Peripheral Biomarkers in Manifest and Premanifest Huntington’s Disease

Huntington's disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inhered expansion of the CAG triplet in the huntingtin gene causing a pathogenic gain-of-function of the mutant huntingtin (mHTT) protein has been identified. In this review, we focus on known biomarkers (e.g., mHTT, neurofilament light chains) and on new biofluid biomarkers that can be quantified in plasma or peripheral blood mononuclear cells from mHTT carriers. Circulating biomarkers may fill current unmet needs in HD management: better stratification of patients amenable to etiologic treatment; the initiation of preventive treatment in premanifest HD; and the identification of peripheral pathogenic central nervous system cascades

Automatic Data Transfer from OMOP-CDM to REDCap: A Semantically-Enriched Framework.

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CADASIL or MS? Consider “Red Flags” but Avoid a Misdiagnosis: Case Series of a Concomitant Diagnosis

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic autosome-dominant disease with chronic clinical course. Rarely, CADASIL may present with atypical relapsing-remitting manifestations, cerebral and spinal white matter lesions, mimicking inflammatory CNS disease as multiple sclerosis (MS). The rarely co-occurrence of MS and CADASIL may represent a hard challenging diagnosis even for an expert neurologist. Here, we present a case series of two patients with CADASIL showing MRI pattern overlapping MS. They were the only case of co-occurrence of CADASIL and MS in their own family. Both patients were treated with anti-inflammatory and anti-platelet drugs, mostly with good response. Pathogenic hypothesis highlights that genetic events, related to monogenic disease, may expose CNS antigens with a consequent self-immune attack. In CADASIL, the function of Notch3 receptor showed a consistent interplay with immune system activity. Indeed, certain mutations of Notch3 receptor show abnormal upregulation of specific pro-inflammatory patterns. However, even if it is not possible to determinate if the proinflammatory activity may be promoted by pathogenic mutations in Notch3, the "apparent" difference between MS and “inflammatory CADASIL” could be considered more semantic than etiologic

Imaging Characteristics of Choroid Plexuses in Presymptomatic Multiple Sclerosis. A Retrospective Study

Background and Objectives Recent imaging studies have suggested a possible involvement of the choroid plexus (CP) in multiple sclerosis (MS). Here, we investigated whether CP changes are already detectable at the earliest stage of MS, preceding symptom onset. Methods This study is a retrospective analysis of 27 patients with presymptomatic MS, 97 patients with clinically definite MS (CDMS), and 53 healthy controls (HCs) who underwent a cross-sectional 3T-MRI acquisition; of which, 22 MS, 19 HCs, and 1 presymptomatic MS (evaluated 8 months before conversion to CDMS) also underwent translocator protein (TSPO) F-18-DPA-714 PET and were included in the analysis. CPs were manually segmented on 3D T1-weighted images for volumetric analysis. CP F-18-DPA-714 uptake, reflecting inflammation, was calculated as the average standardized uptake value (SUV). Multivariable regressions adjusted for age, sex, and ventricular and brain volume were fitted to test CP volume differences between presymptomatic patients and MS or HCs. For the presymptomatic case who also had F-18-DPA-714 PET, CP SUV differences with MS and HCs were assessed through Crawford-Howell tests. To provide further insight into the interpretation of F-18-DPA-714-PET uptake at the CP level, a postmortem analysis of CPs in MS vs HCs was performed to characterize the cellular localization of TSPO expression. Results Compared with HCs, patients with presymptomatic MS had 32% larger CPs (beta = 0.38, p = 0.001), which were not dissimilar to MS CPs (p = 0.69). Moreover, in the baseline scan of the presymptomatic case who later on developed MS, TSPO PET showed 33% greater CP inflammation vs HCs (p = 0.04), although no differences in F-18-DPA-714 uptake were found in parenchymal regions vs controls. CP postmortem analysis identified a population of CD163(+) mononuclear phagocytes expressing TSPO in MS, possibly contributing to the increased F-18-DPA-714 uptake. Discussion We identified an imaging signature in CPs at the presymptomatic MS stage using MRI; in addition, we found an increased CP inflammation with PET in a single presymptomatic patient. These findings suggest a role of CP imaging as an early biomarker and argue for the involvement of the blood-CSF barrier dysfunction in disease development

GWAS-associated Variants, Non-genetic Factors, and Transient Transcriptome in Multiple Sclerosis Etiopathogenesis: a Colocalization Analysis [preprint]

A clinically actionable understanding of multiple sclerosis (MS) etiology goes through GWAS interpretation, prompting research on new gene regulatory models. Our previous works on these topics suggested a stochastic etiologic model where small-scale random perturbations could eventually reach a threshold for MS onset and progression. A new sequencing technology has mapped the transient transcriptome (TT), including intergenic RNAs, and antisense intronic RNAs. Through a rigorous colocalization analysis, here we show that genomic regions coding for the TT were significantly enriched for both MS-associated GWAS variants, and DNA binding sites for molecular transducers mediating putative, non-genetic, etiopathogenetic factors for MS (e.g., vitamin D deficiency, Epstein Barr virus latent infection, B cell dysfunction). These results suggest a model whereby TT-coding regions are hotspots of convergence between genetic ad non-genetic factors of risk/protection for MS (and plausibly for other complex disorders). Our colocalization analysis also provides a freely available data resource at www.mscoloc.com for future research on transcriptional regulation in MS

Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine

Addition of reversine to dividing cells ejects Mad1 and the RZZ complex from unattached kinetochores and prevents resolution of incorrect chromosome–microtubule attachments (see also related papers by Hewitt et al. and Maciejowski et al. in this issue)

Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes

Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity. DOI: http://dx.doi.org/10.7554/eLife.12116.00

Poetiche e mappe della prosa. Le idee letterarie degli anni Zero

Il saggio, interrogandosi sulla persistenza della nozione di "poetica" nell'ipermodernit\ue0, cerca di dar conto delle idee sulla letteratura presenti fra i i prosatori contemporanei, giungendo ad alcune conclusioni provvisorie. Le poetiche costituiscono ancora un campo di forze che, facendo riferimento alla sociologia dei processi culturali di Bourdieu, si potrebbe definire come \u201ccapitale simbolico\u201d. Le convergenze e i posizionamenti dei prosatori contemporanei possono essere schematizzati in tre \u201ccampi\u201d principali: 1) Le opposizioni fra finzione e non finzione. L'indagine sulla "estremo contemporaneo" mostra come i romanzi d\u2019invenzione e l\u2019identificazione romanzesca mediata dai personaggi siano fatti assai meno periferici di quanto esiga la vulgata corrente. 2) Il rapporto con i modelli e con la tradizione. Sembra tornata l\u2019abitudine degli autori a scegliere con consapevolezza dei modelli e a selezionare il proprio canone: in particolare, un nuovo rapporto con il modernismo, da Faulkner a Kafka, circola fra gli scrittori italiani pi\uf9 recenti, congiuntamente a un oscillante canone della contemporaneit\ue0 (da DeLillo a Houellebecq, da Easton Ellis a Capote, da Sebald a Munro), attraversato da riferimenti visivi, filmici e mediatici. 3) La riflessione diretta o indiretta sullo spazio, presente in molti autori, rinvia al pi\uf9 generale problema della rappresentazione della realt\ue0. La ricerca intorno agli \u201ceffetti di spazialit\ue0\u201d messa in atto dai prosatori contemporanei pu\uf2 essere considerata il banco di prova privilegiato per la questione del cosiddetto "ritorno alla realt\ue0". Gli scrittori contemporanei si sono rivolti infatti in gran numero alla rappresentazione dei nonluoghi italiani, utilizzando sia i fortunati generi nonfinzionali sia il romanzo d\u2019invenzione e consentendo una \u201cdicibilit\ue0\u201d di fenomeni urbani e antropologici altrimenti sempre pi\uf9 sfuggenti all\u2019analisi delle stesse discipline predisposte a studiarli

A study of the early life of Gasoline Particulate Filters: reactive and dissipative acoustic effects

[EN] The presence of after-treatment systems (ATS) has some side effects as they modify the wave dynamics, back-pressure and acoustic behavior of the exhaust system, that define the boundary conditions for the main silencing device. Gasoline particulate filters (GPF) have a considerable influence on these traits as their working principle depends on wall-flow monoliths; additionally, particulate filters have an inherent transient behavior due to the loading-regeneration cycles during their operation. In this paper, the steady and unsteady behavior of a typical device containing a three-way catalyst (TWC) and a GPF has been characterized in "new" (prior to any use) and "used" (after regeneration) conditions, with special focus on the role of dissipation. Pressure drop measurements were used in steady flow, whereas an acoustic energy balance was performed in the unsteady case that allows for the identification of the reactive and dissipative contributions. The results obtained for the GPF suggest that after it has been used for a relatively short time it oscillates between a maximum and a minimum loading over load¿regeneration cycles burning the soot, never reaching back brand¿new cleanness due to accumulation into the substrate pores and only suffering from ash accumulation over very long times. The results were then used to analyze the ability of a standard gas-dynamic code to reproduce the influence of the loading on the reactive and dissipative effects observed, with the main conclusion that by properly tuning the model parameters it is possible to reproduce, at least qualitatively, the trends observed in the experiments. The model can thus be used to provide adequate inlet conditions for the design of the exhaust line.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: A lvaro Redondo is supported by Universitat Politecnica de Valencia through the Programa de Ayudas de Investigacion y Desarrollo [PAID-01-19] which grants his predoctoral contract.Torregrosa, AJ.; De La Morena, J.; Sanchis Pacheco, EJ.; Redondo-Navarro, ÁR.; Servetto, E. (2022). A study of the early life of Gasoline Particulate Filters: reactive and dissipative acoustic effects. Proceedings of the Institution of Mechanical Engineers Part D Journal of Automobile Engineering. 1-11. https://doi.org/10.1177/0954407022112733011