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This review describes the scientific basis of a research and breeding pathway designed to boost genetic gains in wheat under drought and heat stress., Despite being the world’s most widely grown crop, research investments in wheat (Triticum aestivum and Triticum durum) fall behind those in other staple crops. Current yield gains will not meet 2050 needs, and climate stresses compound this challenge. However, there is good evidence that heat and drought resilience can be boosted through translating promising ideas into novel breeding technologies using powerful new tools in genetics and remote sensing, for example. Such technologies can also be applied to identify climate resilience traits from among the vast and largely untapped reserve of wheat genetic resources in collections worldwide. This review describes multi-pronged research opportunities at the focus of the Heat and Drought Wheat Improvement Consortium (coordinated by CIMMYT), which together create a pipeline to boost heat and drought resilience, specifically: improving crop design targets using big data approaches; developing phenomic tools for field-based screening and research; applying genomic technologies to elucidate the bases of climate resilience traits; and applying these outputs in developing next-generation breeding methods. The global impact of these outputs will be validated through the International Wheat Improvement Network, a global germplasm development and testing system that contributes key productivity traits to approximately half of the global wheat-growing area.

Undomesticated wild species, crop wild relatives, and landraces represent sources of variation for wheat improvement to address challenges from climate change and the growing human population. Here, we study 56,342 domesticated hexaploid, 18,946 domesticated tetraploid and 3,903 crop wild relatives in a massive-scale genotyping and diversity analysis. Using DArTseqTM technology, we identify more than 300,000 high-quality SNPs and SilicoDArT markers and align them to three reference maps: the IWGSC RefSeq v1.0 genome assembly, the durum wheat genome assembly (cv. Svevo), and the DArT genetic map. On average, 72% of the markers are uniquely placed on these maps and 50% are linked to genes. The analysis reveals landraces with unexplored diversity and genetic footprints defined by regions under selection. This provides fertile ground to develop wheat varieties of the future by exploring specific gene or chromosome regions and identifying germplasm conserving allelic diversity missing in current breeding programs., Genebanks hold comprehensive collections of wild species, wild relatives, and landraces that are useful for genetic improvement. Here, the authors report the genotype of nearly 80,000 wheat accessions using DArTseq technology to show the less explored genetic diversity.

Genetic variation in wheat is needed to address global food security challenges, particularly as climates change. Crop wild relatives are unique reservoirs of useful alleles for crop improvement and are important components of genebank collections. We analyzed how the derivatives of ‘goat grass’ (Aegilops tauschii) have been used to widen the genetic base for wheat breeding and surveyed wheat breeders to elicit adoption estimates. Synthetic hexaploid wheat (SHW) is derived by crossing goat grass with durum wheat, serving as a bridge to transfer desirable traits into modern varieties of bread wheat. Our data show that wheat scientists used 629 unique accessions from 15 countries for pre-breeding, producing 1577 primary SHWs. These derivatives represented 21% of the germplasm distributed by the genebank of the International Maize and Wheat Improvement Center between 2000 and 2018. Over the period, more than 10,000 samples of SHW were sent to 110 institutions in 40 countries, with rising numbers of synthetic hexaploid-derived lines (SHDL) included in international nurseries. Lines were screened for major diseases of wheat. At least 86 varieties have been selected from SHDL and released in 20 countries. Survey estimates indicate the highest scale of adoption in southwest China and India, with 34% and 7% of reported wheat area, respectively. These varieties demonstrate resistance to pests and pathogens, high yield potential, good quality attributes, and suitability for biofortified wheat.

Despite a large number of Aegilops L. species and their diversity in Azerbaijan, a majority of this genetic material has not been characterized at molecular levels. The current study has implemented DArTseq technology to evaluate genetic diversity among 150 accessions of different Aegilops species from Azerbaijan. A total of 61,574 SilicoDArTseq and 30,433 SNP markers were used to assess genetic diversity in Aegilops species. Genetic diversity was measured using Shannon’s genetic diversity index, which was equal to 0.852. Dendrograms were built to establish the relationship among Aegilops species. Both the DArTseq and SNP markers could completely segregate the U genome species from those with D genome with high confidence and allowed assigning most species to separate subclusters. The pattern of clustering within the Aegilops tauschii Coss. to certain extent was related to their geographical regions. Genetic structure among the 150 Aegilops accessions was similar with the cluster analysis. Two groups were identified in the studied population, which were exactly corresponded to two clusters in the dendrogram. Principal coordinate analysis confirmed sub-grouping obtained by cluster analysis. The first two principal coordinates explained 82.34% of the total variation. The study reported a sufficient level of genetic diversity of Aegilops from different eco-geographical regions of Azerbaijan, which can be very useful for their conservation and management, as well as for profitable diversifying the gene pool of hexaploid wheat.

