Adeno-associated virus (AAV)-based gene therapy is a promising strategy to treat muscle diseases. However, this strategy is currently confronted with challenges, including a lack of transduction ...efficiency across the entire muscular system and toxicity resulting from off-target tissue effects. Recently, novel myotropic AAVs named MyoAAVs and AAVMYOs have been discovered using a directed evolution approach, all separately demonstrating enhanced muscle transduction efficiency and liver de-targeting effects. However, these newly discovered AAV variants have not yet been compared.
In this study, we performed a comparative analysis of these various AAV9-derived vectors under the same experimental conditions following different injection time points in two distinct mouse strains.
We highlight differences in transduction efficiency between AAV9, AAVMYO, MyoAAV2A and MyoAAV4A that depend on age at injection, doses and mouse genetic background. In addition, specific AAV serotypes appeared more potent to transduce skeletal muscles including diaphragm and/or to de-target heart or liver.
Our study provides guidance for researchers aiming to establish proof-of-concept approaches for preventive or curative perspectives in mouse models, to ultimately lead to future clinical trials for muscle disorders.
Geldanamycin (GA) is a potent anticancer antibiotic that inhibits Hsp90. Its potential clinical utility is hampered by its severe toxicity. To alleviate this problem, we synthesized a series of ...carbohydrate−geldanamycin conjugates for enzyme-specific activation to increase tumor selectivity. The conjugation was carried out at the C-17-position of GA. Their anticancer activity was tested in a number of cancer cell lines. The enzyme-specific activation of these conjugates was evaluated with β-galactosidase and β-glucosidase. Evidently, glycosylation of C-17-position converted GA to an inactive prodrug before enzyme cleavage. Glucose−GA, as positive control, showed anticancer activity with IC50 of 70.2−380.9 nM in various cancer cells by β-glucosidase activation inside of the tumor cells, which was confirmed by 3-fold inhibition using β-glucosidase specific inhibitor 2,5-dihydroxymethy-3,4-dihydroxypyrrolidine (DMDP). Compared to glucose−GA, galactose− and lactose−GA conjugates exhibited much less activity with IC50 greater than 8000−25 000 nM. However, when galactose− and lactose−GA were incubated with β-galactosidase in the cells, their anticancer activity was enhanced by 3- to 40-fold. The results suggest that GA can be inactivated by glycosylation of C-17-position and reactivated for anticancer activity by β-galactosidase. Therefore, galactose−GA can be exploited in antibody-directed enzyme prodrug therapy (ADEPT) with β-galactosidase for enzyme-specific activation in tumors to increase tumor selectivity.
The NHGRI-EBI GWAS Catalog (www.ebi.ac.uk/gwas) is a FAIR knowledgebase providing detailed, structured, standardised and interoperable genome-wide association study (GWAS) data to >200 000 users per ...year from academic research, healthcare and industry. The Catalog contains variant-trait associations and supporting metadata for >45 000 published GWAS across >5000 human traits, and >40 000 full P-value summary statistics datasets. Content is curated from publications or acquired via author submission of prepublication summary statistics through a new submission portal and validation tool. GWAS data volume has vastly increased in recent years. We have updated our software to meet this scaling challenge and to enable rapid release of submitted summary statistics. The scope of the repository has expanded to include additional data types of high interest to the community, including sequencing-based GWAS, gene-based analyses and copy number variation analyses. Community outreach has increased the number of shared datasets from under-represented traits, e.g. cancer, and we continue to contribute to awareness of the lack of population diversity in GWAS. Interoperability of the Catalog has been enhanced through links to other resources including the Polygenic Score Catalog and the International Mouse Phenotyping Consortium, refinements to GWAS trait annotation, and the development of a standard format for GWAS data.
Peroxisomes are highly metabolic, autonomously replicating organelles that generate reactive oxygen species (ROS) as a by-product of fatty acid β-oxidation. Consequently, cells must maintain ...peroxisome homeostasis, or risk pathologies associated with too few peroxisomes, such as peroxisome biogenesis disorders, or too many peroxisomes, inducing oxidative damage and promoting diseases such as cancer. We report that the PEX5 peroxisome import receptor binds ataxia-telangiectasia mutated (ATM) and localizes this kinase to the peroxisome. In response to ROS, ATM signalling activates ULK1 and inhibits mTORC1 to induce autophagy. Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy. These data reveal an important new role for ATM in metabolism as a sensor of ROS that regulates pexophagy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
A criterion based on chemical explosive mode analysis (CEMA) is proposed to identify different local combustion modes, such as auto-ignition, diffusion-assisted ignition, and local extinction in ...laminar and turbulent premixed flames. The criterion is employed to distinguish between two different propagation modes of one-dimensional (1-D) freely propagating premixed flames, that is the canonical deflagration wave controlled by heat and species back-diffusion, which features a unique flame speed, and the auto-ignition controlled reaction front propagation, which may feature an arbitrary propagation speed. In the CEMA based diagnostic, the local chemistry and diffusion source terms are projected to the chemical explosive mode (CEM), such that the roles of diffusion and chemistry in the CEM can be quantified and compared for identification of the flame propagation mode. The new criterion is further applied to analyze two-dimensional (2-D) DNS datasets of homogeneous charge compression ignition (HCCI) combustion of n-heptane/air with different levels of thermal stratification. Both flame propagation modes are observed and contribute significantly to the overall flame burning in the case with a high level of thermal stratification, while the flame propagation is found dominated by the auto-ignition mode in the case with a low level of thermal stratification, which agrees with the finding in previous studies.
