Reciprocal innovation: A new approach to equitable and mutually beneficial global health partnerships.

Global health researchers often discount mutual learning and benefit to address shared health challenges across high and low- and middle-income settings. Drawing from a 30-year partnership called AMPATH that started between Indiana University in the US and Moi University in Kenya, we describe an innovative approach and program for mutual learning and benefit coined 'reciprocal innovation.' Reciprocal innovation harnesses a bidirectional, co-constituted, and iterative exchange of ideas, resources, and innovations to address shared health challenges across diverse global settings. The success of AMPATH in Kenya, particularly in HIV/AIDS and community health, resulted in several innovations being 'brought back' to the US. To promote the bidirectional flow of learning and innovations, the Indiana CTSI reciprocal innovation program hosts annual meetings of multinational researchers and practitioners to identify shared health challenges, supports pilot grants for projects with reciprocal exchange and benefit, and produces educational and training materials for investigators. The transformative power of global health to address systemic health inequities embraces equitable and reciprocal partnerships with mutual benefit across countries and communities of academics, practitioners, and policymakers. Leveraging a long-standing partnership, the Indiana CTSI has built a reciprocal innovation program with promise to redefine global health for shared wellbeing at a global scale.

Advancing medical technology innovation and clinical translation via a model of industry-enabled technical and educational support: Indiana Clinical and Translational Sciences Institute's Medical Technology Advance Program.

The success rate for translation of newly engineered medical technologies into clinical practice is low. Traversing the "translational valleys of death" requires a high level of knowledge of the complex landscape of technical, ethical, regulatory, and commercialization challenges along a multi-agency path of approvals. The Indiana Clinical and Translational Sciences Institute developed a program targeted at increasing that success rate through comprehensive training, education, and resourcing. The Medical Technology Advance Program (MTAP) provides technical, educational, and consultative assistance to investigators that leverages partnerships with experts in the health products industry to speed progress toward clinical implementation. The training, resourcing, and guidance are integrated through the entire journey of medical technology translation. Investigators are supported through a set of courses that cover bioethics, ethical engineering, preclinical and clinical study design, regulatory submissions, entrepreneurship, and commercialization. In addition to the integrated technical and educational resources, program experts provide direct consultation for planning each phase along the life cycle of translation. Since 2008, nearly 200 investigators have gained assistance from MTAP resulting in over 100 publications and patents. This support via medicine-engineering-industry partnership provides a unique and novel opportunity to expedite new medical technologies into clinical and product implementation.

Erratum: Advancing medical technology innovation and clinical translation via a model of industry-enabled technical and educational support: Indiana Clinical and Translational Sciences Institute's Medical Technology Advance Program - ERRATUM.

[This corrects the article DOI: 10.1017/cts.2021.1.].

Characterization of selenocysteine methyltransferases from Astragalus species with contrasting selenium accumulation capacity.

A group of selenium (Se)-hyperaccumulating species belonging to the genus Astragalus are known for their capacity to accumulate up to 0.6% of their foliar dry weight as Se, with most of this Se being in the form of Se-methylselenocysteine (MeSeCys). Here, we report the isolation and molecular characterization of the gene that encodes a putative selenocysteine methyltransferase (SMT) enzyme from the non-accumulator Astragalus drummondii and biochemically compare it with an authentic SMT enzyme from the Se-hyperaccumulator Astragalus bisulcatus, a related species that lives within the same native habitat. The non-accumulator enzyme (AdSMT) shows a high degree of homology with the accumulator enzyme (AbSMT) but lacks the selenocysteine methyltransferase activity in vitro, explaining why little or no detectable levels of MeSeCys accumulation are observed in the non-accumulator plant. The insertion of mutations on the coding region of the non-accumulator AdSMT enzyme to better resemble enzymes that originate from Se accumulator species results in increased selenocysteine methyltransferase activity, but these mutations were not sufficient to fully gain the activity observed in the AbSMT accumulator enzyme. We demonstrate that SMT is localized predominantly within the chloroplast in Astragalus, the principal site of Se assimilation in plants. By using a site-directed mutagenesis approach, we show that an Ala to Thr amino acid mutation at the predicted active site of AbSMT results in a new enzymatic capacity to methylate homocysteine. The mutated AbSMT enzyme exhibited a sixfold higher capacity to methylate selenocysteine, thereby establishing the evolutionary relationship of SMT and homocysteine methyltransferase enzymes in plants.

The Access Technology Program of the Indiana Clinical Translational Sciences Institute (CTSI): A model to facilitate access to cutting-edge technologies across a state.