Over 50 million people undergo surgeries each year in the United States, with over 70% of them filling opioid prescriptions within one week of the surgery. Due to the highly addictive nature of these opiates, a post-surgical window is a crucial time for pain management to ensure accurate prescription of opioids. Drug prescription nowadays relies primarily on self-reported pain levels to determine the frequency and dosage of pain drug. Patient pain self-reports are, however, influenced by subjective pain tolerance, memories of past painful episodes, current context, and the patient's integrity in reporting their pain level. Therefore, objective measures of pain are needed to better inform pain management. This paper explores a wearable system, named Painometry, which objectively quantifies users' pain perception based-on multiple physiological signals and facial expressions of pain. We propose a sensing technique, called sweep impedance profiling (SIP), to capture the movement of the facial muscle corrugator supercilii, one of the important physiological expressions of pain. We deploy SIP together with other biosignals, including electroencephalography (EEG), photoplethysmogram (PPG), and galvanic skin response (GSR) for pain quantification. From the anatomical and physiological correlations of pain with these signals, we designed Painometry, a multimodality sensing system, which can accurately quantify different levels of pain safely. We prototyped Painometry by building a custom hardware, firmware, and associated software. Our evaluations use the prototype on 23 subjects, which corresponds to 8832 data points from 276 minutes of an IRB-approved experimental pain-inducing protocol. Using leave-one-out cross-validation to estimate performance on unseen data shows 89.5% and 76.7% accuracy of quantification under 3 and 4 pain states, respectively.

A comprehensive understanding of the population structure and genetic diversity of potential germplasm is necessary for making breeding decisions and to fully interpret marker-trait associations. The purpose of this study was to examine the genetic diversity and population structure of a panel of 194 synthetic hexaploid-derived wheat (SHW; Triticum aestivum L.) accessions using 6904 polymorphic single nucleotide polymorphism (SNP) markers. Ancestry-based dissimilarity indices and marker-based genetic distances were positively correlated (r = 0.67). The variation in the primary synthetic parent in the pedigrees accounted for 4.52%, while the degree of the synthetic contribution accounted for only 1.06% of variation in the genetic distance. In addition, variation in the Aegilops tauschii Coss. (syn. Aegilops squarrosa auct. non L.) accession and T. turgidum accession used in the initial cross accounted for 3.48% and 2.75% of the variation in genetic distance, respectively. Using a model-based population structure approach, seven sub-populations were identified in the panel. Results of the model-based population structure analysis was for the most part in agreement with the distance-based clustering using unweighted pair group method with arithmetic mean (UPGMA) of the genetic distance or ancestry data and the principle component analysis of relatedness. We conclude that using a model-based approach provides a more statistically robust estimation of population structure. Results of this study, while highlighting the potential contribution of introgressed genome in the panel, provide the foundation for employing this panel in genome-wide association studies.

Wheat grain yield (GY) improvement using genomic tools is important for achieving yield breakthroughs. To dissect the genetic architecture of wheat GY potential and stress-resilience, we have designed this large-scale genome-wide association study using 100 datasets, comprising 105,000 GY observations from 55,568 wheat lines evaluated between 2003 and 2019 by the International Maize and Wheat Improvement Center and national partners. We report 801 GY-associated genotyping-by-sequencing markers significant in more than one dataset and the highest number of them were on chromosomes 2A, 6B, 6A, 5B, 1B and 7B. We then used the linkage disequilibrium (LD) between the consistently significant markers to designate 214 GY-associated LD-blocks and observed that 84.5% of the 58 GY-associated LD-blocks in severe-drought, 100% of the 48 GY-associated LD-blocks in early-heat and 85.9% of the 71 GY-associated LD-blocks in late-heat, overlapped with the GY-associated LD-blocks in the irrigated-bed planting environment, substantiating that simultaneous improvement for GY potential and stress-resilience is feasible. Furthermore, we generated the GY-associated marker profiles and analyzed the GY favorable allele frequencies for a large panel of 73,142 wheat lines, resulting in 44.5 million datapoints. Overall, the extensive resources presented in this study provide great opportunities to accelerate breeding for high-yielding and stress-resilient wheat varieties.

