An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells.

Duchenne muscular dystrophy is a progressive and incurable neuromuscular disease caused by genetic and biochemical defects of the dystrophin-glycoprotein complex. Here we show the regenerative potential of myogenic progenitors derived from corrected dystrophic induced pluripotent stem cells generated from fibroblasts of mice lacking both dystrophin and utrophin. We correct the phenotype of dystrophic induced pluripotent stem cells using a Sleeping Beauty transposon system carrying the micro-utrophin gene, differentiate these cells into skeletal muscle progenitors and transplant them back into dystrophic mice. Engrafted muscles displayed large numbers of micro-utrophin-positive myofibers, with biochemically restored dystrophin-glycoprotein complex and improved contractile strength. The transplanted cells seed the satellite cell compartment, responded properly to injury and exhibit neuromuscular synapses. We also detect muscle engraftment after systemic delivery of these corrected progenitors. These results represent an important advance towards the future treatment of muscular dystrophies using genetically corrected autologous induced pluripotent stem cells

Sub-3mm spatial resolution from a large monolithic LaBr3 (Ce) scintillator

Abstract A Compton camera prototype for ion beam range monitoring via prompt (< 1 ns) gamma detection in hadron therapy is being developed and characterized at the Medical Physics Department of LMU Munich. The system consists of a large (50x50x30 mm3) monolithic LaBr3(Ce) scintillation crystal as absorber component to detect the multi-MeV Compton scattered photons, together with a stack of 6 double-sided silicon strip detectors (DSSSD) acting as scatterer component. Key ingredient of the γ-source reconstruction is the determination of the γ-ray interaction position in the scintillator, which is read out by a 256-fold segmented multi-anode photomultiplier tube (PMT). From simulations an angular resolution of about 1.5o for the photon source reconstruction can be expected for the energy range around 3 – 5 MeV, provided that a spatial resolution of 3 mm can be reached in the absorbing scintillator [1]. Therefore, particular effort was dedicated to characterize this latter property as a function of the γ-ray energy. Intense, tightly collimated 137Cs and 60Co photon sources were used for 2D irradiation scans (step size 0.5 mm) as prerequisite for studying the performance of the "k-Nearest-Neighbors" algorithm developed at TU Delft [2] (together with its variant "Categorical Average Pattern", CAP) and extending its applicability into the energy range beyond the original 511 keV. In this paper we present our most recent interaction position analysis in the absorbing scintillator, leading to a considerably improved value for the spatial resolution: systematic studies were performed as a function of the k-NN parameters and the PMT segmentation. A trend of improving spatial resolution with increasing photon energy was confirmed, resulting in the realization of the presently optimum spatial resolution of 2.9(1) mm @1.3 MeV, thus reaching the design specifications of the Compton camera absorber. The specification goal was reached also for a reduced PMT segmentation of 8x8 anode segments (each with 6x6 mm2 active area), thus allowing to reduce the complexity of the signal processing while preserving the performance

Continuous Equilibrium in Affine and Information-Based Capital Asset Pricing Models

We consider a class of generalized capital asset pricing models in continuous time with a finite number of agents and tradable securities. The securities may not be sufficient to span all sources of uncertainty. If the agents have exponential utility functions and the individual endowments are spanned by the securities, an equilibrium exists and the agents' optimal trading strategies are constant. Affine processes, and the theory of information-based asset pricing are used to model the endogenous asset price dynamics and the terminal payoff. The derived semi-explicit pricing formulae are applied to numerically analyze the impact of the agents' risk aversion on the implied volatility of simultaneously-traded European-style options.Comment: 24 pages, 4 figure

Edge influence on vegetation at natural and anthropogenic edges of boreal forests in Canada and Fennoscandia

Although anthropogenic edges are an important consequence of timber harvesting, edges due to natural disturbances or landscape heterogeneity are also common. Forest edges have been well studied in temperate and tropical forests, but less so in less productive, disturbance-adapted boreal forests. We synthesized data on forest vegetation at edges of boreal forests and compared edge influence among edge types (fire, cut, lake/wetland; old vs. young), forest types (broadleaf vs. coniferous) and geographic regions. Our objectives were to quantify vegetation responses at edges of all types and to compare the strength and extent of edge influence among different types of edges and forests. Research was conducted using the same general sampling design in Alberta, Ontario and Quebec in Canada, and in Sweden and Finland. We conducted a meta-analysis for a variety of response variables including forest structure, deadwood abundance, regeneration, understorey abundance and diversity, and non-vascular plant cover. We also determined the magnitude and distance of edge influence (DEI) using randomization tests. Some edge responses (lower tree basal area, tree canopy and bryophyte cover; more logs; higher regeneration) were significant overall across studies. Edge influence on ground vegetation in boreal forests was generally weak, not very extensive (DEI usually < 20 m) and decreased with time. We found more extensive edge influence at natural edges, at younger edges and in broadleaf forests. The comparison among regions revealed weaker edge influence in Fennoscandian forests. Synthesis. Edges created by forest harvesting do not appear to have as strong, extensive or persistent influence on vegetation in boreal as in tropical or temperate forested ecosystems. We attribute this apparent resistance to shorter canopy heights, inherent heterogeneity in boreal forests and their adaptation to frequent natural disturbance. Nevertheless, notable differences between forest structure responses to natural (fire) and anthropogenic (cut) edges raise concerns about biodiversity implications of extensive creation of anthropogenic edges. By highlighting universal responses to edge influence in boreal forests that are significant irrespective of edge or forest type, and those which vary by edge type, we provide a context for the conservation of boreal forests. Edges created by forest harvesting do not appear to have as strong, extensive or persistent influence on vegetation in boreal as in tropical or temperate forested ecosystems. We attribute this apparent resistance to shorter canopy heights, inherent heterogeneity in boreal forests and their adaptation to frequent natural disturbance. Nevertheless, notable differences between forest structure responses to natural (fire) and anthropogenic (cut) edges raise concerns about biodiversity implications of extensive creation of anthropogenic edges. By highlighting universal responses to edge influence in boreal forests that are significant irrespective of edge or forest type, and those which vary by edge type, we provide a context for the conservation of boreal forests

