The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure.

Sphingolipids are essential components of cellular membranes and defects in their synthesis or degradation cause severe human diseases. The efficient degradation of sphingolipids in the lysosome requires lipid-binding saposin proteins and hydrolytic enzymes. The glycosphingolipid galactocerebroside is the primary lipid component of the myelin sheath and is degraded by the hydrolase β-galactocerebrosidase (GALC). This enzyme requires the saposin SapA for lipid processing and defects in either of these proteins causes a severe neurodegenerative disorder, Krabbe disease. Here we present the structure of a glycosphingolipid-processing complex, revealing how SapA and GALC form a heterotetramer with an open channel connecting the enzyme active site to the SapA hydrophobic cavity. This structure defines how a soluble hydrolase can cleave the polar glycosyl headgroups of these essential lipids from their hydrophobic ceramide tails. Furthermore, the molecular details of this interaction provide an illustration for how specificity of saposin binding to hydrolases is encoded

When to Use Transdisciplinary Approaches for Environmental Research

Transdisciplinary research (TDR) can help generate solutions to environmental challenges and enhance the uptake of research outputs, thus contributing to advance sustainability in social-ecological systems. Our aim is to support investment decisions in TDR; more specifically, to help funders, researchers, and research users to decide when and why it is most likely to be worth investing in TDR approaches. To achieve our aim, we: 1) define TDR and use a decision tree comparing it with alternative modes of research (i.e., basic, applied, disciplinary, multi-disciplinary, and interdisciplinary research) to help researchers and funders distinguish TDR from other research modes; 2) identify features of the research problem and context (complexity, diverse knowledge systems, contestation, power imbalance, and disagreement on the need for transformative change) where a TDR approach could be more appropriate than the alternative research modes; and 3) explore the idea that the intensity of the contextual features in (2), together with the problem at hand, will help determine where a research project stands in a continuum from low- to high-TDR. We present five studies exemplifying lower- to higher-TDR approaches that are distinguished by: 1) the number and variety of research participants engaged; 2) the strength of involvement of non-academic actors; and 3) the number and variety of disciplines and knowledge systems involved in the research

Comparison of Group-based Outpatient Physiotherapy With Usual Care After Total Knee Replacement: a Feasibility Study For a Randomized Controlled Trial

Objective: To evaluate the feasibility of conducting a randomized controlled trial comparing group-based outpatient physiotherapy with usual care in patients following total knee replacement. Design: A feasibility study for a randomized controlled trial. Setting: One secondary-care hospital orthopaedic centre, Bristol, UK. Participants: A total of 46 participants undergoing primary total knee replacement. Interventions: The intervention group were offered six group-based exercise sessions after surgery. The usual care group received standard postoperative care. Participants were not blinded to group allocation. Outcome measures: Feasibility was assessed by recruitment, reasons for non-participation, attendance, and completion rates of study questionnaires that included the Lower Extremity Functional Scale and Knee Injury and Osteoarthritis Outcome Score. Results: Recruitment rate was 37%. Five patients withdrew or were no longer eligible to participate. Intervention attendance was high (73%) and 84% of group participants reported they were ‘very satisfied’ with the exercises. Return of study questionnaires at six months was lower in the usual care (75%) than in the intervention group (100%). Mean (standard deviation) Lower Extremity Functional Scale scores at six months were 45.0 (20.8) in the usual care and 57.8 (15.2) in the intervention groups. Conclusion: Recruitment and retention of participants in this feasibility study was good. Group-based physiotherapy was acceptable to participants. Questionnaire return rates were lower in the usual care group, but might be enhanced by telephone follow-up. The Lower Extremity Functional Scale had high responsiveness and completion rates. Using this outcome measure, 256 participants would be required in a full-scale randomized controlled trial

Genomic signatures of population decline in the malaria mosquito Anopheles gambiae