INTRODUCTION: Access to cutting-edge technologies is essential for investigators to advance translational research. The Indiana Clinical and Translational Sciences Institute (CTSI) spans three major and preeminent universities, four large academic campuses across the state of Indiana, and is mandate to provide best practices to a whole state. METHODS: To address the need to facilitate the availability of innovative technologies to its investigators, the Indiana CTSI implemented the Access Technology Program (ATP). The activities of the ATP, or any program of the Indiana CTSI, are challenged to connect technologies and investigators on the multiple Indiana CTSI campuses by the geographical distances between campuses (1-4 hr driving time). RESULTS: Herein, we describe the initiatives developed by the ATP to increase the availability of state-of-the-art technologies to its investigators on all Indiana CTSI campuses, and the methods developed by the ATP to bridge the distance between campuses, technologies, and investigators for the advancement of clinical translational research. CONCLUSIONS: The methods and practices described in this publication may inform other approaches to enhance translational research, dissemination, and usage of innovative technologies by translational investigators, especially when distance or multi-campus cultural differences are factors to efficient application.

Proteomic Analysis of 3T3-L1 Adipocytes Treated with Insulin and TNF-α.

Insulin resistance is an indication of early stage Type 2 diabetes (T2D). Insulin resistant adipose tissues contain higher levels of insulin than the physiological level, as well as higher amounts of intracellular tumor necrosis factor-α (TNF-α) and other cytokines. However, the mechanism of insulin resistance remains poorly understood. To better understand the roles played by insulin and TNF-α in insulin resistance, we performed proteomic analysis of differentiated 3T3-L1 adipocytes treated with insulin (Ins), TNF-α (TNF), and both (Ins + TNF). Out of the 693 proteins identified, the abundances of 78 proteins were significantly different (p < 0.05). Carnitine parmitoyltransferase-2 (CPT2), acetyl CoA carboxylase 1 (ACCAC-1), ethylmalonyl CoA decarboxylase (ECHD1), and methylmalonyl CoA isomerase (MCEE), enzymes required for fatty acid ß-oxidation and respiratory electron transport, and ß-glucuronidase, an enzyme responsible for the breakdown of complex carbohydrates, were down-regulated in all the treatment groups, compared to the control group. In contrast, superoxide dismutase 2 (SOD2), protein disulfide isomerase (PDI), and glutathione reductase, which are the proteins responsible for cytoskeletal structure, protein folding, degradation, and oxidative stress responses, were up-regulated. This suggests higher oxidative stress in cells treated with Ins, TNF, or both. We proposed a conceptual metabolic pathway impacted by the treatments and their possible link to insulin resistance or T2D.

Project development teams: a novel mechanism for accelerating translational research.

The trend in conducting successful biomedical research is shifting from individual academic labs to coordinated collaborative research teams. Teams of experienced investigators with a wide variety of expertise are now critical for developing and maintaining a successful, productive research program. However, assembling a team whose members have the right expertise requires a great deal of time and many resources. To assist investigators seeking such resources, the Indiana Clinical and Translational Sciences Institute (Indiana CTSI) created the Project Development Teams (PDTs) program to support translational research on and across the Indiana University-Purdue University Indianapolis, Indiana University, Purdue University, and University of Notre Dame campuses. PDTs are multidisciplinary committees of seasoned researchers who assist investigators, at any stage of research, in transforming ideas/hypotheses into well-designed translational research projects. The teams help investigators capitalize on Indiana CTSI resources by providing investigators with, as needed, mentoring and career development; protocol development; pilot funding; institutional review board, regulatory, and/or nursing support; intellectual property support; access to institutional technology; and assistance with biostatistics, bioethics, recruiting participants, data mining, engaging community health, and collaborating with other investigators.Indiana CTSI leaders have analyzed metrics, collected since the inception of the PDT program in 2008 from both investigators and team members, and found evidence strongly suggesting that the highly responsive teams have become an important one-stop venue for facilitating productive interactions between basic and clinical scientists across four campuses, have aided in advancing the careers of junior faculty, and have helped investigators successfully obtain external funds.

Production of Se-methylselenocysteine in transgenic plants expressing selenocysteine methyltransferase.

