Is the NIH policy for sharing GWAS data running the risk of being counterproductive?

Through their current policy on data sharing, the National Institutes of Health (NIH) are inadvertently placing a serious and potentially insuperable burden upon non-US researchers who perform patient-based genomics studies in collaboration with US institutions. Because this policy could adversely affect future transnational scientific collaborations, we explore some of its likely consequences and suggest possible courses of remedial action wherever feasible

Biomaterialbanken - Rechtliche Rahmenbedingungen

Der Aufbau und Betrieb von großen Biomaterialbanken wird zunehmend wichtiger: Materialbanken, die Proben langfristig für medizinisch-wissenschaftliche Analysen verfügbar machen, bieten ein großes Potential für die Klärung drängender Fragen der medizinischen Forschung. Dies gilt besonders, wenn die Proben mit Daten zum Erkrankungsverlauf der jeweiligen Patienten zusammengeführt werden. Die zunehmende Vernetzung in der biomedizinischen Forschung führt auch zum Aufbau übergreifender Daten- und Probensammlungen. Dabei stellt sich eine Vielzahl von rechtlichen und organisatorischen Fragen, für die in Deutschland bisher eine eindeutige Regelung fehlte. Die TMF hat diese Fragen aufgegriffen und in einem interdisziplinären Projekt viele Aspekte geklärt, die den Forschern nun in Form von Handlungsleitfäden und Mustertexten an die Hand gegeben werden. Der vorliegende zweite Band der TMF-Schriftenreihe beleuchtet aus juristischer Sicht die rechtlichen Rahmenbedingungen für den Aufbau und Betrieb von Biomaterialbanken: umfassendes Rechtsgutachten; Zusammenstellung der Rechtsvorschriften; Musterverträge können von der TMF zur Verfügung gestellt werden

Hydrogel-Guided, rAAV-Mediated IGF-I Overexpression Enables Long-Term Cartilage Repair and Protection against Perifocal Osteoarthritis in a Large-Animal Full-Thickness Chondral Defect Model at One Year In Vivo

[Abstract] The regeneration of focal articular cartilage defects is complicated by the reduced quality of the repair tissue and the potential development of perifocal osteoarthritis (OA). Biomaterial-guided gene therapy may enhance cartilage repair by controlling the release of therapeutic sequences in a spatiotemporal manner. Here, the benefits of delivering a recombinant adeno-associated virus (rAAV) vector coding for the human insulin-like growth factor I (IGF-I) via an alginate hydrogel (IGF-I/AlgPH155) to enhance repair of full-thickness chondral defects following microfracture surgery after one year in minipigs versus control (lacZ/AlgPH155) treatment are reported. Sustained IGF-I overexpression is significantly achieved in the repair tissue of defects treated with IGF-I/AlgPH155 versus those receiving lacZ/AlgPH155 for one year and in the cartilage surrounding the defects. Administration of IGF-I/AlgPH155 significantly improves parameters of cartilage repair at one year relative to lacZ/AlgPH155 (semiquantitative total histological score, cell densities, matrix deposition) without deleterious or immune reactions. Remarkably, delivery of IGF-I/AlgPH155 also significantly reduces perifocal OA and inflammation after one year versus lacZ/AlgPH155 treatment. Biomaterial-guided rAAV gene transfer represents a valuable clinical approach to promote cartilage repair and to protect against OA.J.M. and H.M. contributed equally to this work. The authors thankDr. R. J. Samulski (The Gene Therapy Center, University of North Carolina,Chapel Hill, NC, USA), Dr. X. Xiao (The Gene Therapy Center, Universityof Pittsburgh, Pittsburgh, PA, USA), and E. F. Terwilliger (Division ofExperimental Medicine, Harvard Institutes of Medicine and Beth Israel Deaconess Medical Center, Boston, MA, USA) for providing thegenomic AAV-2 plasmid clones and the 293 cell line. This work wassupported by a grant from the Deutsche Arthrose-Hilfe e.V. (M.C.,H.M.) and by the Saarland University within the funding programmeOpen Access Publishing.Open access funding enabled and organized by Projekt DEAL

Hydrogel-Guided, rAAV-Mediated IGF-I Overexpression Enables Long-Term Cartilage Repair and Protection against Perifocal Osteoarthritis in a Large-Animal Full-Thickness Chondral Defect Model at One Year In Vivo

