α_1L-adrenoceptors mediate contraction of human erectile tissue

α1-adrenoceptor antagonists can impact upon sexual function and have potential in the treatment of erectile dysfunction. Human erectile tissue contains predominantly α1A-adrenoceptors, and here we examined whether contractions of this tissue are mediated by the functional phenotype, the α1L-adrenoceptor. Functional experiments using subtype selective agonists and antagonists, along with radioligand ([3H]tamsulosin) binding assays, were used to determine the α1-adrenoceptor population. A61603, a α1A-adrenoceptor agonist, was a full agonist with a potency 21-fold greater than that of noradrenaline. The α1A- and α1D-adrenoceptor antagonist tamsulosin antagonized noradrenaline responses with high affinity (pKD = 9.7 ± 0.3), whilst BMY7378 (100 nM) (α1D-adrenoceptor antagonist) failed to antagonize responses. In contrast, relatively low affinity estimates were obtained for both prazosin (pKD = 8.2 ± 0.1) and RS17053 (pKD = 6.9 ± 0.2), antagonists which discriminate between the α1A- and α1L-adrenoceptors. [3H]Tamsulosin bound with high affinity to the receptors of human erectile tissue (pKD = 10.3 ± 0.1) with a receptor density of 28.1 ± 1.4 fmol mg−1 protein. Prazosin displacement of [3H]tamsulosin binding revealed a single homogenous population of binding sites with a relatively low affinity for prazosin (pKi = 8.9). Taken together these data confirm that the receptor mediating contraction in human erectile tissue has the pharmacological properties of the α1L-adrenoceptor. Keywords: Erectile tissue, α1-adrenoceptor subtypes, α1L-adrenoceptor, Tamsulosin, Prazosi

Parallel synthesis and splicing redirection activity of cell-penetrating peptide conjugate libraries of a PNA cargo

A novel method for the parallel synthesis of peptide-biocargo conjugates was developed that utilizes affinity purification for fast isolation of the conjugates in order to avoid time consuming HPLC purification. The methodology was applied to create two libraries of cell-penetrating peptide (CPP)-PNA705 conjugates from parallel-synthesized peptide libraries. The conjugates were tested for their ability to induce splicing redirection in HeLa pLuc705 cells. The results demonstrate how the novel methodology can be applied for screening purposes in order to find suitable CPP-biocargo combinations and further optimization of CPPs.</p

Promoting writing amongst peers: establishing a community of writing practice for early career academics

In the current research-focused climate, academics are facing increasing pressure to produce research outputs. This pressure can prove particularly daunting for early career (EC) academics, who are simultaneously attempting to master new teaching and administrative demands while establishing their own independent research trajectories. Previous reports suggest that academic writing retreats can be an effective way of increasing research outputs. Such retreats generally involve academics from a range of career stages and require expert facilitators. Through organising a series of structured writing events, this project aims to cultivate an enduring community of practice for academic writers. Reflecting on our EC retreat and subsequent writing days with academics from different career stages, we suggest that success hinged on three key factors: (1) A formal structure comprising bounded periods of intense writing, flanked by group reviewing and goal-setting; (2) Co-located writing with participants based in a shared space, away from their usual workstation and distractions; (3) Peer discussions involving participants at a similar career stage. Specifically we found that writing amongst ‘equals’ increased productivity and confidence amongst EC academics

Cytosolic Phospholipase A2α and Eicosanoids Regulate Expression of Genes in Macrophages Involved in Host Defense and Inflammation

Acknowledgments: We thank Dr. Robert Barkley and Charis Uhlson for mass spectrometry analysis. Funding: This work was supported by grants from the National Institutes of Health HL34303 (to C.C.L., R.C.M. and D.L.B), DK54741 (to J.V.B.), GM5322 (to D.L.W.) and the Wellcome Trust (to N.A.R.G. and G.D.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Prospective Trial of CPAP in Community-Dwelling Adults with Down Syndrome and Obstructive Sleep Apnea Syndrome

Adults with Down syndrome (DS) are predisposed to obstructive sleep apnoea (OSA), but the effectiveness and acceptability of continuous positive airway pressure treatment (CPAP) in this group has rarely been formally assessed. This study was designed as a pilot randomised, parallel controlled trial for one month, continuing as an uncontrolled cohort study whereby the control group also received the intervention. Symptomatic, community-dwelling DS individuals exhibiting ≥10 apnoeas/hypopneas per hour in bed on a Type 3 home sleep study were invited to participate in this study, with follow-up at 1, 3, 6, and 12 months from baseline. Measurements of sleepiness, behaviour, cognitive function and general health were undertaken; the primary outcome was a change in the pictorial Epworth Sleepiness Scale (pESS) score. Twenty-eight participants (19 male) were enrolled: age 28 ± 9 year; body mass index 31.5 ± 7.9 kg/m2; 39.6 ± 32.2 apnoeas/hypopneas per hour in bed; pESS 11 ± 6/24. The pilot randomised controlled trial at one month demonstrated no change between the groups. At 12 months, participant (p = 0.001) pESS and Disruptive (p 0.0001), Anxiety/Antisocial (p = 0.024), and Depressive (p = 0.008) behaviour scores were reduced compared to baseline. Improvement was noted in verbal (p = 0.001) and nonverbal intelligence scores (p = 0.011). General health scores also improved (p = 0.02). At the end of the trial, 19 participants continued on treatment. Use of CPAP in adults with DS and OSA led to a number of significant, sustained improvements in sleepiness and behavioural/emotional outcomes at 12 months