BACKGROUND: It has become increasingly evident that dietary Se plays a significant role in reducing the incidence of lung, colorectal and prostate cancer in humans. Different forms of Se vary in their chemopreventative efficacy, with Se-methylselenocysteine being one of the most potent. Interestingly, the Se accumulating plant Astragalus bisulcatus (Two-grooved poison vetch) contains up to 0.6% of its shoot dry weight as Se-methylselenocysteine. The ability of this Se accumulator to biosynthesize Se-methylselenocysteine provides a critical metabolic shunt that prevents selenocysteine and selenomethionine from entering the protein biosynthetic machinery. Such a metabolic shunt has been proposed to be vital for Se tolerance in A. bisulcatus. Utilization of this mechanism in other plants may provide a possible avenue for the genetic engineering of Se tolerance in plants ideally suited for the phytoremediation of Se contaminated land. Here, we describe the overexpression of a selenocysteine methyltransferase from A. bisulcatus to engineer Se-methylselenocysteine metabolism in the Se non-accumulator Arabidopsis thaliana (Thale cress). RESULTS: By over producing the A. bisulcatus enzyme selenocysteine methyltransferase in A. thaliana, we have introduced a novel biosynthetic ability that allows the non-accumulator to accumulate Se-methylselenocysteine and gamma-glutamylmethylselenocysteine in shoots. The biosynthesis of Se-methylselenocysteine in A. thaliana also confers significantly increased selenite tolerance and foliar Se accumulation. CONCLUSION: These results demonstrate the feasibility of developing transgenic plant-based production of Se-methylselenocysteine, as well as bioengineering selenite resistance in plants. Selenite resistance is the first step in engineering plants that are resistant to selenate, the predominant form of Se in the environment.

Methyl jasmonate alters N partitioning, N reserves accumulation and induces gene expression of a 32-kDa vegetative storage protein that possesses chitinase activity in Medicago sativa taproots.

This study presents the effects of methyl jasmonate (MeJA) on growth, N uptake, N partitioning, and N storage in taproots of non-nodulated alfalfa (cv. Lodi). When compared to untreated plants, addition of 100 micro M MeJA to the nutrient solution for 14 days reduced total growth and modified biomass partitioning between shoots and roots in favour of taproots and lateral roots. MeJA decreased N uptake (after 7 days) and increased N partitioning towards roots after 14 days. This preferential N partitioning to roots was accompanied by increased N storage in taproots as soluble proteins. Compared to total soluble proteins, VSP accumulation occurred earlier (7 days), and was greater (2-fold increase) in plants treated with 100 micro M MeJA. Steady-state transcript levels for two VSPs (32 and 57 kDa) also increased markedly (about 4-fold) in roots of plants treated with 100 micro M MeJA. This suggests that MeJA could act directly (transcriptional regulation) or indirectly (via the changes of N partitioning among alfalfa organs) on N storage as soluble proteins and in particular, VSPs. Because the deduced amino acid sequence of the 32 kDa VSP clone reveals high homology with Class III chitinases, we propose that the 32 kDa VSP may have a role in pathogen defense, in addition to its function as a storage protein.

Analysis of sulfur and selenium assimilation in Astragalus plants with varying capacities to accumulate selenium.

Several Astragalus species have the ability to hyperaccumulate selenium (Se) when growing in their native habitat. Given that the biochemical properties of Se parallel those of sulfur (S), we examined the activity of key S assimilatory enzymes ATP sulfurylase (ATPS), APS reductase (APR), and serine acetyltransferase (SAT), as well as selenocysteine methyltransferase (SMT), in eight Astragalus species with varying abilities to accumulate Se. Se hyperaccumulation was found to positively correlate with shoot accumulation of S-methylcysteine (MeCys) and Se-methylselenocysteine (MeSeCys), in addition to the level of SMT enzymatic activity. However, no correlation was observed between Se hyperaccumulation and ATPS, APR, and SAT activities in shoot tissue. Transgenic Arabidopsis thaliana overexpressing both ATPS and APR had a significant enhancement of selenate reduction as a proportion of total Se, whereas SAT overexpression resulted in only a slight increase in selenate reduction to organic forms. In general, total Se accumulation in shoots was lower in the transgenic plants overexpressing ATPS, PaAPR, and SAT. Root growth was adversely affected by selenate treatment in both ATPS and SAT overexpressors and less so in the PaAPR transgenic plants. Such observations support our conclusions that ATPS and APR are major contributors of selenate reduction in planta. However, Se hyperaccumulation in Astragalus is not driven by an overall increase in the capacity of these enzymes, but rather by either an increased Se flux through the S assimilatory pathway, generated by the biosynthesis of the sink metabolites MeCys or MeSeCys, or through an as yet unidentified Se assimilation pathway.