Transcriptomic indices of fast and slow disease progression in two mouse models of amyotrophic lateral sclerosis

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Dynamic and cell-specific DACH1 expression in human neocortical and striatal development

DACH1 is the human homolog of the Drosophila dachshund gene, which is involved in the development of the eye, nervous system, and limbs in the fly. Here, we systematically investigate DACH1 expression patterns during human neurodevelopment, from 5 to 21 postconceptional weeks. By immunodetection analysis, we found that DACH1 is highly expressed in the proliferating neuroprogenitors of the developing cortical ventricular and subventricular regions, while it is absent in the more differentiated cortical plate. Single-cell global transcriptional analysis revealed that DACH1 is specifically enriched in neuroepithelial and ventricular radial glia cells of the developing human neocortex. Moreover, we describe a previously unreported DACH1 expression in the human striatum, in particular in the striatal medium spiny neurons. This finding qualifies DACH1 as a new striatal projection neuron marker, together with PPP1R1B, BCL11B, and EBF1. We finally compared DACH1 expression profile in human and mouse forebrain, where we observed spatio-temporal similarities in its expression pattern thus providing a precise developmental description of DACH1 in the 2 mammalian species

Successful sequencing of Huntington’s disease CAG microsatellite orthologs from museum collection specimens

Huntington's Disease is an inherited neurodegenerative disorder affecting human and caused by the expansion of a CAG repeat microsatellite localized in the 5\u2019 end of the Huntingtin (Htt) gene, ultimately leading to neuronal loss in brain and motor and neuropsychiatric disturbances. To obtain information on Htt orthologous genes, a potential source of genomic DNA is represented by museum collections. Here we aimed at the characterization of orthologous sequences of the human microsatellite by assessing 141 specimens from Museo di Storia Naturale di Milano, Museo di Storia Naturale di Pavia and Acquario Civico di Milano. Samples belonged to four vertebrate groups: mammals (n=66), amphibians (n=1), fishes (n=22) and reptiles (n=52). Small fragments of tissues preserved in ethanol (n=52), stored frozen (n=79) and tissues that had undergone a tanning process (n=10) were used. These specimens ranged from recently collected to over 50-years-old specimens. Genomic DNA was extracted with two different commercial kits (Macherey-Nagel, Zymo Research) and its quality assessed by ultraviolet-visible spectrophotometry and gel electrophoresis. DNA extraction yielded fragments of highly variable length, probably depending on initial sample preservation conditions. Specific primers designed to encompass the CAG tract and targeting the most conservative regions of the different templates were used to amplify the sequences of interest. Amplicon length ranged from 100 to 250 base pairs. About 50% of the PCR reactions performed were successful and the relative products have been correctly sequenced. This study demonstrates that museum collections are a valuable resource of genomic material to amplify triplet repeat loci and restates the importance of specimens conservation for scientific research

Human cortical organoids expose a differential function of GSK3 on cortical neurogenesis

The regulation of the proliferation and polarity of neural progenitors is crucial for the development of the brain cortex. Animal studies have implicated glycogen synthase kinase 3 (GSK3) as a pivotal regulator of both proliferation and polarity, yet the functional relevance of its signaling for the unique features of human corticogenesis remains to be elucidated. We harnessed human cortical brain organoids to probe the longitudinal impact of GSK3 inhibition through multiple developmental stages. Chronic GSK3 inhibition increased the proliferation of neural progenitors and caused massive derangement of cortical tissue architecture. Single-cell transcriptome profiling revealed a direct impact on early neurogenesis and uncovered a selective role of GSK3 in the regulation of glutamatergic lineages and outer radial glia output. Our dissection of the GSK3-dependent transcriptional network in human corticogenesis underscores the robustness of the programs determining neuronal identity independent of tissue architecture

Evoluzione del gene Hdh nei primati

Il gene Hdh si origina senza la tripletta CAG in Dictyostelium discoideum (Dd), circa 800 milioni di anni fa, prima della divergenza dei protostomi-deuterostomi (Zuccato et al., Physiol Rev 2010). La tripletta CAG compare in seguito ed ? esclusiva della branca dei deuterostomi (Tartari et al., Mol Biol Evol 2008). Due ripetizioni CAGs si trovano nel gene Hdh del riccio di mare (Strongylocentrotus purpuratus, Sp), la prima specie ad avere un sistema nervoso primitivo, e due ripetizioni si trovano anche nell\u27anfiosso (Branchiostoma floridae, Bf), che presenta un rudimentale tubo nervoso e un primo tentativo di cefalizzazione. Quattro ripetizioni CAG si riscontrano nei pesci pi? evoluti, negli anfibi e negli uccelli. Il numero di triplette CAG aumenta ulteriormente nei mammiferi e raggiunge la lunghezza massima nella nostra specie (Tartari et al., Mol Biol Evol 2008). In Homo sapiens il gene Hdh si trova sul braccio corto del cromosoma 4 e presenta la sequenza trinucleotidica ripetuta da 11 a 35 volte. Un recente studio su 278 individui normali ha rivelato che chi ha pi? CAG nel range sano ha pi? materia grigia (Muhlau et al., PlosOne 2012), indicazione del fatto che il numero di CAG potrebbe influire sulla normale struttura del cervello. Infatti, un numero di triplette CAG superiore a 35 causa la Corea di Huntington, una malattia neurodegenerativa che insorge tanto pi? precocemente quanto maggiore ? il numero delle ripetizioni CAG. Al fine di verificare se il progressivo incremento del numero di ripetizioni CAG nel gene Hdh durante l\u27evoluzione avesse un possibile ruolo nelle funzioni cognitive emergenti del cervello dei mammiferi, abbiamo analizzato il gene Hdh in diverse specie di primati non umani per analizzare la variabilit? interspecifica e intraspecifica. I risultati sperimentali e le ricostruzioni filogenetiche sostengono che il numero di ripetizioni CAG aumenta nel corso dell\u27evoluzione dei deuterostomi e sembra essere correlato con l\u27aspetto e/o l\u27evoluzione dei sistemi nervosi progressivamente pi? complessi

Effects of Externally Rated Job Demand and Control on Depression Diagnosis Claims in an Industrial Cohort

This study examined whether externally rated job demand and control were associated with depression diagnosis claims in a heavy industrial cohort. The retrospective cohort sample consisted of 7,566 hourly workers aged 18–64 years who were actively employed at 11 US plants between January 1, 1996, and December 31, 2003, and free of depression diagnosis claims during an initial 2-year run-in period. Logistic regression analysis was used to model the effect of tertiles of demand and control exposure on depression diagnosis claims. Demand had a significant positive association with depression diagnosis claims in bivariate models and models adjusted for demographic (age, gender, race, education, job grade, tenure) and lifestyle (smoking status, body mass index, cholesterol level) variables (high demand odds ratio = 1.39, 95% confidence interval: 1.04, 1.86). Control was associated with greater risk of depression diagnosis at moderate levels in unadjusted models only (odds ratio = 1.47, 95% confidence interval: 1.12, 1.93), while low control, contrary to expectation, was not associated with depression. The effects of the externally rated demand exposure were lost with adjustment for location. This may reflect differences in measurement or classification of exposure, differences in depression diagnosis by location, or other location-specific factors

Using complex networks to model, simulate and understand the dynamics of psychotherapeutic processes: An experimental study proposal

The goal of our study was to utilize the science of complex interactions to bridge the gap in research concerning psychotherapy. In particular, we chose to focus on the use of graph theory to model and simulate the topology and dynamics of the psychotherapeutic relationship, given how in the past few years such method has been instrumental in understanding complex dynamic systems. © 2018 IEEE