Mechanism of action of VP1-001 in cryAB(R120G)-associated and age-related cataracts

PurposeWe previously identified an oxysterol, VP1-001 (also known as compound 29), that partially restores the transparency of lenses with cataracts. To understand the mechanism of VP1-001, we tested the ability of its enantiomer, ent-VP1-001, to bind and stabilize αB-crystallin (cryAB) in vitro and to produce a similar therapeutic effect in cryAB(R120G) mutant and aged wild-type mice with cataracts. VP1-001 and ent-VP1-001 have identical physicochemical properties. These experiments are designed to critically evaluate whether stereoselective binding to cryAB is required for activity.MethodsWe compared the binding of VP1-001 and ent-VP1-001 to cryAB using in silico docking, differential scanning fluorimetry (DSF), and microscale thermophoresis (MST). Compounds were delivered by six topical administrations to mouse eyes over 2 weeks, and the effects on cataracts and lens refractive measures in vivo were examined. Additionally, lens epithelial and fiber cell morphologies were assessed via transmission electron microscopy.ResultsDocking studies suggested greater binding of VP1-001 into a deep groove in the cryAB dimer compared with ent-VP1-001. Consistent with this prediction, DSF and MST experiments showed that VP1-001 bound cryAB, whereas ent-VP1-001 did not. Accordingly, topical treatment of lenses with ent-VP1-001 had no effect, whereas VP1-001 produced a statistically significant improvement in lens clarity and favorable changes in lens morphology.ConclusionsThe ability of VP1-001 to bind native cryAB dimers is important for its ability to reverse lens opacity in mouse models of cataracts

Monitoring to conservation: The science–policy nexus of plastics and seabirds

Seabirds have been the messengers of marine plastics pollution since the 1950s, not long after plastics began to be commercially manufactured. In the decades since, a number of multilateral agreements have emerged to address marine plastics pollution that have been informed by research and monitoring on plastic ingestion in seabirds. Seabirds continue to serve as effective monitors for plastics pollution in the oceans, and increasingly of the chemical contamination from the marine environment as plastic additives and chemicals can adsorb and accumulate in seabirds’ tissues. Plastics pollution has far-reaching ecological impacts, but the motivation for addressing the issue has escalated rapidly at the international level. Seabirds are also the most globally threatened group of birds and require concerted conservation actions to mitigate population declines from multiple pressures. However, most policy mechanisms focus on the monitoring and mitigation of anthropogenically induced stressors, using seabird data, and often fail to include mechanisms to conserve the messengers. In this review, we discuss how research on the impacts of plastics on seabirds is used to inform policy and highlight the competing interests of monitoring and conservation that emerge from this approach. Finally, we discuss policy opportunities to ensure seabirds can continue to be the indicators of ocean health and simultaneously achieve conservation goals

Prevalence of microplastics and anthropogenic debris within a deep-sea food web

Microplastic particles (\u3c5 mm) are ubiquitous throughout global marine ecosystems, including the deep sea. Ingestion of microplastics and other anthropogenic microparticles is reported in diverse marine taxa across trophic levels. Trophic transfer, or the movement of microplastics across trophic levels, is reported in laboratory studies but not yet widely measured in marine food webs. The Monterey Bay submarine canyon ecosystem contains a well-studied, known deep-sea food web in which to examine the trophic fate of microplastics. We measured microplastic abundance across 17 genera spanning approximately 5 trophic levels and a diversity of feeding behaviors. Samples were collected using remotely operated vehicles and oblique midwater trawls, and gut contents of all individuals examined (n = 157) were analyzed for microplastic abundance and other anthropogenic particles greater than 100 μm using stereo microscopy. Microparticles were analyzed with Raman spectroscopy to confirm material type. Anthropogenic particles were found in all genera examined, across crustacean, fish, mollusk, and gelatinous organisms, in amounts ranging from 0 to 24 particles per individual. There was no significant relationship between microplastic amount and fish trophic level, suggesting that the trophic transfer of microparticles is not occurring. Body size was positively correlated with microplastic abundance across all taxa. The fish genus Scomber sp. drove this relationship, suggesting higher microparticle abundance in mobile individuals with broad horizontal distributions. Future work should examine physiological pathways for microplastic transport within organisms (e.g. excretion, accumulation on gills, internal translocation of particles) and between organisms within shared habitats to more fully understand the fate of microplastics within aquatic food webs

