The ‘Dark Side’ and ‘Bright Side’ of Personality: When Too Much Conscientiousness and Too Little Anxiety Are Detrimental with Respect to the Acquisition of Medical Knowledge and Skill

Theory suggests that personality traits evolved to have costs and benefits, with the effectiveness of a trait dependent on how these costs and benefits relate to the present circumstances. This suggests that traits that are generally viewed as positive can have a ‘dark side’ and those generally viewed as negative can have a ‘bright side’ depending on changes in context. We test this in a sample of 220 UK medical students with respect to associations between the Big 5 personality traits and learning outcomes across the 5 years of a medical degree. The medical degree offers a changing learning context from pre-clinical years (where a more methodical approach to learning is needed) to the clinical years (where more flexible learning is needed, in a more stressful context). We argue that while trait conscientiousness should enhance pre-clinical learning, it has a ‘dark side’ reducing the acquisition of knowledge in the clinical years. We also suggest that anxiety has a ‘bright side’ enhancing the acquisition of skills in the clinical years. We also explore if intelligence enhances learning across the medical degree. Using confirmatory factor analysis and structural equation modelling we show that medical skills and knowledge assessed in the pre-clinical and clinical years are psychometrically distinguishable, forming a learning ‘backbone’, whereby subsequent learning outcomes are predicted by previous ones. Consistent with our predictions conscientiousness enhanced preclinical knowledge acquisition but reduced the acquisition of clinical knowledge and anxiety enhanced the acquisition of clinical skills. We also identified a curvilinear U shaped association between Surgency (extraversion) and pre-clinical knowledge acquisition. Intelligence predicted initial clinical knowledge, and had a positive total indirect effect on clinical knowledge and clinical skill acquisition. For medical selection, this suggests that selecting students high on conscientiousness may be problematic, as it may be excluding those with some degree of moderate anxiety

Enhanced Cognition and Hypoglutamatergic Signaling in a Growth Hormone Receptor Knockout Mouse Model of Successful Aging.

Growth hormone receptor knockout (GHR-KO) mice are long lived with improved health span, making this an excellent model system for understanding biochemical mechanisms important to cognitive reserve. The purpose of the present study was to elucidate differences in cognition and glutamatergic dynamics between aged (20- to 24-month-old) GHR-KO and littermate controls. Glutamate plays a critical role in hippocampal learning and memory and is implicated in several neurodegenerative disorders, including Alzheimer\u27s disease. Spatial learning and memory were assessed using the Morris water maze (MWM), whereas independent dentate gyrus (DG), CA3, and CA1 basal glutamate, release, and uptake measurements were conducted in isoflurane anesthetized mice utilizing an enzyme-based microelectrode array (MEA) coupled with constant potential amperometry. These MEAs have high temporal and low spatial resolution while causing minimal damage to the surrounding parenchyma. Littermate controls performed worse on the memory portion of the MWM behavioral task and had elevated DG, CA3, and CA1 basal glutamate and stimulus-evoked release compared with age-matched GHR-KO mice. CA3 basal glutamate negatively correlated with MWM performance. These results support glutamatergic regulation in learning and memory and may have implications for therapeutic targets to delay the onset of, or reduce cognitive decline, in Alzheimer\u27s disease

How U.S. Ocean Policy and Market Power Can Reform the Coral Reef Wildlife Trade

As the world’s largest importer of marine ornamental species for the aquaria, curio, home décor, and jewelry industries, the United States has an opportunity to leverage its considerable market power to promote more sustainable trade and reduce the effects of ornamental trade stress on coral reefs worldwide. Evidence indicates that collection of some coral reef animals for these trades has caused virtual elimination of local populations, major changes in age structure, and promotion of collection practices that destroy reef habitats. Management and enforcement of collection activities in major source countries such as Indonesia and the Philippines remain weak. Strengthening US trade laws and enforcement capabilities combined with increasing consumer and industry demand for responsible conservation can create strong incentives for improving management in source countries. This is particularly important in light of the March 2010 failure of the parties to the Convention on International Trade in Endangered Species (CITES) to take action on key groups of corals