The international collections of plant genetic resources for food and agriculture (PGRFA) hosted by 11 CGIAR Centers are important components of the United Nations Food and Agriculture Organization&rsquo, s global system of conservation and use of PGRFA. They also play an important supportive role in realizing Target 2.5 of the Sustainable Development Goals. This paper analyzes CGIAR genebanks&rsquo, trends in acquiring and distributing PGRFA over the last 35 years, with a particular focus on the last decade. The paper highlights a number of factors influencing the Centers&rsquo, acquisition of new PGRFA to include in the international collections, including increased capacity to analyze gaps in those collections and precisely target new collecting missions, availability of financial resources, and the state of international and national access and benefit-sharing laws and phytosanitary regulations. Factors contributing to Centers&rsquo, distributions of PGRFA included the extent of accession-level information, users&rsquo, capacity to identify the materials they want, and policies. The genebanks&rsquo, rates of both acquisition and distribution increased over the last decade. The paper ends on a cautionary note concerning the potential of unresolved tensions regarding access and benefit sharing and digital genomic sequence information to undermine international cooperation to conserve and use PGRFA.

Extragonadal non-gestational choriocarcinoma is a rare but well-described phenomenon occurring in patients with midline germ cell tumors. Choriocarcinoma (ChC) is an aggressive neoplasm usually developing in women as a rare complication of pregnancy. In male patients ChC occurs in the testes, usually as a component of mixed germ cell tumors. Very few patients develop extragonadal choriocarcinoma with the tumor occurring in midline locations, such as the mediastinum, retroperitoneum, and central nervous system (mostly pineal gland). Non-midline choriocarcinoma can occur in the lung, gastrointestinal tract, and breast, sometimes blended with another primary malignancy. A midline choriocarcinoma manifesting as a head and neck malignancy is exceptional. During an evaluation of multiple enlarged cervical lymph nodes suspected to be lymphoma in a 72-year-old man, a core biopsy was taken from one of the left neck lymph nodes which histologically showed a necrotic malignancy with strong diffuse pancytokeratin staining. After an initial interpretation of metastatic carcinoma, further samples were taken from both tonsils and from a right level 5 neck lymph node. Histologically, all samples contained the same tumor, showing profound pleomorphism and multinucleated syncytial-type giant cells. A panel of immunohistochemistry studies were performed, including β-human chorionic gonadotropin, with positive findings leading to a diagnosis of extragonadal non-gestational choriocarcinoma.

Breeding for grain yield (GY) in bread wheat at the International Maize and Wheat Improvement Center (CIMMYT) involves three-stage testing at Obregon, Mexico in different selection environments (SEs). To understand the efficiency of selection in the SEs, we performed a large retrospective quantitative genetics study using CIMMYT’s yield trials evaluated in the SEs (2013-2014 to 2017-2018), the South Asia Bread Wheat Genomic Prediction Yield Trials (SABWGPYTs) evaluated in five target sites in India, Pakistan and Bangladesh (2014-2015 to 2017-2018) and the Elite Spring Wheat Yield Trials (ESWYTs) evaluated in several sites globally (2003-2004 to 2016-2017). First, we compared the narrow-sense heritabilities in the Obregon SEs and target sites and observed that the mean heritability in the SEs was 44.2% and 92.3% higher than the mean heritabilities in the SABWGPYT and ESWYT sites, respectively. Second, we observed significant GCs between a SE in Obregon and all the five SABWGPYT sites and 65.1% of the ESWYT sites, demonstrating the efficiency of indirect selection in the Obregon SEs. Third, we observed high ratios of response to indirect selection in the SEs of Obregon with a mean of 0.80 + 0.21 and 2.6 + 5.4 in the SABWGPYT and ESWYT sites, respectively. Furthermore, our results also indicated that for all the SABWGPYT sites and 82% of the ESWYT sites, a response greater than 0.5 can be achieved by indirect selection in Obregon. We also performed genomic prediction for GY in the target sites using the performance of the same lines in the SEs of Obregon and observed moderate mean prediction accuracies of 0.24 + 0.08 and 0.28 + 0.08 in the SABWGPYT and ESWYT sites, respectively using the genotype x environment (GxE) model. However, we observed similar accuracies using the baseline model with environment and line effects and no advantage of modeling GxE interactions. Overall, this study provides important insights into the suitability of the Obregon SEs in breeding for GY, while the variable genomic predictabilities of GY and the high year-to-year GY fluctuations reported, highlight the importance of multi-environment testing across time and space to stave off GxE induced uncertainties in varietal yields.

