A Phosphomimetic Mutation Stabilizes SOD1 and Rescues Cell Viability in the Context of an ALS-Associated Mutation

The majority of amyotrophic lateral sclerosis (ALS)-related mutations in the enzyme Cu,Zn superoxide dismutase (SOD1), as well as a post-translational modification, glutathionylation, destabilize the protein and lead to a misfolded oligomer that is toxic to motor neurons. The biophysical role of another physiological SOD1 modification, T2-phosphorylation, has remained a mystery. Here, we find that a phosphomimetic mutation, T2D, thermodynamically stabilizes SOD1 even in the context of a strongly SOD1-destabilizing mutation, A4V, one of the most prevalent and aggressive ALS-associated mutations in North America. This stabilization protects against formation of toxic SOD oligomers and positively impacts motor neuron survival in cellular assays. We solve the crystal structure of T2D-SOD1 and explain its stabilization effect using discrete molecular dynamics (DMD) simulations. These findings imply that T2-phosphorylation may be a plausible innate cellular protection response against SOD1-induced cytotoxicity, and stabilizing the SOD1 native conformation might offer us viable pharmaceutical strategies against currently incurable ALS

Biomarker Validation of Dietary Intervention in Two Multiethnic Populations

Introduction: Intervention studies have been designed to change dietary and lifestyle factors associated with chronic diseases, but self-reported behavior change may incorporate intervention-related bias. This study examines plasma nutrient concentration and correlations with self-reports in the Healthy Directions intervention study. The Healthy Directions intervention studies were designed to increase multivitamin use, fruit and vegetable consumption, and physical activity in working-class, multiethnic populations. Methods: Participants in both studies completed interviewer-administered questionnaires that collected information on sociodemographic and health behavior characteristics. Postintervention blood samples were collected from 209 participants and pooled in pairs within study and within intervention group. Results: We found significantly higher plasma concentrations of retinol (P = .01) and α-carotene (P = .03) in the intervention than in the usual care group. Self-reported multivitamin users had significantly higher concentrations of retinol (P < .001), β-carotene (P = .02), and α-tocopherol (P < .001). Those who reported four or more fruit and vegetable servings per day had higher lutein and zeaxanthin (P = .05) and β-cryptoxanthin (P = .05) concentrations than those consuming fewer. Plasma nutrient concentrations were associated with reported multivitamin use and fruit and vegetable intake, but the correlations were generally higher in the usual care group. Conclusion: We found significant postintervention differences in plasma carotenoid and tocopherol concentrations by treatment group, multivitamin use, and fruit and vegetable intake. However, because we only obtained postintervention blood samples, we were unable to assess preintervention-to-postintervention changes in plasma nutrients. Self-reported intakes were significantly correlated with plasma nutrient concentrations, but the strength of the correlations differed by group, suggesting some intervention-related bias in the questionnaire responses

Nutrient addition increases grassland sensitivity to droughts

Grasslands worldwide are expected to experience an increase in extreme events such asdrought, along with simultaneous increases in mineral nutrient inputs as a result of human industrialactivities. These changes are likely to interact because elevated nutrient inputs may alter plantdiversity and increase the sensitivity to droughts. Dividing a system?s sensitivity to drought intoresistance to change during the drought and rate of recovery after the drought generates insights intodifferent dimensions of the system?s resilience in the face of drought. Here, we examine the effects ofexperimental nutrient fertilization and the resulting diversity loss on the resistance to and recoveryfrom severe regional droughts. We do this at 13 North American sites spanning gradients of aridity, 5annual grasslands in California and 8 perennial grasslands in the Great Plains. We measured rate ofresistance as the change in annual aboveground biomass (ANPP) per unit change in growing seasonprecipitation as conditions declined from normal to drought. We measured recovery as the change inANPP during the post drought period and the return to normal precipitation. Resistance and recoverydid not vary across the 400 mm range of mean growing season precipitation spanned by our sites inthe Great Plains. However, chronic nutrient fertilization in the Great Plains reduced drought resistanceand increased drought recovery. In the California annual grasslands, arid sites had a greater recoverypost-drought than mesic sites, and nutrient addition had no consistent effects on resistance orrecovery. Across all study sites, we found that pre-drought species richness in natural grasslands wasnot consistently associated with rates of resistance to or recovery from the drought, in contrast toearlier findings from experimentally assembled grassland communities. Taken together, these resultssuggest that human-induced eutrophication may destabilize grassland primary production, but theeffects of this may vary across regions and flora, especially between perennial and annual-dominatedgrasslands.Fil: Bharath, Siddharth. University of Minnesota; Estados UnidosFil: Borer, Elizabeth. University of Minnesota; Estados UnidosFil: Biederman, Lori A.. owa State University; Estados UnidosFil: Blumenthal, Dana M.. State University of Colorado - Fort Collins; Estados UnidosFil: Fay, Philip A.. United States Department of Agriculture; Estados UnidosFil: Gherardi, Laureano. Arizona State University; Estados UnidosFil: Knops, Johannes M. H.. United States Department of Agriculture; Estados UnidosFil: Leakey, Andrew D. B.. State University of Colorado - Fort Collins; Estados UnidosFil: Yahdjian, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Seabloom, Eric. University of Minnesota; Estados Unido