Translational Model for External Volume Expansion in Irradiated Skin

Introduction: External Volume Expansion (EVE) treatment has gained popularity in breast reconstruction, enriching recipient sites for fat grafting. For patients receiving radiotherapy (XRT), results of EVE use vary, partly because the effects of EVE on irradiated tissue are not well understood. Based on our previous work with EVE and XRT, we developed a new translational model to investigate the effects of EVE in the setting of chronic radiation skin injury. Methods: Twenty-Eight SKH1-E mice received 50Gy of beta-radiation to each flank. Animals were monitored until chronic radiation fibrosis developed (8 weeks). EVE was then applied to one side for 6hrs on 5 consecutive days. The opposite side served as control. Hyperspectral Imaging (HSI) was used to assess perfusion changes before and after EVE. Mice were sacrificed at 5 days (n=14) and 15 days (n=14) after last application for histological analysis. Tissue samples were stained for vascularity (CD31) and collagen composition (Picro-Sirius red). Results: All animals developed skin fibrosis 8 weeks post-radiation, and changes in perfusion verified skin damage. EVE application induced edema on treated sides. Five days post-application, both sides were hypo-perfused as seen by HSI; with the EVE side 13% more ischemic than the untreated side (p\u3c0.001). Perfusion returned to control side levels by day 15. Blood vessels increased 20% by day 5 in EVE versus control. Collagen composition showed no difference in scar index analysis. Conclusion: EVE temporarily augments radiation-induced hypo-perfusion, likely due to transient edema. Fibrosis remained unchanged after EVE, possibly accounting for the limited expansion seen in patients. It appears that EVE induces angiogenic effect but does not affect dermal collagen composition. Future efforts should focus on reducing fibrosis post radiation to allow EVE to achieve its full potential, to benefit irradiated patients

Hyperspectral imaging for early detection of oxygenation and perfusion changes in irradiated skin

Studies examining acute oxygenation and perfusion changes in irradiated skin are limited. Hyperspectral imaging (HSI), a method of wide-field, diffuse reflectance spectroscopy, provides noninvasive, quantified measurements of cutaneous oxygenation and perfusion. This study examines whether HSI can assess acute changes in oxygenation and perfusion following irradiation. Skin on both flanks of nude mice (n=20) was exposed to 50 Gy of beta radiation from a strontium-90 source. Hyperspectral images were obtained before irradiation and on selected days for three weeks. Skin reaction assessment was performed concurrently with HSI. Desquamative injury formed in all irradiated areas. Skin reactions were first seen on day 7, with peak formation on day 14, and resolution beginning by day 21. HSI demonstrated increased tissue oxygenation on day 1 before cutaneous changes were observed (

Quantifying and Mitigating Motor Phenotypes Induced by Antisense Oligonucleotides in the Central Nervous System [preprint]

Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into the cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes. The effect of sugar and phosphate modifications on these phenotypes has not previously been systematically studied. Using a behavioral scoring assay customized to reflect the timing and nature of these effects, we show that both sugar and phosphate modifications influence acute motor phenotypes. Among sugar analogues, PS-DNA induces the strongest motor phenotype while 2’-substituted RNA modifications improve the tolerability of PS-ASOs. This helps explain why gapmer ASOs have been more challenging to develop clinically relative to steric blocker ASOs, which have a reduced tendency to induce these effects. Reducing the PS content of gapmer ASOs, which contain a stretch of PS-DNA, improves their toxicity profile, but in some cases also reduces their efficacy or duration of effect. Reducing PS content improved the acute tolerability of ASOs in both mice and sheep. We show that this acute toxicity is not mediated by the major nucleic acid sensing innate immune pathways. Formulating ASOs with calcium ions before injecting into the CNS further improved their tolerability, but through a mechanism at least partially distinct from the reduction of PS content. Overall, our work identifies and quantifies an understudied aspect of oligonucleotide toxicology in the CNS, explores its mechanism, and presents platform-level medicinal chemistry approaches that improve tolerability of this class of compounds

Market-Driven Innovation

A new method for starting the iterative innovation process from the market side based on a sociological trend has been developed. It eliminates the traditional difference between the innovators and the sociological group that carries this trend, which can only be achieved by combining real-world innovation with innovation education. The method for market need discovery is presented as a step-by-step process with detailed reasoning, followed by a real-world example that details the outcomes at every step along the way. The example concludes with a detailed description of the outcome after the first innovation iteration cycle. The richness of the resulting concept demonstrates that an innovation process can be successfully started from the market side via the proposed method

Population-based differences in the outcome and presentation of lung cancer patients based upon racial, histologic, and economic factors in all lung patients and those with metastatic disease