The value of exotic wheat genetic resources for accelerating grain yield gains is largely unproven and unrealized. We used next-generation sequencing, together with multi-environment phenotyping, to study the contribution of exotic genomes to 984 three-way-cross-derived (exotic/elite1//elite2) pre-breeding lines (PBLs). Genomic characterization of these lines with haplotype map-based and SNP marker approaches revealed exotic specific imprints of 16.1 to 25.1%, which compares to theoretical expectation of 25%. A rare and favorable haplotype (GT) with 0.4% frequency in gene bank identified on chromosome 6D minimized grain yield (GY) loss under heat stress without GY penalty under irrigated conditions. More specifically, the ‘T’ allele of the haplotype GT originated in Aegilops tauschii and was absent in all elite lines used in study. In silico analysis of the SNP showed hits with a candidate gene coding for isoflavone reductase IRL-like protein in Ae. tauschii. Rare haplotypes were also identified on chromosomes 1A, 6A and 2B effective against abiotic/biotic stresses. Results demonstrate positive contributions of exotic germplasm to PBLs derived from crosses of exotics with CIMMYT’s best elite lines. This is a major impact-oriented pre-breeding effort at CIMMYT, resulting in large-scale development of PBLs for deployment in breeding programs addressing food security under climate change scenarios.

Development of winter wheat (Triticum aestivum) synthetics started at CIMMYT-Mexico in 2004, when winter durum wheat (Triticum turgidum) germplasm from Ukraine and Romania was crossed with Aegilops tauschii accessions from the Caspian Sea region. Chromosomes were doubled after pollination and embryo rescue, but chromosome number and cytological validation was not performed. F2 populations were grown in Mexico and were shipped to Turkey in 2008. During 2009–2015, these populations were subjected to rigorous pedigree selection under dry, cold, disease-affected environments of the Central Anatolian Plateau. The wide segregation and partial sterility observed in 2009 gradually decreased and, by 2016, most of the F8 single spike progenies demonstrated good fertility and agronomic performance. Since 2013, lines have been selected from synthetic populations and evaluated at multiple sites. Superior lines were characterized for resistance to leaf, stripe and stem rust, plant height, and reaction to common bunt and soil-borne pathogens. Thousand kernel weight of many lines exceeded 50 g, compared with the check varieties that barely reached 40 g. Threshability of synthetic lines varied from 0 to 95%, demonstrating genetic variation for this important domestication trait. Screening against Hessian fly, sunny pest and Russian wheat aphid identified several resistant genotypes. Both durum and Aegilops parents affected synthetic wheat traits. Several studies are underway to reveal the genetic diversity of synthetic lines and the basis of resistance to diseases and insects. This synthetic germplasm represents a new winter bread wheat parental pool. It is available upon request to interested breeding/research programmes.

Synthetic hexaploid (SH) wheat (AABBD’D’) is developed by artificially generating a fertile hybrid between tetraploid durum wheat (Triticum turgidum, AABB) and diploid wild goat grass (Aegilops tauschii, D’D’). Over three decades, the International Maize and Wheat Improvement Center (CIMMYT) has developed and utilized SH wheat to bridge gene transfer from Ae. tauschii and durum wheat to hexaploid bread wheat. This is a unique example of success utilizing wild relatives in mainstream breeding at large scale worldwide. Our study aimed to determine the genetic contribution of SH wheat to CIMMYT’s global spring bread wheat breeding program. We estimated the theoretical and empirical contribution of D’ to synthetic derivative lines using the ancestral pedigree and marker information using over 1,600 advanced lines and their parents. The average marker-estimated D’ contribution was 17.5% with difference in genome segments suggesting application of differential selection pressure. The pedigree-based contribution was correlated with marker-based estimates without providing chromosome segment specific variation. Results from international yield trials showed that 20% of the lines were synthetic derived with an average D’ contribution of 15.6%. Our results underline the importance of SH wheat in maintaining and enhancing genetic diversity and genetic gain over years and is important for development of a more targeted introgression strategy. The study provides retrospective view into development and utilization of SH in the CIMMYT Global Wheat Program.