Current efforts on microplastic monitoring in Arctic fish and how to proceed

In this review, we investigated published data on the occurrence of microplastic in Arctic fish, and the suitability of the data and species for risk assessment and monitoring. As of 11.11.2021, we found nine studies in the peer-reviewed literature, one thesis and one report, confirming the occurrence of microplastic in fishes from multiple Arctic regions. The studies varied in methodology, detection and quantification limitations, reported categories of size, shape, and chemical identity. All these factors influence the numbers of microplastic reported, thus limiting comparability and hindering integrative analysis. The physiological impacts of the reported microplastic contamination cannot be determined, as all studies targeted stomach/intestine contents and did not use methods with limits of detection low enough to determine particle translocation from the intestine to other organs, tissues or body fluids within the fish. Furthermore, there is a fundamental lack of understanding the transfer and the effects of plastic additives to Arctic fishes. In addition to discussing methodological challenges and knowledge gaps, we consider ecosystem needs, commercial interests, Indigenous people’s subsistence, food safety and food sovereignty concerns, and developed a framework to harmonize and facilitate pan-Arctic microplastic monitoring.Current efforts on microplastic monitoring in Arctic fish and how to proceedacceptedVersio

Effects of a refugee elective on medical student perceptions

<p>Abstract</p> <p>Background</p> <p>There are growing numbers of refugees throughout the world. Refugee health is a relatively unstudied and rarely taught component of medical education. In response to this need, a Refugee Health Elective was begun. Medical student perceptions toward cultural aspects of medicine and refugee health before and after participation in the elective were measured.</p> <p>Methods</p> <p>Preliminary questionnaires were given to all preclinical students at the academic year commencement with follow-up questionnaires at the refugee elective's conclusion. Both questionnaires examined students' comfort in interacting with patients and familiarity with refugee medical issues, alternative medical practices, and social hindrances to medical care. The preliminary answers served as a control and follow-up questionnaire data were separated into participant/non-participant categories. All preclinical medical students at two Midwestern medical schools were provided the opportunity to participate in the Refugee Health Elective and surveys. The 3 data groups were compared using unadjusted and adjusted analysis techniques with the Kruskall-Wallis, Bonferroni and ANCOVA adjustment. P-values < 0.05 were considered significant.</p> <p>Results</p> <p>408 and 403 students filled out the preliminary and follow-up questionnaires, respectfully, 42 of whom participated in the elective. Students considering themselves minorities or multilingual were more likely to participate. Elective participants were more likely to be able to recognize the medical/mental health issues common to refugees, to feel comfortable interacting with foreign-born patients, and to identify cultural differences in understanding medical/mental health conditions, after adjusting for minority or multilingual status.</p> <p>Conclusion</p> <p>As medical schools integrate a more multicultural curriculum, a Refugee Health Elective for preclinical students can enhance awareness and promote change in attitude toward medical/mental health issues common to refugees. This elective format offers tangible and effective avenues for these topics to be addressed.</p

Predicting reliability through structured expert elicitation with the repliCATS (Collaborative Assessments for Trustworthy Science) process

As replications of individual studies are resource intensive, techniques for predicting the replicability are required. We introduce the repliCATS (Collaborative Assessments for Trustworthy Science) process, a new method for eliciting expert predictions about the replicability of research. This process is a structured expert elicitation approach based on a modified Delphi technique applied to the evaluation of research claims in social and behavioural sciences. The utility of processes to predict replicability is their capacity to test scientific claims without the costs of full replication. Experimental data supports the validity of this process, with a validation study producing a classification accuracy of 84% and an Area Under the Curve of 0.94, meeting or exceeding the accuracy of other techniques used to predict replicability. The repliCATS process provides other benefits. It is highly scalable, able to be deployed for both rapid assessment of small numbers of claims, and assessment of high volumes of claims over an extended period through an online elicitation platform, having been used to assess 3000 research claims over an 18 month period. It is available to be implemented in a range of ways and we describe one such implementation. An important advantage of the repliCATS process is that it collects qualitative data that has the potential to provide insight in understanding the limits of generalizability of scientific claims. The primary limitation of the repliCATS process is its reliance on human-derived predictions with consequent costs in terms of participant fatigue although careful design can minimise these costs. The repliCATS process has potential applications in alternative peer review and in the allocation of effort for replication studies