Population genomic features such as nucleotide diversity and linkage disequilibrium are expected to be strongly shaped by changes in population size, and might therefore be useful for monitoring the success of a control campaign. In the Kilifi district of Kenya, there has been a marked decline in the abundance of the malaria vector Anopheles gambiae subsequent to the rollout of insecticide-treated bed nets. To investigate whether this decline left a detectable population genomic signature, simulations were performed to compare the effect of population crashes on nucleotide diversity, Tajima's D, and linkage disequilibrium (as measured by the population recombination parameter ρ). Linkage disequilibrium and ρ were estimated for An. gambiae from Kilifi, and compared them to values for Anopheles arabiensis and Anopheles merus at the same location, and for An. gambiae in a location 200 km from Kilifi. In the first simulations ρ changed more rapidly after a population crash than the other statistics, and therefore is a more sensitive indicator of recent population decline. In the empirical data, linkage disequilibrium extends 100-1000 times further, and ρ is 100-1000 times smaller, for the Kilifi population of An. gambiae than for any of the other populations. There were also significant runs of homozygosity in many of the individual An. gambiae mosquitoes from Kilifi. These results support the hypothesis that the recent decline in An. gambiae was driven by the rollout of bed nets. Measuring population genomic parameters in a small sample of individuals before, during and after vector or pest control may be a valuable method of tracking the effectiveness of interventions

The validity of US nutritional surveillance: USDA's loss-adjusted food availability data series 1971-2010

The purpose of this study was to examine the validity of the 1971-2010 United States Department of Agriculture’s (USDA’s) loss-adjusted food availability (LAFA) per capita caloric consumption estimates. Estimated total daily energy expenditure (TEE) was calculated for nationally representative samples of US adults, 20-74 years, using the Institute of Medicine’s predictive equations with “low-active” (TEE L-ACT) and “sedentary” (TEE SED) physical activity values. TEE estimates were subtracted from LAFA estimates to create disparity values (kcal/d). A validated mathematical model was applied to calculate expected weight change in reference individuals resulting from the disparity. From 1971-2010, the disparity between LAFA and TEE L-ACT varied by 394 kcal/d—(P < 0.001), from −205 kcal/d (95% CI: −214, −196) to +189 kcal/d (95% CI: 168, 209). The disparity between LAFA and TEE SED varied by 412 kcal/d (P < 0.001), from −84 kcal/d (95% CI: −93, −76) to +328 kcal/d (95% CI: 309, 348). Our model suggests that if LAFA estimates were actually consumed, reference individuals would have lost ~1-4 kg/y from 1971-1980 (an accumulated loss of ~12 to ~36 kg), and gained ~3-7 kg/y from 1988-2010 (an accumulated gain of ~42 to ~98 kg). These estimates differed from the actual measured increments of 10 kg and 9 kg in reference men and women, respectively, over the 39-year period. The USDA LAFA data provided inconsistent, divergent estimates of per capita caloric consumption over its 39-year history. The large, variable misestimation suggests that the USDA LAFA per capita caloric intake estimates lack validity and should not be used to inform public policy

“Artlift” Arts-on-Referral Intervention in UK Primary Care: Updated findings from an ongoing observational study

Background: Arts for health interventions are an accepted option for medical management of mental wellbeing in health care. Updated findings are presented from a prospective longitudinal follow-up (observational) design study of an arts on referral programme in UK general practice, over a 7-year period (2009–2016). Methods: Primary care process and mental wellbeing outcomes were investigated, including progress through the intervention, changes in mental wellbeing, and factors associated with those outcomes. A total of n =1297 patients were referred to an eight or 10-week intervention over a period from 2009 to 2016. Patient sociodemographic information was recorded at baseline, and patient progress (e.g. attendance) assessed throughout the intervention. Results: Of all referrals, 51.7% completed their course of prescribed art (the intervention). Of those that attended, 74.7% engaged with the intervention as rated by the artists leading the courses. A significant increase in wellbeing was observed from pre- to post-intervention (t = −19.29, df =523, P < 0.001, two-tailed) for those that completed and/or engaged. A sub sample (N =103) of these referrals self-reported multi-morbidities. These multiple health care service users were majority completers (79.6%), and were rated as having engaged (81.0%). This group also had a significant increase in well-being, although this was smaller than for the group as a whole (t = −7.38, df =68, P < 0.001). Conclusion: Findings confirm that art interventions can be effective in the promotion of well-being for those that complete, including those referred with multi-morbidity, with significant changes in wellbeing evident across the intervention periods