Structural genomic variations represent a major driving force of evolution, and a burst of large segmental gene duplications occurred in the human lineage during its separation from nonhuman ...primates. SRGAP2, a gene recently implicated in neocortical development, has undergone two human-specific duplications. Here, we find that both duplications (SRGAP2B and SRGAP2C) are partial and encode a truncated F-BAR domain. SRGAP2C is expressed in the developing and adult human brain and dimerizes with ancestral SRGAP2 to inhibit its function. In the mouse neocortex, SRGAP2 promotes spine maturation and limits spine density. Expression of SRGAP2C phenocopies SRGAP2 deficiency. It underlies sustained radial migration and leads to the emergence of human-specific features, including neoteny during spine maturation and increased density of longer spines. These results suggest that inhibition of SRGAP2 function by its human-specific paralogs has contributed to the evolution of the human neocortex and plays an important role during human brain development.
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► SRGAP2 has undergone two partial duplications, specifically in the human genome ► One copy (SRGAP2C) is expressed in the human brain and antagonizes ancestral SRGAP2 ► Ancestral SRGAP2 promotes dendritic spine maturation and limits spine density in vivo ► Human SRGAP2C induces neoteny and leads to higher density of spines with longer necks
A truncated duplicate gene present only in humans antagonizes the function of its parental paralog in neural development, leading to human-specific neuronal features such as increased dendritic spine density.
'Food addiction' shares a similar neurobiological and behavioral framework with substance addiction. However whether, and to what degree, 'food addiction' contributes to obesity in the general ...population is unknown.
to assess 1) the prevalence of 'food addiction' in the Newfoundland population; 2) if clinical symptom counts of 'food addiction' were significantly correlated with the body composition measurements; 3) if food addicts were significantly more obese than controls, and 4) if macronutrient intakes are associated with 'food addiction'.
A total of 652 adults (415 women, 237 men) recruited from the general population participated in this study. Obesity was evaluated by Body Mass Index (BMI) and Body Fat percentage measured by dual-energy X-ray absorptiometry. 'Food addiction' was assessed using the Yale Food Addiction Scale and macronutrient intake was determined from the Willet Food Frequency Questionnaire.
The prevalence of 'food addiction' was 5.4% (6.7% in females and 3.0% in males) and increased with obesity status. The clinical symptom counts of 'food addiction' were positively correlated with all body composition measurements across the entire sample (p<0.001). Obesity measurements were significantly higher in food addicts than controls; Food addicts were 11.7 (kg) heavier, 4.6 BMI units higher, and had 8.2% more body fat and 8.5% more trunk fat. Furthermore, food addicts consumed more calories from fat and protein compared with controls.
Our results demonstrated that 'food addiction' contributes to severity of obesity and body composition measurements from normal weight to obese individuals in the general population with higher rate in women as compared to men.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The visual system exploits multiple signals, including monocular and binocular cues, to determine the motion of objects through depth. In the laboratory, sensitivity to different three-dimensional ...(3D) motion cues varies across observers and is often weak for binocular cues. However, laboratory assessments may reflect factors beyond inherent perceptual sensitivity. For example, the appearance of weak binocular sensitivity may relate to extensive prior experience with two-dimensional (2D) displays in which binocular cues are not informative. Here we evaluated the impact of experience on motion-in-depth (MID) sensitivity in a virtual reality (VR) environment. We tested a large cohort of observers who reported having no prior VR experience and found that binocular cue sensitivity was substantially weaker than monocular cue sensitivity. As expected, sensitivity was greater when monocular and binocular cues were presented together than in isolation. Surprisingly, the addition of motion parallax signals appeared to cause observers to rely almost exclusively on monocular cues. As observers gained experience in the VR task, sensitivity to monocular and binocular cues increased. Notably, most observers were unable to distinguish the direction of MID based on binocular cues above chance level when tested early in the experiment, whereas most showed statistically significant sensitivity to binocular cues when tested late in the experiment. This result suggests that observers may discount binocular cues when they are first encountered in a VR environment. Laboratory assessments may thus underestimate the sensitivity of inexperienced observers to MID, especially for binocular cues.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Soluble amyloid-β oligomers (Aβo) trigger Alzheimer’s disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrPC). At the postsynaptic density (PSD), extracellular Aβo ...bound to lipid-anchored PrPC activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Aβo-PrPC with Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrPC-bound Aβo to activate Fyn. PrPC and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Aβo-PrPC generates mGluR5-mediated increases of intracellular calcium in Xenopus oocytes and in neurons, and the latter is also driven by human AD brain extracts. In addition, signaling by Aβo-PrPC-mGluR5 complexes mediates eEF2 phosphorylation and dendritic spine loss. For mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory, and synapse density. Thus, Aβo-PrPC complexes at the neuronal surface activate mGluR5 to disrupt neuronal function.
•Among transmembrane PSD proteins, only mGluR5 couples Aβo-PrPC to Fyn kinase•mGluR5 also links Aβo-PrPC to calcium signaling and protein translation control•AD brain extract-induced dysregulation of neuronal calcium requires PrPC-mGluR5•Transgenic mouse memory deficits and synapse loss are reversed by mGluR5 antagonist
Amyloid-β oligomers trigger Alzheimer’s pathophysiology by binding to PrPC and disrupting synapses. Um et al. show that the mGluR5 metabotropic glutamate receptor links Aβo-PrPC to intracellular signaling. For AD mice, mGluR5 antagonism reverses deficits in learning, memory, and synapse density.
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