Environmental Exposure to Emissions from Petrochemical Sites and Lung Cancer: The Lower Mississippi Interagency Cancer Study

To investigate potential links between environmental exposure to petrochemical plant emissions and lung cancer, a population-based case-control study (LMRICS) was conducted in eleven Louisiana parishes bordering the Mississippi River. Cases and age, gender, and race-matched controls were interviewed regarding potential risk factors. Residential history was geocoded to provide indices of long-term proximity to industrial sites. Cases were more likely to have lived near a petrochemical site. Models adjusted for other risk factors, however, showed small or no association with lung cancer (odds ratio for residence within a half-mile of a site = 1.10, 95% confidence interval 0.58–2.08). While associations were strongest for exposures exceeding 15 years, none approached statistical significance and there was no clear dose-response across exposure duration, distance categories, or when sites were grouped according to carcinogenicity rating of chemical releases. Residential proximity to petrochemical plants along the lower Mississippi thus showed no significant association with lung cancer

The Effect of Tele-ICU Innovation on Progressive Care Unit Patient Population

Introduction: Although, Tele-ICU is integrated into 11% of US critical care delivery, Tele-innovation\u27s advanced monitoring, clinical decision-support functions and cognitive affordances have not been examined in PCU. We compared significant well established outcomes and quality measures between PCU standard of care and PCU Tele-intervention, namely, hospital length of stay (LOS), mortality, APACHE IV severity adjusted mortality and MSDRG severity adjusted mortality. Methods: Data about n = 13, 421 patients from 6 hospitals (Observational Case Control design) from Jan 2012 – Mar 2015 were analyzed. PCU standard of care control n=7047, PCU Tele-intervention n=6374. PCU inclusion time was defined as PCU Index = first contiguous PCU census encounter \u3e 24 hours (time thresholds derived from greater than median LOS). Intervention group inclusion defined as \u3e 24 hours Tele-intervention during PCU Index time. Results:The two groups were fairly balanced. Comparing outcomes in PCU Tele-intervention vs. PCU standard of care, respectfully, the intervention group is older (70+/-16 vs. 65+/-18, p Conclusions: In our population, Tele-ICU approach resulted in significantly decreased mortality and much shorter PCU Index LOS. These findings provide evidence of the effectiveness of Tele-innovation and validate the impact on quality and cost in the progressive care setting, providing a rationale for extension of access to Tele-PCU care services across broader hospital populations. Further investigation is needed to examine influence of Tele-PCU care service on severity adjusted predictions across varying practice settings

Benchmarking Relatedness Inference Methods with Genome-Wide Data from Thousands of Relatives

Inferring relatedness from genomic data is an essential component of genetic association studies, population genetics, forensics, and genealogy. While numerous methods exist for inferring relatedness, thorough evaluation of these approaches in real data has been lacking. Here, we report an assessment of 12 state-of-the-art pairwise relatedness inference methods using a data set with 2485 individuals contained in several large pedigrees that span up to six generations. We find that all methods have high accuracy (92–99%) when detecting first- and second-degree relationships, but their accuracy dwindles to \u3c43% for seventh-degree relationships. However, most identical by descent (IBD) segment-based methods inferred seventh-degree relatives correct to within one relatedness degree for \u3e76% of relative pairs. Overall, the most accurate methods are Estimation of Recent Shared Ancestry (ERSA) and approaches that compute total IBD sharing using the output from GERMLINE and Refined IBD to infer relatedness. Combining information from the most accurate methods provides little accuracy improvement, indicating that novel approaches, such as new methods that leverage relatedness signals from multiple samples, are needed to achieve a sizeable jump in performance

Detection and Identification of Salmonella enterica, Escherichia coli, and Shigella spp. via PCR-ESI-MS: Isolate Testing and Analysis of Food Samples

An assay to identify the common food-borne pathogens Salmonella, Escherichia coli, Shigella, and Listeria monocytogenes was developed in collaboration with Ibis Biosciences (a division of Abbott Molecular) for the Plex-ID biosensor system, a platform that uses electrospray ionization mass spectroscopy (ESI-MS) to detect the base composition of short PCR amplicons. The new food-borne pathogen (FBP) plate has been experimentally designed using four gene segments for a total of eight amplicon targets. Initial work built a DNA base count database that contains more than 140 Salmonella enterica, 139 E. coli, 11 Shigella, and 36 Listeria patterns and 18 other Enterobacteriaceae organisms. This assay was tested to determine the scope of the assay\u27s ability to detect and differentiate the enteric pathogens and to improve the reference database associated with the assay. More than 800 bacterial isolates of S. enterica, E. coli, and Shigella species were analyzed. Overall, 100% of S. enterica, 99% of E. coli, and 73% of Shigella spp. were detected using this assay. The assay was also able to identify 30% of the S. enterica serovars to the serovar level. To further characterize the assay, spiked food matrices and food samples collected during regulatory field work were also studied. While analysis of preenrichment media was inconsistent, identification of S. enterica from selective enrichment media resulted in serovar-level identifications for 8 of 10 regulatory samples. The results of this study suggest that this high-throughput method may be useful in clinical and regulatory laboratories testing for these pathogens