Expanding spectrum of PCDH12 related phenotype begs exploration of multipronged pathomechanisms

The lack of effective disease-modifying therapeutics to tackle Alzheimer’s disease (AD) is unsettling considering the actual prevalence of this devastating neurodegenerative disorder worldwide. Intermittent hypoxic conditioning (IHC) is a powerful non-pharmacological procedure known to enhance brain resilience. In this context, the aim of the present study was to investigate the potential long-term protective impact of IHC against AD-related phenotype, putting a special focus on cognition and mitochondrial bioenergetics and dynamics. For this purpose, six-month-old male triple transgenic AD mice (3×Tg-AD) were submitted to an IHC protocol for two weeks and the behavioral assessment was performed at 8.5 months of age, while the sacrifice of mice occurred at nine months of age and their brains were removed for the remaining analyses. Interestingly, IHC was able to prevent anxiety-like behavior and memory and learning deficits and significantly reduced brain cortical levels of amyloid-β (Aβ) in 3×Tg-AD mice. Concerning brain energy metabolism, IHC caused a significant increase in brain cortical levels of glucose and a robust improvement of the mitochondrial bioenergetic profile in 3×Tg-AD mice, as mirrored by the significant increase in mitochondrial membrane potential (ΔΨm) and respiratory control ratio (RCR). Notably, the improvement of mitochondrial bioenergetics seems to result from an adaptative coordination of the distinct but intertwined aspects of the mitochondrial quality control axis. Particularly, our results indicate that IHC favors mitochondrial fusion and promotes mitochondrial biogenesis and transport and mitophagy in the brain cortex of 3×Tg-AD mice. Lastly, IHC also induced a marked reduction in synaptosomal-associated protein 25 kDa (SNAP-25) levels and a significant increase in both glutamate and GABA levels in the brain cortex of 3×Tg-AD mice, suggesting a remodeling of the synaptic microenvironment. Overall, these results demonstrate the effectiveness of the IHC paradigm in forestalling the AD-related phenotype in the 3×Tg-AD mouse model, offering new insights to AD therapy and forcing a rethink concerning the potential value of non-pharmacological interventions in clinical practice.

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An exploratory assessment of the applicability of direct-to-consumer genetic testing to translational research in Japan

BMC Research Notes ◽

10.1186/s13104-021-05696-4 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Masahiro Inoue ◽

Shota Arichi ◽

Tsuyoshi Hachiya ◽

Anna Ohtera ◽

Seok-Won Kim ◽

...

Keyword(s):

Genetic Testing ◽

Translational Research ◽

Drug Target ◽

Target Genes ◽

Healthy Individuals ◽

Alcohol Sensitivity ◽

Direct To Consumer ◽

Disease States ◽

Multiple Phenotypes ◽

Related Phenotype

Abstract Objective In order to assess the applicability of a direct-to-consumer (DTC) genetic testing to translational research for obtaining new knowledge on relationships between drug target genes and diseases, we examined possibility of these data by associating SNPs and disease related phenotype information collected from healthy individuals. Results A total of 12,598 saliva samples were collected from the customers of commercial service for SNPs analysis and web survey were conducted to collect phenotype information. The collected dataset revealed similarity to the Japanese data but distinguished differences to other populations of all dataset of the 1000 Genomes Project. After confirmation of a well-known relationship between ALDH2 and alcohol-sensitivity, Phenome-Wide Association Study (PheWAS) was performed to find association between pre-selected drug target genes and all the phenotypes. Association was found between GRIN2B and multiple phenotypes related to depression, which is considered reliable based on previous reports on the biological function of GRIN2B protein and its relationship with depression. These results suggest possibility of using SNPs and phenotype information collected from healthy individuals as a translational research tool for drug discovery to find relationship between a gene and a disease if it is possible to extract individuals in pre-disease states by properly designed questionnaire.