A Changing Paradigm in High School Mathematics

In the United States, the prevailing high school mathematics course sequence begins with a year of Algebra I, followed by a year of geometry and a year of Algebra II. Educators and others have raised concerns about the extent to which this sequence, which prioritizes the mastery of algebra, is appropriate for the longer term education and career goals of students who do not intend to pursue STEM degrees in college. These concerns have impelled educators and policymakers to reexamine the prominence of algebra in high school mathematics curricula and to consider new approaches that provide students with more mathematics course options better aligned with their academic and career goals. This paper explores existing approaches to high school mathematics curricula as well as new developments in the field. The authors discuss a range of high school mathematics course sequences and look at some of the systemic challenges embedded within the traditional paradigm. They also examine federal and state changes to the provision of high school mathematics in the early 21st century, the influence of postsecondary institutions on high school math curricula, and innovative high school math reforms occurring in Ohio, California, Oregon, Texas, and Washington. The paper concludes with a discussion of how the Charles A. Dana Center’s new initiative, Launch Years, works to reimagine high school mathematics and its relationship to postsecondary education and careers

Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

Protein aggregation is a hallmark of neurodegenerative disease and is hypothesized to cause neuron death. Despite extensive study of disease-associated aggregating proteins, mechanisms of neuron death remain a mystery, and no cures or effective treatments yet exist. Here, we demonstrate the toxicity of a small aggregate of the Cu,Zn superoxide dismutase (SOD1) protein, associated with amyotrophic lateral sclerosis (ALS). We present an experimentally verified structural model of this toxic species and show that SOD1 mutants designed to promote formation of this aggregate increase cell death, providing a direct link between aggregate presence and neuron death. Knowledge of toxic species and the ability to manipulate their formation provides a valuable direction for pursuit of therapeutic strategies in ALS

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs

Population genomics of domestic and wild yeasts

The natural genetics of an organism is determined by the distribution of sequences of its genome. Here we present one- to four-fold, with some deeper, coverage of the genome sequences of over seventy isolates of the domesticated baker&#x27;s yeast, _Saccharomyces cerevisiae_, and its closest relative, the wild _S. paradoxus_, which has never been associated with human activity. These were collected from numerous geographic locations and sources (including wild, clinical, baking, wine, laboratory and food spoilage). These sequences provide an unprecedented view of the population structure, natural (and artificial) selection and genome evolution in these species. Variation in gene content, SNPs, indels, copy numbers and transposable elements provide insights into the evolution of different lineages. Phenotypic variation broadly correlates with global genome-wide phylogenetic relationships however there is no correlation with source. _S. paradoxus_ populations are well delineated along geographic boundaries while the variation among worldwide _S. cerevisiae_ isolates show less differentiation and is comparable to a single _S. paradoxus_ population. Rather than one or two domestication events leading to the extant baker&#x27;s yeasts, the population structure of _S. cerevisiae_ shows a few well defined geographically isolated lineages and many different mosaics of these lineages, supporting the notion that human influence provided the opportunity for outbreeding and production of new combinations of pre-existing variation

Plant species’ origin predicts dominance and response to nutrient enrichment and herbivores in global grasslands