Mechanistic disease stratification will be crucial to develop a precision medicine approach for future disease modifying therapy in sporadic Parkinson’s disease (sPD). Mitochondrial and lysosomal dysfunction are key mechanisms in the pathogenesis of sPD and therefore promising targets for therapeutic intervention. We investigated mitochondrial and lysosomal function in skin fibroblasts of 100 sPD patients and 50 age-matched controls. A combination of cellular assays, RNA-seq based pathway analysis and genotyping was applied. Distinct subgroups with mitochondrial (mito-sPD) or lysosomal (lyso-sPD) dysfunction were identified. Mitochondrial dysfunction correlated with reduction in complex I and IV protein levels. RNA-seq based pathway analysis revealed marked activation of the lysosomal pathway with enrichment for lysosomal disease gene variants in lyso-sPD. Conversion of fibroblasts to induced neuronal progenitor cells and subsequent differentiation into tyrosine hydroxylase positive neurons confirmed and further enhanced both mitochondrial and lysosomal abnormalities. Treatment with ursodeoxycholic acid improved mitochondrial membrane potential and intracellular ATP levels even in sPD patient fibroblast lines with comparatively mild mitochondrial dysfunction. The results of our study suggest that in-depth phenotyping and focussed assessment of putative neuroprotective compounds in peripheral tissue are a promising approach towards disease stratification and precision medicine in sPD.

This study examines genomic prediction within 8416 Mexican landrace accessions and 2403 Iranian landrace accessions stored in gene banks. The Mexican and Iranian collections were evaluated in separate field trials, including an optimum environment for several traits, and in two separate environments (drought, D and heat, H) for the highly heritable traits, days to heading (DTH), and days to maturity (DTM). Analyses accounting and not accounting for population structure were performed. Genomic prediction models include genotype × environment interaction (G × E). Two alternative prediction strategies were studied: (1) random cross-validation of the data in 20% training (TRN) and 80% testing (TST) (TRN20-TST80) sets, and (2) two types of core sets, “diversity” and “prediction”, including 10% and 20%, respectively, of the total collections. Accounting for population structure decreased prediction accuracy by 15–20% as compared to prediction accuracy obtained when not accounting for population structure. Accounting for population structure gave prediction accuracies for traits evaluated in one environment for TRN20-TST80 that ranged from 0.407 to 0.677 for Mexican landraces, and from 0.166 to 0.662 for Iranian landraces. Prediction accuracy of the 20% diversity core set was similar to accuracies obtained for TRN20-TST80, ranging from 0.412 to 0.654 for Mexican landraces, and from 0.182 to 0.647 for Iranian landraces. The predictive core set gave similar prediction accuracy as the diversity core set for Mexican collections, but slightly lower for Iranian collections. Prediction accuracy when incorporating G × E for DTH and DTM for Mexican landraces for TRN20-TST80 was around 0.60, which is greater than without the G × E term. For Iranian landraces, accuracies were 0.55 for the G × E model with TRN20-TST80. Results show promising prediction accuracies for potential use in germplasm enhancement and rapid introgression of exotic germplasm into elite materials.

There is strong evidence of a key role for mitochondrial dysfunction in both sporadic and all forms of familial Parkinson's disease (PD). However, none of the clinical trials carried out with putative mitochondrial rescue agents has been successful. Firm establishment of a wet biomarker or a reliable readout from imaging studies detecting mitochondrial dysfunction and reflecting disease progression is also awaited. We will provide an overview of our current knowledge about mitochondrial dysfunction in PD and related drug screens. We will also summarize previously undertaken mitochondrial wet biomarker studies and relevant imaging studies with particular focus on 31P-MRI Spectroscopy. We will conclude with an overview of clinical trials which tested putative mitochondrial rescue agents in PD patients. Parkinson's disease is a common, relentlessly progressive neurodegenerative disorder. The pathological hallmark is loss of dopaminergic neurons in the substantia nigra. The resulting motor presentation includes rest tremor, bradykinesia and rigidity but the importance of non-motor symptoms such as cognitive impairment and depression is increasingly recognized, too. Currently available dopaminergic treatment often only addresses the motor impairment partially. This review will summarize our current knowledge about mitochondrial dysfunction as a key target for disease-modifying treatment for PD. We will also provide an update on mitochondrial readouts in PD patients, namely imaging and putative mitochondrial biomarkers, which may become highly relevant in the context of future drug trials. This article is protected by copyright. All rights reserved.