A global model of the response of tropical and sub-tropical forest biodiversity to anthropogenic pressures

Habitat loss and degradation, driven largely by agricultural expansion and intensification, present the greatest immediate threat to biodiversity. Tropical forests harbour among the highest levels of terrestrial species diversity and are likely to experience rapid land-use change in the coming decades. Synthetic analyses of observed responses of species are useful for quantifying how land use affects biodiversity and for predicting outcomes under land-use scenarios. Previous applications of this approach have typically focused on individual taxonomic groups, analysing the average response of the whole community to changes in land use. Here, we incorporate quantitative remotely sensed data about habitats in, to our knowledge, the first worldwide synthetic analysis of how individual species in four major taxonomic groups—invertebrates, ‘herptiles’ (reptiles and amphibians), mammals and birds—respond to multiple human pressures in tropical and sub-tropical forests. We show significant independent impacts of land use, human vegetation offtake, forest cover and human population density on both occurrence and abundance of species, highlighting the value of analysing multiple explanatory variables simultaneously. Responses differ among the four groups considered, and—within birds and mammals—between habitat specialists and habitat generalists and between narrow-ranged and wide-ranged species

Bridging the research-implementation gap in IUCN Red List assessments

The International Union for Conservation of Nature (IUCN) Red List of Threatened Species is central in biodiversity conservation, but insufficient resources hamper its long-term growth, updating, and consistency. Models or automated calculations can alleviate those challenges by providing standardised estimates required for assessments, or prioritising species for (re-)assessments. However, while numerous scientific papers have proposed such methods, few have been integrated into assessment practice, highlighting a critical research-implementation gap. We believe this gap can be bridged by fostering communication and collaboration between academic researchers and Red List practitioners, and by developing and maintaining user-friendly platforms to automate application of the methods. We propose that developing methods better encompassing Red List criteria, systems, and drivers is the next priority to support the Red List.Peer reviewe

A developmental approach to diversifying neuroscience through effective mentorship practices: perspectives on cross-identity mentorship and a critical call to action.

Many early-career neuroscientists with diverse identities may not have mentors who are more advanced in the neuroscience pipeline and have a congruent identity due to historic biases, laws, and policies impacting access to education. Cross-identity mentoring relationships pose challenges and power imbalances that impact the retention of diverse early career neuroscientists, but also hold the potential for a mutually enriching and collaborative relationship that fosters the mentee\u27s success. Additionally, the barriers faced by diverse mentees and their mentorship needs may evolve with career progression and require developmental considerations. This article provides perspectives on factors that impact cross-identity mentorship from individuals participating in Diversifying the Community of Neuroscience (CNS)-a longitudinal, National Institute of Neurological Disorders and Stroke (NINDS) R25 neuroscience mentorship program developed to increase diversity in the neurosciences. Participants in Diversifying CNS were comprised of 14 graduate students, postdoctoral fellows, and early career faculty who completed an online qualitative survey on cross-identity mentorship practices that impact their experience in neuroscience fields. Qualitative survey data were analyzed using inductive thematic analysis and resulted in four themes across career levels: (1) approach to mentorship and interpersonal dynamics, (2) allyship and management of power imbalance, (3) academic sponsorship, and (4) institutional barriers impacting navigation of academia. These themes, along with identified mentorship needs by developmental stage, provide insights mentors can use to better support the success of their mentees with diverse intersectional identities. As highlighted in our discussion, a mentor\u27s awareness of systemic barriers along with active allyship are foundational for their role