Exotic species dominate many communities; however the functional significance of species' biogeographic origin remains highly contentious. This debate is fuelled in part by the lack of globally replicated, systematic data assessing the relationship between species provenance, function and response to perturbations. We examined the abundance of native and exotic plant species at 64 grasslands in 13 countries, and at a subset of the sites we experimentally tested native and exotic species responses to two fundamental drivers of invasion, mineral nutrient supplies and vertebrate herbivory. Exotic species are six times more likely to dominate communities than native species. Furthermore, while experimental nutrient addition increases the cover and richness of exotic species, nutrients decrease native diversity and cover. Native and exotic species also differ in their response to vertebrate consumer exclusion. These results suggest that species origin has functional significance, and that eutrophication will lead to increased exotic dominance in grasslands

Drivers of the microbial metabolic quotient across global grasslands

Aim: The microbial metabolic quotient (MMQ; mg CO2-C/mg MBC/h), defined as the amount of microbial CO2 respired (MR; mg CO2-C/kg soil/h) per unit of microbial biomass C (MBC; mg C/kg soil), is a key parameter for understanding the microbial regulation of the carbon (C) cycle, including soil C sequestration. Here, we experimentally tested hypotheses about the individual and interactive effects of multiple nutrient addition (nitrogen + phosphorus + potassium + micronutrients) and herbivore exclusion on MR, MBC and MMQ across 23 sites (five continents). Our sites encompassed a wide range of edaphoclimatic conditions; thus, we assessed which edaphoclimatic variables affected MMQ the most and how they interacted with our treatments. Location: Australia, Asia, Europe, North/South America. Time period: 2015–2016. Major taxa: Soil microbes. Methods: Soils were collected from plots with established experimental treatments. MR was assessed in a 5-week laboratory incubation without glucose addition, MBC via substrate-induced respiration. MMQ was calculated as MR/MBC and corrected for soil temperatures (MMQsoil). Using linear mixed effects models (LMMs) and structural equation models (SEMs), we analysed how edaphoclimatic characteristics and treatments interactively affected MMQsoil. Results: MMQsoil was higher in locations with higher mean annual temperature, lower water holding capacity and lower soil organic C concentration, but did not respond to our treatments across sites as neither MR nor MBC changed. We attributed this relative homeostasis to our treatments to the modulating influence of edaphoclimatic variables. For example, herbivore exclusion, regardless of fertilization, led to greater MMQsoil only at sites with lower soil organic C (&lt; 1.7%). Main conclusions: Our results pinpoint the main variables related to MMQsoil across grasslands and emphasize the importance of the local edaphoclimatic conditions in controlling the response of the C cycle to anthropogenic stressors. By testing hypotheses about MMQsoil across global edaphoclimatic gradients, this work also helps to align the conflicting results of prior studies

The use of phylogeny to interpret cross-cultural patterns in plant use and guide medicinal plant discovery: an example from Pterocarpus (Leguminosae)

The study of traditional knowledge of medicinal plants has led to discoveries that have helped combat diseases and improve healthcare. However, the development of quantitative measures that can assist our quest for new medicinal plants has not greatly advanced in recent years. Phylogenetic tools have entered many scientific fields in the last two decades to provide explanatory power, but have been overlooked in ethnomedicinal studies. Several studies show that medicinal properties are not randomly distributed in plant phylogenies, suggesting that phylogeny shapes ethnobotanical use. Nevertheless, empirical studies that explicitly combine ethnobotanical and phylogenetic information are scarce.In this study, we borrowed tools from community ecology phylogenetics to quantify significance of phylogenetic signal in medicinal properties in plants and identify nodes on phylogenies with high bioscreening potential. To do this, we produced an ethnomedicinal review from extensive literature research and a multi-locus phylogenetic hypothesis for the pantropical genus Pterocarpus (Leguminosae: Papilionoideae). We demonstrate that species used to treat a certain conditions, such as malaria, are significantly phylogenetically clumped and we highlight nodes in the phylogeny that are significantly overabundant in species used to treat certain conditions. These cross-cultural patterns in ethnomedicinal usage in Pterocarpus are interpreted in the light of phylogenetic relationships.This study provides techniques that enable the application of phylogenies in bioscreening, but also sheds light on the processes that shape cross-cultural ethnomedicinal patterns. This community phylogenetic approach demonstrates that similar ethnobotanical uses can arise in parallel in different areas where related plants are available. With a vast amount of ethnomedicinal and phylogenetic information available, we predict that this field, after further refinement of the techniques, will expand into similar research areas, such as pest management or the search for bioactive plant-based compounds