To investigate the interrelation between economic, marital, and known histopathologic/therapeutic prognostic factors in presentation and survival of patients with lung cancer in nine different ethnic groups. A retrospective review of the SEER database was conducted through the years 2007-2012. Population differences were assessed via chi-square testing. Multivariable analyses (MVA) were used to detect overall survival (OS) differences in the total population (TP, N = 153,027) and for those patients presenting with Stage IV (N = 70,968). Compared to Whites, Blacks were more likely to present with younger age, male sex, lower income, no insurance, single/widowed partnership, less squamous cell carcinomas, and advanced stage; and experience less definitive surgery, lower OS, and lung cancer-specific (LCSS) survival. White Hispanics presented with younger age, higher income, lower rates of insurance, single/widowed partnership status, advanced stage, more adenocarcinomas, and lower rates of definitive surgery, but no difference in OS and LCSS than Whites. In the TP and Stage IV populations, MVAs revealed that OS was better or equivalent to Whites for all other ethnic groups and was positively associated with insurance, marriage, and higher income. Blacks presented with more advanced disease and were more likely to succumb to lung cancer, but when adjusted for prognostic factors, they had a better OS in the TP compared to Whites. Disparities in income, marital status, and insurance rather than race affect OS of patients with lung cancer. Because of their presentation with advanced disease, Black and Hispanics are likely to have increased benefit from lung cancer screening

Population-based differences in the outcome and presentation of lung cancer patients based upon racial, histologic, and economic factors in all lung patients and those with metastatic disease

To investigate the interrelation between economic, marital, and known histopathologic/therapeutic prognostic factors in presentation and survival of patients with lung cancer in nine different ethnic groups. A retrospective review of the SEER database was conducted through the years 2007-2012. Population differences were assessed via chi-square testing. Multivariable analyses (MVA) were used to detect overall survival (OS) differences in the total population (TP, N = 153,027) and for those patients presenting with Stage IV (N = 70,968). Compared to Whites, Blacks were more likely to present with younger age, male sex, lower income, no insurance, single/widowed partnership, less squamous cell carcinomas, and advanced stage; and experience less definitive surgery, lower OS, and lung cancer-specific (LCSS) survival. White Hispanics presented with younger age, higher income, lower rates of insurance, single/widowed partnership status, advanced stage, more adenocarcinomas, and lower rates of definitive surgery, but no difference in OS and LCSS than Whites. In the TP and Stage IV populations, MVAs revealed that OS was better or equivalent to Whites for all other ethnic groups and was positively associated with insurance, marriage, and higher income. Blacks presented with more advanced disease and were more likely to succumb to lung cancer, but when adjusted for prognostic factors, they had a better OS in the TP compared to Whites. Disparities in income, marital status, and insurance rather than race affect OS of patients with lung cancer. Because of their presentation with advanced disease, Black and Hispanics are likely to have increased benefit from lung cancer screening

A Dimer of the Toll-Like Receptor 4 Cytoplasmic Domain Provides a Specific Scaffold for the Recruitment of Signalling Adaptor Proteins

The Toll-like receptor 4 (TLR4) is a class I transmembrane receptor expressed on the surface of immune system cells. TLR4 is activated by exposure to lipopolysaccharides derived from the outer membrane of Gram negative bacteria and forms part of the innate immune response in mammals. Like other class 1 receptors, TLR4 is activated by ligand induced dimerization, and recent studies suggest that this causes concerted conformational changes in the receptor leading to self association of the cytoplasmic Toll/Interleukin 1 receptor (TIR) signalling domain. This homodimerization event is proposed to provide a new scaffold that is able to bind downstream signalling adaptor proteins. TLR4 uses two different sets of adaptors; TRAM and TRIF, and Mal and MyD88. These adaptor pairs couple two distinct signalling pathways leading to the activation of interferon response factor 3 (IRF-3) and nuclear factor κB (NFκB) respectively. In this paper we have generated a structural model of the TLR4 TIR dimer and used molecular docking to probe for potential sites of interaction between the receptor homodimer and the adaptor molecules. Remarkably, both the Mal and TRAM adaptors are strongly predicted to bind at two symmetry-related sites at the homodimer interface. This model of TLR4 activation is supported by extensive functional studies involving site directed mutagenesis, inhibition by cell permeable peptides and stable protein phosphorylation of receptor and adaptor TIR domains. Our results also suggest a molecular mechanism for two recent findings, the caspase 1 dependence of Mal signalling and the protective effects conferred by the Mal polymorphism Ser180Leu