The regeneration of focal articular cartilage defects is complicated by the reduced quality of the repair tissue and the potential development of perifocal osteoarthritis (OA). Biomaterial-guided gene therapy may enhance cartilage repair by controlling the release of therapeutic sequences in a spatiotemporal manner. Here, the benefits of delivering a recombinant adeno-associated virus (rAAV) vector coding for the human insulin-like growth factor I (IGF-I) via an alginate hydrogel (IGF-I/AlgPH155) to enhance repair of full-thickness chondral defects following microfracture surgery after one year in minipigs versus control (lacZ/AlgPH155) treatment are reported. Sustained IGF-I overexpression is significantly achieved in the repair tissue of defects treated with IGF-I/AlgPH155 versus those receiving lacZ/AlgPH155 for one year and in the cartilage surrounding the defects. Administration of IGF-I/AlgPH155 significantly improves parameters of cartilage repair at one year relative to lacZ/AlgPH155 (semiquantitative total histological score, cell densities, matrix deposition) without deleterious or immune reactions. Remarkably, delivery of IGF-I/AlgPH155 also significantly reduces perifocal OA and inflammation after one year versus lacZ/AlgPH155 treatment. Biomaterial-guided rAAV gene transfer represents a valuable clinical approach to promote cartilage repair and to protect against OA

Trophic position and foraging ecology of Ross, Weddell, and crabeater seals revealed by compound-specific isotope analysis

Ross seals Ommatophoca rossii are one of the least studied marine mammals, with little known about their foraging ecology. Research to date using bulk stable isotope analysis suggests that Ross seals have a trophic position intermediate between that of Weddell Leptonychotes weddellii and crabeater Lobodon carcinophaga seals. However, consumer bulk stable isotope values not only reflect trophic dynamics, but also variations in baseline isotope values, which can be substantial. We used compound-specific isotope analysis of amino acids (CSI-AA) to separate isotopic effects of a shifting baseline versus trophic structure on the foraging ecology of these ecologically important Antarctic pinnipeds. We found that Ross seals forage in an open ocean food web, while crabeater and Weddell seals forage within similar food webs closer to shore. However, isotopic evidence suggests that crabeater seals are likely following sea ice, while Weddell seals target productive areas of the continental shelf of West Antarctica. Our CSI-AA data indicate that Ross seals have a high trophic position equivalent to that of Weddell seals, contrary to prior conclusions from nitrogen isotope results on bulk tissues. CSI-AA indicates that crabeater seals are at a trophic position lower than that of Ross and Weddell seals, consistent with a krill-dominated diet. Our results redefine the view of the trophic dynamics and foraging ecology of the Ross seal, and also highlight the importance of quantifying baseline isotope variations in foraging studies

Thermosensitive Hydrogel Based on PEO-PPO-PEO Poloxamers for a Controlled In Situ Release of Recombinant Adeno-Associated Viral Vectors for Effective Gene Therapy of Cartilage Defects

Advanced biomaterial-guided delivery of gene vectors is an emerging and highly attractive therapeutic solution for targeted articular cartilage repair, allowing for a controlled and minimally invasive delivery of gene vectors in a spatiotemporally precise manner, reducing intra-articular vector spread and possible loss of the therapeutic gene product. As far as it is known, the very first successful in vivo application of such a biomaterial-guided delivery of a potent gene vector in an orthotopic large animal model of cartilage damage is reported here. In detail, an injectable and thermosensitive hydrogel based on poly(ethylene oxide) (PEO)-poly(propylene oxide) (PPO)-PEO poloxamers, capable of controlled release of a therapeutic recombinant adeno-associated virus (rAAV) vector overexpressing the chondrogenic sox9 transcription factor in full-thickness chondral defects, is applied in a clinically relevant minipig model in vivo. These comprehensive analyses of the entire osteochondral unit with multiple standardized evaluation methods indicate that rAAV-FLAG-hsox9/PEO-PPO-PEO hydrogel-augmented microfracture significantly improves cartilage repair with a collagen fiber orientation more similar to the normal cartilage and protects the subchondral bone plate from early bone loss

Thermosensitive Hydrogel Based on PEO–PPO–PEO Poloxamers for a Controlled In Situ Release of Recombinant Adeno-Associated Viral Vectors for Effective Gene Therapy of Cartilage Defects