The original article was corrected. Author Muhammad Kundi should instead read: Muhammad Sohail.

To accelerate genetic gains in breeding, physiological trait (PT) characterization of candidate parents can help make more strategic crosses, increasing the probability of accumulating favorable alleles compared to crossing relatively uncharacterized lines. In this study, crosses were designed to complement “source” with “sink” traits, where at least one parent was selected for favorable expression of biomass and/or radiation use efficiency—source—and the other for sink-related traits like harvest-index, kernel weight and grains per spike. Female parents were selected from among genetic resources—including landraces and products of wide-crossing (i.e. synthetic wheat)—that had been evaluated in Mexico at high yield potential or under heat stress, while elite lines were used as males. Progeny of crosses were advanced to the F4 generation within Mexico, and F4-derived F5 and F6 generations were yield tested to populate four international nurseries, targeted to high yield environments (2nd and 3rd WYCYT) for yield potential, and heat stressed environments (2nd and 4th SATYN) for climate resilience, respectively. Each nursery was grown as multi-location yield trials. Genetic gains were achieved in both temperate and hot environments, with most new PT-derived lines expressing superior yield and biomass compared to local checks at almost all international sites. Furthermore, the tendency across all four nurseries indicated either the superiority of the best new PT lines compared with the CIMMYT elite checks, or the superiority of all new PT lines as a group compared with all checks, and in some cases, both. Results support—in a realistic breeding context—the hypothesis that yield and radiation use efficiency can be increased by improving source:sink balance, and validate the feasibility of incorporating exotic germplasm into mainstream breeding efforts to accelerate genetic gains for yield potential and climate resilience.

Exploring the short and largely forgotten history of adult-oriented 8-bit video games produced for the Atari 2600 home game console, this essay argues that the games represent an important attempt by media producers to bridge the adult film and interactive entertainment industries. Although American Multiple Industries, Playaround, and Universal Gamex failed to establish a market, their titles nevertheless demonstrate how adult games function as desire machines within an erotic economy that sells a host of anticipatory pleasures. Indeed, the resulting public outcry not only led to the game industry’s first sex-based controversy, but the antagonism signals the desire to regulate sexual expression on a new media technology as game producers—following the lead of adult video professionals—attempted to transport users’ joysticks from living rooms into bedrooms.

Climate change and slow yield gains pose a major threat to global wheat production. Underutilized genetic resources including landraces and wild relatives are key elements for developing high-yielding and climate-resilient wheat varieties. Landraces introduced into Mexico from Europe, also known as Creole wheats, are adapted to a wide range of climatic regimes and represent a unique genetic resource. Eight thousand four hundred and sixteen wheat landraces representing all dimensions of Mexico were characterized through genotyping-by-sequencing technology. Results revealed sub-groups adapted to specific environments of Mexico. Broadly, accessions from north and south of Mexico showed considerable genetic differentiation. However, a large percentage of landrace accessions were genetically very close, although belonged to different regions most likely due to the recent (nearly five centuries before) introduction of wheat in Mexico. Some of the groups adapted to extreme environments and accumulated high number of rare alleles. Core reference sets were assembled simultaneously using multiple variables, capturing 89% of the rare alleles present in the complete set. Genetic information about Mexican wheat landraces and core reference set can be effectively utilized in next generation wheat varietal improvement.

Background In contact sports (eg, American football or rugby), injuries resulting from impacts are widespread. There have been several attempts to identify and collate, within a conceptual framework, factors influencing the likelihood of an injury. To effectively define an injury event it is necessary to systematically consider all potential causal factors but none of the previous approaches are complete in this respect. Aims First, to develop a superior deterministic contextual sequential (DCS) model to promote a complete and logical description of interrelated injury event factors. Second, to demonstrate systematic use of the model to construct enhanced perspectives for impact-injury research. Method Previous models were examined and elements of best practice synthesised into a new DCS framework description categorising the types of causal factors influencing injury. The approach9s internal robustness is demonstrated by consideration of its completeness, lack of redundancy and logical consistency. Results The model9s external validity and worth are demonstrated through its use to generate superior descriptive injury models, experimental protocols and intervention opportunities. Comprehensive research perspectives have been developed using a common rugby impact-injury scenario as an example; this includes: a detailed description of the injury event, an experimental protocol for a human-on-surrogate reconstruction, and a series of practical interventions in the sport of rugby aimed at mitigating the risk of injury. Conclusions Our improved characterisation tool presents a structured approach to identify pertinent factors relating to an injury.