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Cerebrospinal fluid metabolomics identifies 19 brain-related phenotype associations

Communications Biology ◽

10.1038/s42003-020-01583-z ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Daniel J. Panyard ◽

Kyeong Mo Kim ◽

Burcu F. Darst ◽

Yuetiva K. Deming ◽

Xiaoyuan Zhong ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Drug Targets ◽

Large Scale ◽

Prediction Models ◽

Genome Wide Association ◽

Large Samples ◽

Genome Wide ◽

Metabolomic Data ◽

Related Phenotype ◽

Omic Data

AbstractThe study of metabolomics and disease has enabled the discovery of new risk factors, diagnostic markers, and drug targets. For neurological and psychiatric phenotypes, the cerebrospinal fluid (CSF) is of particular importance. However, the CSF metabolome is difficult to study on a large scale due to the relative complexity of the procedure needed to collect the fluid. Here, we present a metabolome-wide association study (MWAS), which uses genetic and metabolomic data to impute metabolites into large samples with genome-wide association summary statistics. We conduct a metabolome-wide, genome-wide association analysis with 338 CSF metabolites, identifying 16 genotype-metabolite associations (metabolite quantitative trait loci, or mQTLs). We then build prediction models for all available CSF metabolites and test for associations with 27 neurological and psychiatric phenotypes, identifying 19 significant CSF metabolite-phenotype associations. Our results demonstrate the feasibility of MWAS to study omic data in scarce sample types.

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Cruciate Ligament Cell Sheets Can Be Rapidly Produced on Thermoresponsive poly(glycidyl ether) Coating and Successfully Used for Colonization of Embroidered Scaffolds

Cells ◽

10.3390/cells10040877 ◽

2021 ◽

Vol 10 (4) ◽

pp. 877

Author(s):

Ingrid Zahn ◽

Daniel David Stöbener ◽

Marie Weinhart ◽

Clemens Gögele ◽

Annette Breier ◽

...

Keyword(s):

Gene Expression ◽

Type I Collagen ◽

Cruciate Ligament ◽

Glycidyl Ether ◽

Stable Gene ◽

Type I ◽

Cell Sheets ◽

Thermoresponsive Polymers ◽

Related Phenotype ◽

Anterior Cruciate

Anterior cruciate ligament (ACL) cell sheets combined with biomechanically competent scaffolds might facilitate ACL tissue engineering. Since thermoresponsive polymers allow a rapid enzyme-free detachment of cell sheets, we evaluated the applicability of a thermoresponsive poly(glycidyl ether) (PGE) coating for cruciate ligamentocyte sheet formation and its influence on ligamentocyte phenotype during sheet-mediated colonization of embroidered scaffolds. Ligamentocytes were seeded on surfaces either coated with PGE or without coating. Detached ligamentocyte sheets were cultured separately or wrapped around an embroidered scaffold made of polylactide acid (PLA) and poly(lactic-co-ε-caprolactone) (P(LA-CL)) threads functionalized by gas-phase fluorination and with collagen foam. Ligamentocyte viability, protein and gene expression were determined in sheets detached from surfaces with or without PGE coating, scaffolds seeded with sheets from PGE-coated plates and the respective monolayers. Stable and vital ligamentocyte sheets could be produced within 24 h with both surfaces, but more rapidly with PGE coating. PGE did not affect ligamentocyte phenotype. Scaffolds could be colonized with sheets associated with high cell survival, stable gene expression of ligament-related type I collagen, decorin, tenascin C and Mohawk after 14 d and extracellular matrix (ECM) deposition. PGE coating facilitates ligamentocyte sheet formation, and sheets colonizing the scaffolds displayed a ligament-related phenotype.

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Random errors in protein synthesis activate an age-dependent program of muscle atrophy in mice

Communications Biology ◽

10.1038/s42003-021-02204-z ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

James Moore ◽

Rashid Akbergenov ◽

Martina Nigri ◽

Patricia Isnard-Petit ◽

Amandine Grimm ◽

...

Keyword(s):

Protein Synthesis ◽

Muscle Atrophy ◽

Strength Analysis ◽

Dependent Manner ◽

Random Errors ◽

Age Related ◽

Related Phenotype ◽

Age Dependent ◽

Translation Accuracy ◽

Transcriptomic Changes

AbstractRandom errors in protein synthesis are prevalent and ubiquitous, yet their effect on organismal health has remained enigmatic for over five decades. Here, we studied whether mice carrying the ribosomal ambiguity (ram) mutation Rps2-A226Y, recently shown to increase the inborn error rate of mammalian translation, if at all viable, present any specific, possibly aging-related, phenotype. We introduced Rps2-A226Y using a Cre/loxP strategy. Resulting transgenic mice were mosaic and showed a muscle-related phenotype with reduced grip strength. Analysis of gene expression in skeletal muscle using RNA-Seq revealed transcriptomic changes occurring in an age-dependent manner, involving an interplay of PGC1α, FOXO3, mTOR, and glucocorticoids as key signaling pathways, and finally resulting in activation of a muscle atrophy program. Our results highlight the relevance of translation accuracy, and show how disturbances thereof may contribute to age-related pathologies.

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