Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity

Pompe disease is a severe disorder caused by loss of acid α-glucosidase (GAA), leading to glycogen accumulation in tissues and neuromuscular and cardiac dysfunction. Enzyme replacement therapy is the only available treatment. AT845 is an adeno-associated viral vector designed to express human GAA specifically in skeletal muscle and heart. Systemic administration of AT845 in Gaa−/− mice led to a dose-dependent increase in GAA activity, glycogen clearance in muscles and heart, and functional improvement. AT845 was tolerated in cynomolgus macaques at low doses, while high doses caused anti-GAA immune response, inflammation, and cardiac abnormalities resulting in unscheduled euthanasia of two animals. Conversely, a vector expressing the macaque GAA caused no detectable pathology, indicating that the toxicity observed with AT845 was an anti-GAA xenogeneic immune response. Western blot analysis showed abnormal processing of human GAA in cynomolgus muscle, adding to the species-specific effects of enzyme expression. Overall, these studies show that AAV-mediated GAA delivery to muscle is efficacious in Gaa−/− mice and highlight limitations in predicting the toxicity of AAV vectors encoding human proteins in non-human species

GATE : a simulation toolkit for PET and SPECT

Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols, and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at the address http://www-lphe.epfl.ch/GATE/

Depressive symptoms and suicide in 56,000 older Chinese: a Hong Kong cohort study

Objective: To examine dose-response associations between depressive symptoms and suicide and modification effects of sex, age and health status in older Chinese. Methods: We used the Chinese version of the 15-item Geriatric Depression Scale (GDS) to measure depressive symptoms (GDS score ≥ 8) and Cox regression to examine association with suicide mortality in a population-based cohort of 55,946 individuals, aged 65 years or above, enrolled from July 1998 to December 2000 at one of 18 Elderly Health Centres of Hong Kong Department of Health. The cohort was followed up for suicide mortality till 31 March 2009 (mean follow-up 8.7 years). Results: Depressive symptoms were associated with suicide in men [hazard ratio (HR) 2.03, 95% confidence interval (CI) 0.96-4.29] and women (HR = 2.36, 95% CI 1.31-4.24) after adjusting for age, education, monthly expenditure, smoking, alcohol drinking, physical activity, body mass index, health status, and self-rated health. There was no threshold for GDS score and suicide in either sex. Age, sex and health status did not modify the association. Conclusions: Depressive symptoms predict higher suicide risk in older Chinese in a dose-response pattern. These associations were not attenuated by adjustment for health status, suggesting that depressive symptoms in older people are likely to be an independent causal factor for suicide. The GDS score showed no threshold in predicting suicide risk, suggesting that older people with low GDS scores deserve further attention and those with very high scores need urgent intervention. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201

Mapping the internal recognition surface of an octanuclear coordination cage using guest libraries

Size and shape criteria for guest binding inside the cavity of an octanuclear cubic coordination cage in water have been established using a new fluorescence displacement assay to quantify guest binding. For aliphatic cyclic ketones of increasing size (from C5 to C11), there is a linear relationship between ΔG for guest binding and the guest’s surface area: the change in ΔG for binding is 0.3 kJ mol–1 Å–2, corresponding to 5 kJ mol–1 for each additional CH2 group in the guest, in good agreement with expectations based on hydrophobic desolvation. The highest association constant is K = 1.2 × 106 M–1 for cycloundecanone, whose volume is approximately 50% of the cavity volume; for larger C12 and C13 cyclic ketones, the association constant progressively decreases as the guests become too large. For a series of C10 aliphatic ketones differing in shape but not size, ΔG for guest binding showed no correlation with surface area. These guests are close to the volume limit of the cavity (cf. Rebek’s 55% rule), so the association constant is sensitive to shape complementarity, with small changes in guest structure resulting in large changes in binding affinity. The most flexible members of this series (linear aliphatic ketones) did not bind, whereas the more preorganized cyclic ketones all have association constants of 104–105 M–1. A crystal structure of the cage·cycloundecanone complex shows that the guest carbonyl oxygen is directed into a binding pocket defined by a convergent set of CH groups, which act as weak hydrogen-bond donors, and also shows close contacts between the exterior surface of the disc-shaped guest and the interior surface of the pseudospherical cage cavity despite the slight mismatch in shape

Effect of Surfactants on the Structure and Morphology of Magnesium Borate Hydroxide Nanowhiskers Synthesized by Hydrothermal Route

Magnesium borate hydroxide (MBH) nanowhiskers were synthesized using a one step hydrothermal process with different surfactants. The effect surfactants have on the structure and morphology of the MBH nanowhiskers has been investigated. The X-ray diffraction profile confirms that the as-synthesized material is of single phase, monoclinic MgBO2(OH). The variations in the size and shape of the different MBH nanowhiskers have been discussed based on the surface morphology analysis. The annealing of MBH nanowhiskers at 500 °C for 4 h has significant effect on the crystal structure and surface morphology. The UV–vis absorption spectra of the MBH nanowhiskers synthesized with and without surfactants show enhanced absorption in the low-wavelength region, and their optical band gaps were estimated from the optical band edge plots. The photoluminescence spectra of the MBH nanowhiskers produced with and without surfactants show broad emission band with the peak maximum at around 400 nm, which confirms the dominant contribution from the surface defect states

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

\ua9 The Author(s) 2024.In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases

Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia

Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features