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Sub-3mm spatial resolution from a large monolithic LaBr3 (Ce) scintillator

Abstract A Compton camera prototype for ion beam range monitoring via prompt (< 1 ns) gamma detection in hadron therapy is being developed and characterized at the Medical Physics Department of LMU Munich. The system consists of a large (50x50x30 mm3) monolithic LaBr3(Ce) scintillation crystal as absorber component to detect the multi-MeV Compton scattered photons, together with a stack of 6 double-sided silicon strip detectors (DSSSD) acting as scatterer component. Key ingredient of the γ-source reconstruction is the determination of the γ-ray interaction position in the scintillator, which is read out by a 256-fold segmented multi-anode photomultiplier tube (PMT). From simulations an angular resolution of about 1.5o for the photon source reconstruction can be expected for the energy range around 3 – 5 MeV, provided that a spatial resolution of 3 mm can be reached in the absorbing scintillator [1]. Therefore, particular effort was dedicated to characterize this latter property as a function of the γ-ray energy. Intense, tightly collimated 137Cs and 60Co photon sources were used for 2D irradiation scans (step size 0.5 mm) as prerequisite for studying the performance of the "k-Nearest-Neighbors" algorithm developed at TU Delft [2] (together with its variant "Categorical Average Pattern", CAP) and extending its applicability into the energy range beyond the original 511 keV. In this paper we present our most recent interaction position analysis in the absorbing scintillator, leading to a considerably improved value for the spatial resolution: systematic studies were performed as a function of the k-NN parameters and the PMT segmentation. A trend of improving spatial resolution with increasing photon energy was confirmed, resulting in the realization of the presently optimum spatial resolution of 2.9(1) mm @1.3 MeV, thus reaching the design specifications of the Compton camera absorber. The specification goal was reached also for a reduced PMT segmentation of 8x8 anode segments (each with 6x6 mm2 active area), thus allowing to reduce the complexity of the signal processing while preserving the performance

An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells.

Duchenne muscular dystrophy is a progressive and incurable neuromuscular disease caused by genetic and biochemical defects of the dystrophin-glycoprotein complex. Here we show the regenerative potential of myogenic progenitors derived from corrected dystrophic induced pluripotent stem cells generated from fibroblasts of mice lacking both dystrophin and utrophin. We correct the phenotype of dystrophic induced pluripotent stem cells using a Sleeping Beauty transposon system carrying the micro-utrophin gene, differentiate these cells into skeletal muscle progenitors and transplant them back into dystrophic mice. Engrafted muscles displayed large numbers of micro-utrophin-positive myofibers, with biochemically restored dystrophin-glycoprotein complex and improved contractile strength. The transplanted cells seed the satellite cell compartment, responded properly to injury and exhibit neuromuscular synapses. We also detect muscle engraftment after systemic delivery of these corrected progenitors. These results represent an important advance towards the future treatment of muscular dystrophies using genetically corrected autologous induced pluripotent stem cells

Data from: Edge influence on vegetation at natural and anthropogenic edges of boreal forests in Canada and Fennoscandia

1. Although anthropogenic edges are an important consequence of timber harvesting, edges due to natural disturbances or landscape heterogeneity are also common. Forest edges have been well-studied in temperate and tropical forests, but less so in less productive, disturbance-adapted boreal forests. 2. We synthesized data on forest vegetation at edges of boreal forests and compared edge influence among edge types (fire, cut, lake/wetland; old vs. young), forest types (broadleaf vs. coniferous) and geographic regions. Our objectives were to quantify vegetation responses at edges of all types and to compare the strength and extent of edge influence among different types of edges and forests. 3. Research was conducted using the same general sampling design in Alberta, Ontario and Quebec in Canada, and in Sweden and Finland. We conducted a meta-analysis for a variety of response variables including forest structure, deadwood abundance, regeneration, understorey abundance and diversity, and nonvascular plant cover. We also determined the magnitude and distance of edge influence using randomization tests. 4. Some edge responses (lower tree basal area, tree canopy and bryophyte cover; more logs; higher regeneration) were significant overall across studies. Edge influence on ground vegetation in boreal forests was generally weak, not very extensive (distance of edge influence usually < 20 m) and decreased with time. We found more extensive edge influence at natural edges, at younger edges and in broadleaf forests. The comparison among regions revealed weaker edge influence in Fennoscandian forests. 5. Synthesis. Edges created by forest harvesting do not appear to have as strong, extensive or persistent influence on vegetation in boreal as in tropical or temperate forested ecosystems. We attribute this apparent resistance to shorter canopy heights, inherent heterogeneity in boreal forests and their adaptation to frequent natural disturbance. Nevertheless, notable differences between forest structure responses to natural (fire) and anthropogenic (cut) edges raise concerns about biodiversity implications of extensive creation of anthropogenic edges. By highlighting universal responses to edge influence in boreal forests that are significant irrespective of edge or forest type, and those which vary by edge type, we provide a context for the conservation of boreal forests