Identification of cells that are endowed with maximum potency could be critical for the clinical success of cell-based therapies. We investigated whether cells with an enhanced efficacy for cardiac cell therapy could be enriched from adult human skeletal muscle on the basis of their adhesion properties to tissue culture flasks following tissue dissociation. Cells that adhered slowly displayed greater myogenic purity and more readily differentiated into myotubes in vitro than rapidly adhering cells (RACs). The slowly adhering cell (SAC) population also survived better than the RAC population in kinetic in vitro assays that simulate conditions of oxidative and inflammatory stress. When evaluated for the treatment of a myocardial infarction (MI), intramyocardial injection of the SACs more effectively improved echocardiographic indexes of left ventricular (LV) remodeling and contractility than the transplantation of the RACs. Immunohistological analysis revealed that hearts injected with SACs displayed a reduction in myocardial fibrosis and an increase in infarct vascularization, donor cell proliferation, and endogenous cardiomyocyte survival and proliferation in comparison with the RAC-treated hearts. In conclusion, these results suggest that adult human skeletal muscle-derived cells are inherently heterogeneous with regard to their efficacy for enhancing cardiac function after cardiac implantation, with SACs outperforming RACs.

Objectives The aim of this study was to evaluate the therapeutic potential of human skeletal muscle-derived myoendothelial cells for myocardial infarct repair.Background We have recently identified and purified a novel population of myoendothelial cells from human skeletal muscle. These cells coexpress myogenic and endothelial cell markers and produce robust muscle regeneration when injected into cardiotoxin-injured skeletal muscle.Methods Myoendothelial cells were isolated from biopsies of human skeletal muscle using a fluorescence-activated cell sorter along with populations of regular myoblasts and endothelial cells. Acute myocardial infarction was induced in male immune-deficient mice, and cells were directly injected into the ischemic area. Cardiac function was assessed by echocardiography, and donor cell engraftment, angiogenesis, scar tissue, endogenous cardiomyocyte proliferation, and apoptosis were all evaluated by immunohistochemistry.Results A greater improvement in left ventricular function was observed after intramyocardial injection of myoendothelial cells when compared with that seen in hearts injected with myoblast or endothelial cells. Transplanted myoendothelial cells generated robust engraftments within the infarcted myocardium, and also stimulated angiogenesis, attenuation of scar tissue, and proliferation and survival of endogenous cardiomyocytes more effectively than transplanted myoblasts or endothelial cells.Conclusions Our findings suggest that myoendothelial cells represent a novel cell population from human skeletal muscle that may hold promise for cardiac repair. (J Am Coll Cardiol 2008; 52: 1869-80) (c) 2008 by the American College of Cardiology Foundation

Objectives We investigated whether vascular endothelial growth factor (VEGF) was associated with the angiogenic and therapeutic effects induced after transplantation of skeletal muscle-derived stem cells (MDSCs) into a myocardial infarction (MI). Background Because very few MDSCs were found to differentiate into new blood vessels when injected into the heart, the mechanism underlying the occurrence of angiogenesis after MDSC transplantation is currently unknown. In the present study, we used a gain- or loss-of-VEGF function approach with skeletal MDSCs engineered to express VEGF or soluble Flt1, a VEGF-specific antagonist, to identify the involvement of VEGF in MDSC transplantation-induced neoangiogenesis. Methods Vascular endothelial growth factor- and soluble Flt1-engineered MDSCs were injected into an acute MI. Angiogenesis and cardiac function were evaluated by immunohistochemistry and echocardiography. Results Both control and VEGF-overexpressing MDSCs induced angiogenesis, prevented adverse cardiac remodeling, and improved function compared with saline-injected hearts. However, these therapeutic effects were diminished in hearts transplanted with MDSCs expressing soluble Flt1 despite successful cell engraftment. In vitro experiments demonstrated that MDSCs increased secretion of VEGF in response to hypoxia and cyclic stretch (likely conditions in ischemic hearts), suggesting that transplanted MDSCs release VEGF in vivo. Conclusions Our findings suggest that VEGF is essential for the induction of angiogenesis and functional improvements observed after MDSC transplantation for infarct repair.