structures provide insights into a mechanism for lipid droplet-associated proteins anchoring to membranes as well as a basis for HSD17B13 variants disrupting function. Two series of inhibitors interact with the active site residues and the bound cofactor similarly, yet they occupy different paths leading to the active site. These structures provide ideas for structure-based design of inhibitors that may be used in the treatment of liver disease.

Enhanced neurotrauma services: physician input into traumatic brain injury care.

Elderly trauma victims whose care is shared between surgeons and physicians have improved clinical outcomes and shorter hospital lengths of stay (LOS). To test whether a similar benefit can be gained for patients suffering traumatic brain injury (TBI), a quality improvement project (QIP) was run in which a neurologist was enrolled into the pre-existing neurotrauma team. Mortality rates, LOS and rates of readmission within 30 days of discharge were compared between two cohorts of TBI patients: 80 admittedly prior to the QIP and 80 admitted during the QIP. The two cohorts were well matched for age, gender, mechanism of injury, Glasgow coma score and types of injury. The QIP was not associated with a reduction in mortality but was associated with a significant reduction in mean LOS (from 25.7 days to 17.5 days; p=0.04) and a reduction in readmissions (from seven to zero patients; p=0.01).

Improving the Quality of Neuropsychological Assessment Practice: The Development of a Self-Assessment Audit Tool.

OBJECTIVE: Strict competency frameworks exist for training in, and provision of, clinical neuropsychological assessment practice. However, as in all disciplines, daily clinical practice may drift from the gold standard practice without routine monitoring and audit. A simple-to-use, but thorough and evidence-based audit tool has been developed to facilitate the tracking, maintenance, and discussion of best practice over time. METHOD: A literature search and liaison with experienced neuropsychology colleagues did not unearth any pre-existing audit standards. Therefore, 39 new standards were generated, which were guided by best practice literature and clinical neuropsychology colleague discussions, to form the proposed self-assessment audit tool. Due to the diverse nature of services, both core and supplementary standards are proposed to enable the audit to be tailored to suit individual services' needs. RESULTS: During its development, the tool has so far been trialed in two U.K. National Health Service clinical services in different localities, on three occasions, with a total patient population of N = 78 in order to refine the standards and to generate practice recommendations. CONCLUSIONS: This audit tool is presented for services to self-assess their neuropsychological assessment practice. The authors plan to take this work forward with the British Psychological Society's Division of Neuropsychology as a policy document for self-assessment and peer review. Other potential developments include contributing to clinical neuropsychology training tools and refining audit standards for use more widely, such as in pediatric services, or internationally with diverse populations.

Discovery of Small-Molecule CD33 Pre-mRNA Splicing Modulators.

CD33/Siglec 3 is a myeloid lineage cell surface receptor that is known to regulate microglia activity. Multiple genome-wide association studies (GWAS) have identified genetic variants in the CD33 gene that convey protection from late-onset Alzheimer's disease. Furthermore, mechanistic studies into GWAS-linked variants suggest that disease protection is attributed to the alternative splicing of exon 2 of the CD33 pre-mRNA. Using a phenomimetic screen, a series of compounds were found to enhance the exclusion of CD33 exon 2, acting as a chemomimetic of the GWAS-linked gene variants. Additional studies confirmed that meyloid lineage cells treated with several of these compounds have a reduced full-length V-domain containing CD33 protein, while targeted RNA-seq concordantly demonstrated that compound 1 increases exon 2 skipping in cellular mRNA pools. These studies demonstrate how pharmacological interventions can be used to manipulate disease-relevant pre-mRNA splicing and provide a starting point for future efforts to identify small molecules that alter neuroimmune function that is rooted in the human biology of neurodegenerative disease.

The impact of keels and tails on turtle swimming performance and their potential as models for biomimetic design.

Stability and turning performance are two key metrics of locomotor performance in animals, and performance in both of these metrics can be improved through a variety of morphological structures. Aquatic vehicles are often designed with keels and rudders to improve their stability and turning performance, but how keels and rudders function in rigid-bodied animals is less understood. Aquatic turtles are a lineage of rigid-bodied animals that have the potential to function similarly to engineered vehicles, and also might make use of keels and rudders to improve their stability and turning performance. To test these possibilities, we trained turtles to follow a mechanically controlled prey stimulus under three sets of conditions: with no structural modifications, with different sized and shaped keels, and with restricted tail use. We predicted that keels in turtles would function similarly to those in aquatic vehicles to reduce oscillations, and that turtles would use the tail like a rudder to reduce oscillations and improve turning performance. We found that the keel designs we tested did not reduce oscillations in turtles, but that the tail was used similarly to a rudder, with benefits to both the magnitude of oscillations they experienced and turning performance. These data show how variation in the accessory structures of rigid-bodied animals can impact swimming performance, and suggest that such variation among turtles could serve as a biomimetic model in designing aquatic vehicles that are stable as well as maneuverable and agile.

Pemphigus vulgaris: a multidisciplinary approach to management.

Pemphigus vulgaris (PV) is a rare but potentially life-threatening autoimmune disease affecting the mucosa and the skin. The disease is caused by circulating antibodies to desmosomes (important adhesion proteins linking cells together). Disruption of these intercellular connections results in a loss of cohesion between cells (acantholysis). The clinical result of this process is the development of multiple blisters that easily rupture, leaving behind painful sloughing eroded areas of mucosa and/or skin. We report a case of severe PV in a 56-year-old man presenting with widespread, painful, eroded mucocutaneous lesions. The severity of the disease demanded a range of medical and surgical specialties to successfully manage the problem. This paper highlights the importance of an early multidisciplinary team approach to improve the outcome of patients suffering with this disease.

Effects of intrinsic and extrinsic motivation on attention and memory.

It is well recognised that motivational factors can influence neuropsychological performance. The aim of this study was to explore individual differences in intrinsic motivation and reward-seeking and the effect of these on attentional and mnemonic processes, in the presence or absence of financial incentives. Forty participants (18-35years) completed two testing sessions where the Attentional Network Test (ANT) and the Newcastle Spatial Memory Test (NSMT) were administered. After a baseline assessment, participants were re-tested after randomisation to a non-motivated (control) group or to a motivated group, where payment was contingent upon performance. Performance in the motivated group was significantly improved compared to the control group on the NSMT (condition by session; F(1,33)=4.52, p=0.041) and the ANT, with participants increasing performance to cued presentations within the alerting network (F(1,36)=5.48, p=0.025) and being less distracted by incongruent stimuli in the executive control network (F(1,36)=6.74, p=0.014). There were significant negative correlations between the 'Interest/ Enjoyment' Intrinsic Motivation Inventory subscale and both NSMT between-search errors and ANT(alerting). In the motivated group, those who had higher self-reported internal motivation were less susceptible to- or affected by- the external motivation of financial incentive. The effects of motivational factors should not be overlooked when interpreting absolute levels of performance in neuropsychological processes.