Network impact score is an independent predictor of post-stroke cognitive impairment: A multicenter cohort study in 2341 patients with acute ischemic stroke

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Accurate prediction of PSCI risk is challenging. The recently developed network impact score, which integrates information on infarct location and size with brain network topology, may improve PSCI risk prediction. AIMS: To determine if the network impact score is an independent predictor of PSCI, and of cognitive recovery or decline. METHODS: We pooled data from patients with acute ischemic stroke from 12 cohorts through the Meta VCI Map consortium. PSCI was defined as impairment in ≥ 1 cognitive domain on neuropsychological examination, or abnormal Montreal Cognitive Assessment. Cognitive recovery was defined as conversion from PSCI 24 months) and cognitive recovery or decline using logistic regression. Models were adjusted for age, sex, education, prior stroke, infarct volume, and study site. RESULTS: We included 2341 patients with 4657 cognitive assessments. PSCI was present in 398/844 patients (47%) 24 months. Cognitive recovery occurred in 64/181 (35%) patients and cognitive decline in 26/287 (9%). The network impact score predicted PSCI in the univariable (OR 1.50, 95%CI 1.34-1.68) and multivariable (OR 1.27, 95%CI 1.10-1.46) GEE model, with similar ORs in the logistic regression models for specified post-stroke intervals. The network impact score was not associated with cognitive recovery or decline. CONCLUSIONS: The network impact score is an independent predictor of PSCI. As such, the network impact score may contribute to a more precise and individualized cognitive prognostication in patients with ischemic stroke. Future studies should address if multimodal prediction models, combining the network impact score with demographics, clinical characteristics and other advanced brain imaging biomarkers, will provide accurate individualized prediction of PSCI. A tool for calculating the network impact score is freely available at https://metavcimap.org/features/software-tools/lsm-viewer/

Behavioral responses of terrestrial mammals to COVID-19 lockdowns

COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals' 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.acceptedVersio

Behavioral responses of terrestrial mammals to COVID-19 lockdowns

COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals' 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.acceptedVersio

DenseNet and Support Vector Machine classifications of major depressive disorder using vertex-wise cortical features

Major depressive disorder (MDD) is a complex psychiatric disorder that affects the lives of hundreds of millions of individuals around the globe. Even today, researchers debate if morphological alterations in the brain are linked to MDD, likely due to the heterogeneity of this disorder. The application of deep learning tools to neuroimaging data, capable of capturing complex non-linear patterns, has the potential to provide diagnostic and predictive biomarkers for MDD. However, previous attempts to demarcate MDD patients and healthy controls (HC) based on segmented cortical features via linear machine learning approaches have reported low accuracies. In this study, we used globally representative data from the ENIGMA-MDD working group containing an extensive sample of people with MDD (N=2,772) and HC (N=4,240), which allows a comprehensive analysis with generalizable results. Based on the hypothesis that integration of vertex-wise cortical features can improve classification performance, we evaluated the classification of a DenseNet and a Support Vector Machine (SVM), with the expectation that the former would outperform the latter. As we analyzed a multi-site sample, we additionally applied the ComBat harmonization tool to remove potential nuisance effects of site. We found that both classifiers exhibited close to chance performance (balanced accuracy DenseNet: 51%; SVM: 53%), when estimated on unseen sites. Slightly higher classification performance (balanced accuracy DenseNet: 58%; SVM: 55%) was found when the cross-validation folds contained subjects from all sites, indicating site effect. In conclusion, the integration of vertex-wise morphometric features and the use of the non-linear classifier did not lead to the differentiability between MDD and HC. Our results support the notion that MDD classification on this combination of features and classifiers is unfeasible