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SummaryHuntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. Here we report correction of HD human induced pluripotent stem cells (hiPSCs) using a CRISPR-Cas9 and piggyBac transposon-based approach. We show that both HD and corrected isogenic hiPSCs can be differentiated into excitable, synaptically active forebrain neurons. We further demonstrate that phenotypic abnormalities in HD hiPSC-derived neural cells, including impaired neural rosette formation, increased susceptibility to growth factor withdrawal, and deficits in mitochondrial respiration, are rescued in isogenic controls. Importantly, using genome-wide expression analysis, we show that a number of apparent gene expression differences detected between HD and non-related healthy control lines are absent between HD and corrected lines, suggesting that these differences are likely related to genetic background rather than HD-specific effects. Our study demonstrates correction of HD hiPSCs and associated phenotypic abnormalities, and the importance of isogenic controls for disease modeling using hiPSCs.

Coronavirus, uses the Angiotensin Converting Enzyme-2 Receptor to enter airway cells. Viral endocytosis is mediated by several factors, including clathrin, the adaptor protein-2 complex (AP2) and the adaptor-associated kinase-1 (AAK1). 2 According to a recent report, 3 COVID-19, the disease caused by SARS-CoV-2, is characterized by three clinical patterns: no symptoms, mild to moderate disease, severe pneumonia requiring admission to Intensive Care Unit (ICU) in up to 31% of the patients. 3 Thus far, there is no specific therapy for COVID-19 infection. No benefit of lopinavir-ritonavir treatment resulted in a recent trial. 4 Hydroxychloroquine, currently used in view of its "in vitro" observed effect of reduction of viral replication, seems unsatisfactory. 5 Elevated proinflammatory cytokine/chemokine responses seem associated with respiratory failure. 3 Recently, tocilizumab, an interleukin-6 inhibitor, was reported as effective in patients with severe COVID-19 pneumonia. 6 Baricitinib, another inhibitor of cytokine-release, seems an interesting anti-inflammatory drug. It is a Janus kinase inhibitor (anti-JAK) licensed for the treatment of rheumatoid arthritis (RA) with good efficacy and safety records. 7 Moreover it seems to have anti-viral effects by its affinity for AP2-associated protein AAK1, reducing SARS-CoV-2 endocytosis. 8 On this basis, we assessed the safety of baricitinib therapy combined with lopinavir-ritonavir in moderate COVID-19 pneumonia patients and we evaluated its clinical impact.All consecutive hospitalized patients (March 16th −30th) with moderate COVID-19 pneumonia, older than 18 years, were treated for 2 weeks with baricitinib tablets 4 mg/day added to ritonavir-lopinavir therapy. The last consecutive patients with moderate COVID-19 pneumonia receiving standard of care therapy (lopinavir/ritonavir tablets 250 mg/bid and hydroxychloroquine 400 mg/day/orally for 2 weeks) admitted before the date of the first baricitinib-treated patient served as controls. Antibiotics were scheduled only in the case of suspected bacterial infection.Inclusion criteria were: a. SARS-Co-V2 positivity in the nasal/oral swabs; b. presence of at least 3 of the following symptoms: fever, cough, myalgia, fatigue; c. evidence of radiological pneumonia . After discharge, patients treated with baricitinib were planned to be followed for additional 6 weeks. Exclusion criteria: history of thrombophlebitis (TP), latent tuberculosis infection (QuantiFERON Plus-test positivity, Qiagen, Germany 9 ), pregnancy and lactation.Mild to moderate COVID-19 disease definition: presence of bilateral pneumonia with or without ground glass opacity and in absence of consolidation, not requiring intubation at enrollment; arterial oxygen saturation (SpO2) > 92% at room-air, and ratio arterial oxygen partial pressure/fractional inspired oxygen (PaO2/FiO2) 10 0-30 0 mmHg. Parameters daily accessed were: fever, pulmonary function, Modified Early Warning Score (MEWS), 10 pulse rate, blood pressure. After the initial execution, r...

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HIGHLIGHTS d Generation of isogenic HD (IsoHD) hESCs to enable the study of CAG length effects d IsoHD hESCs and neural cells exhibit CAG-dependent phenotypic abnormalities d CNS and peripheral cell types of interest can be differentiated from IsoHD hESCs d Large-scale, unbiased-omics analyses reveal cell-typespecific, CAG-dependent effects

White matter (WM) atrophy is a significant feature of Huntington disease (HD), although its aetiology and early pathological manifestations remain poorly defined. In this study, we aimed to characterize WM-related features in the transgenic YAC128 and BACHD models of HD. Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural WM abnormalities occur from an early age in YAC128 mice. Similarly, electron microscopy analysis of myelinated fibres of the corpus callosum indicated that myelin sheaths are thinner in YAC128 mice as early as 1.5 months of age, well before any neuronal loss can be detected. Transcript levels of myelin-related genes in striatal and cortical tissues were significantly lower in YAC128 mice from 2 weeks of age, and these findings were replicated in differentiated primary oligodendrocytes from YAC128 mice, suggesting a possible mechanistic explanation for the observed structural deficits. Concordant with these observations, we demonstrate reduced expression of myelin-related genes at 3 months of age and WM microstructural abnormalities using DT-MRI at 12 months of age in the BACHD rats. These findings indicate that WM deficits in HD are an early phenotype associated with cell-intrinsic effects of mutant huntingtin on myelin-related transcripts in oligodendrocytes, and raise the possibility that WM abnormalities may be an early contributing factor to the pathogenesis of HD.

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Optimized method for synthesis of CsPbI3 NCs using dodecyldimethylammonium bromide as capping molecules can achieve enhanced stability.