[Abstract] Advanced biomaterial-guided delivery of gene vectors is an emerging and highly attractive therapeutic solution for targeted articular cartilage repair, allowing for a controlled and minimally invasive delivery of gene vectors in a spatiotemporally precise manner, reducing intra-articular vector spread and possible loss of the therapeutic gene product. As far as it is known, the very first successful in vivo application of such a biomaterial-guided delivery of a potent gene vector in an orthotopic large animal model of cartilage damage is reported here. In detail, an injectable and thermosensitive hydrogel based on poly(ethylene oxide) (PEO)–poly(propylene oxide) (PPO)–PEO poloxamers, capable of controlled release of a therapeutic recombinant adeno-associated virus (rAAV) vector overexpressing the chondrogenic sox9 transcription factor in full-thickness chondral defects, is applied in a clinically relevant minipig model in vivo. These comprehensive analyses of the entire osteochondral unit with multiple standardized evaluation methods indicate that rAAV-FLAG-hsox9/PEO–PPO–PEO hydrogel-augmented microfracture significantly improves cartilage repair with a collagen fiber orientation more similar to the normal cartilage and protects the subchondral bone plate from early bone loss.H.M. and L.G. contributed equally to this work. This project wassupported by the Deutsche Forschungsgemeinschaft (DFG RE 3828/2-1). All animal experiments were conducted in agreement with the nationallegislation on protection of animals and the National Institutes ofHealth (NIH) Guidelines for the Care and Use of Laboratory Animals(NIH Publication 85-23, Rev 1985) and were approved by the SaarlandUniversity Animal Committee according to German guidelines.Deutschland. Deutsche Forschungsgemeinschaft; DFG RE 3828/2-

Financing Direct Democracy: Revisiting the Research on Campaign Spending and Citizen Initiatives

The conventional view in the direct democracy literature is that spending against a measure is more effective than spending in favor of a measure, but the empirical results underlying this conclusion have been questioned by recent research. We argue that the conventional finding is driven by the endogenous nature of campaign spending: initiative proponents spend more when their ballot measure is likely to fail. We address this endogeneity by using an instrumental variables approach to analyze a comprehensive dataset of ballot propositions in California from 1976 to 2004. We find that both support and opposition spending on citizen initiatives have strong, statistically significant, and countervailing effects. We confirm this finding by looking at time series data from early polling on a subset of these measures. Both analyses show that spending in favor of citizen initiatives substantially increases their chances of passage, just as opposition spending decreases this likelihood

Seasonal and ocean basin-scale assessment of amino acid δ15N trends in a Southern Ocean marine predator

The Southern Ocean exhibits substantial spatio-temporal variation in biogeochemical processes that shape interactions and productivity across food webs. Stable isotopes in marine predators provide an opportunity to capture such variations, yet few studies have accounted for variability in the isotopic baseline when interpreting predator isotope values. Using bulk δ15N and δ13C values and the δ15N values of amino acids (AAs) of blood from female Antarctic fur seals (AFSs) Arctocephalus gazella, we investigated spatial and seasonal variation in baseline δ15N (δ15Nbaseline) values across 3 Southern Ocean basins (Indian, Pacific and Atlantic) to facilitate robust comparison of consumer trophic ecology. We detected spatial and seasonal differences in δ15Nbaseline values across the basins, using the source AAs phenylalanine (Phe) and lysine (Lys), consistent with the latitudinal gradient of AFS colonies and seasonal changes in seal foraging movement. The δ15N values of source AAs from Marion Island and Cape Shirreff were representative of particulate organic matter δ15N values in the Indian and southwest Atlantic sector, respectively, whereas more complex patterns were observed in the Atlantic sector around Bird Island. Variations in bulk δ15N values can also be attributed to changes in AFS diet, with females foraging in the Atlantic and Pacific targeting higher trophic level prey in winter. Trophic position estimation using Phe and leucine (Leu) suggested that females encompass more than 2 trophic levels. Our study highlights the utility of using Lys alongside Phe to assess seasonal and ocean basin-level variations in the isotopic baseline and Leu/Phe for AFS trophic position estimation

RAD sequencing and a hybrid Antarctic fur seal genome assembly reveal rapidly decaying linkage disequilibrium, global population structure and evidence for inbreeding

Recent advances in high throughput sequencing have transformed the study of wild organisms by facilitating the generation of high quality genome assemblies and dense genetic marker datasets. These resources have the potential to significantly advance our understanding of diverse phenomena at the level of species, populations and individuals, ranging from patterns of synteny through rates of linkage disequilibrium (LD) decay and population structure to individual inbreeding. Consequently, we used PacBio sequencing to refine an existing Antarctic fur seal (Arctocephalus gazella) genome assembly and genotyped 83 individuals from six populations using restriction site associated DNA (RAD) sequencing. The resulting hybrid genome comprised 6,169 scaffolds with an N50 of 6.21 Mb and provided clear evidence for the conservation of large chromosomal segments between the fur seal and dog (Canis lupus familiaris). Focusing on the most extensively sampled population of South Georgia, we found that LD decayed rapidly, reaching the background level by around 400 kb, consistent with other vertebrates but at odds with the notion that fur seals experienced a strong historical bottleneck. We also found evidence for population structuring, with four main Antarctic island groups being resolved. Finally, appreciable variance in individual inbreeding could be detected, reflecting the strong polygyny and site fidelity of the species. Overall, our study contributes important resources for future genomic studies of fur seals and other pinnipeds while also providing a clear example of how high throughput sequencing can generate diverse biological insights at multiple levels of organization