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

KMT2B Is Selectively Required for Neuronal Transdifferentiation, and Its Loss Exposes Dystonia Candidate Genes

Transdifferentiation of fibroblasts into induced neuronal cells (iNs) by the neuron-specific transcription factors Brn2, Myt1l, and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress regarding the transcriptional hierarchy underlying transdifferentiation, the enablers of the concomitant epigenome resetting remain to be elucidated. Here, we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and combined inactivation. We found that Kmt2b, whose human homolog's mutations cause dystonia, is selectively required for iN conversion through suppression of the alternative myocyte program and induction of neuronal maturation genes. The identification of KMT2B-vulnerable targets allowed us, in turn, to expose, in a cohort of 225 patients, 45 unique variants in 39 KMT2B targets, which represent promising candidates to dissect the molecular bases of dystonia. Barbagiovanni et al. demonstrate that KMT2B, in contrast to KMT2A, is fundamental for the epigenetic and transcriptomic resetting underlying transdifferentiation of fibroblasts into induced neuronal cells (iNs), acting both in the suppression of alternative fates and in the promotion of iN maturation. Transdifferentiation-specific KMT2B targets reveal dystonia-causative gene candidates

Specific changes in skeletal muscle myosin heavy chain composition in cardiac failure: differences compared with disuse atrophy as assessed on microbiopsies by high resolution electrophoresis

Heart. 1996 Oct;76(4):337-43. Specific changes in skeletal muscle myosin heavy chain composition in cardiac failure: differences compared with disuse atrophy as assessed on microbiopsies by high resolution electrophoresis. Vescovo G, Serafini F, Facchin L, Tenderini P, Carraro U, Dalla Libera L, Catani C, Ambrosio GB. Source Department of Internal Medicine I, Venice City Hospital, Italy. Abstract OBJECTIVE: In congestive heart failure (CHF) the skeletal muscle of the lower limbs develops a myopathy with atrophy and shift from the slow type to the fast type fibres. The aim was to test the hypothesis that this myopathy is specific and not simply related to detraining, by comparing patients with different degrees of CHF with patients with severe muscle atrophy due to disuse. DESIGN: Case-control study involving 50-150 micrograms needle biopsies of the gastrocnemius muscle. By an electrophoretic micromethod, the three isoforms of myosin heavy chains (MHC) were separated. PATIENTS: Five patients restricted to bed for more than one year because of stroke with disuse atrophy and normal ventricular function, and 19 with CHF were studied. There were seven age matched controls. MAIN OUTCOME MEASURES: The percentage of MHC1 (slow isoform), MHC2a (fast oxidative), and MHC2b (fast glycolytic) was determined by densitometric scan and correlated with indices of severity of cardiac failure. RESULTS: Ejection fraction was 42.5 (SD 15.2)% in CHF, 59.5 (1.0)% in disuse atrophy and 60.3 (1.4)% in controls (P < 0.001 v both). The degree of muscle atrophy as calculated by the body mass index/gastrocnemius cross sectional area, showed a profound degree of atrophy in patients with muscle disuse [0.94 (0.39)]. This was worse than in the controls [4.27 (0.16), P < 0.0005] and the CHF patients [2.60 (1.10), P < 0.005]. Atrophy in CHF patients was also greater than in controls (P < 0.005). MHC1 was lower in CHF than in disuse atrophy [51.83 (15.04) v 84.5 (17.04), P < 0.01] while MHC2b was higher [23.5 (7.4) v 7.25 (7.92), P < 0.001]. There was a similar trend for MHC2a [24.83 (15.01) v 8.25 (9.12), P < 0.05]. Within the CHF group there was a positive correlation between NYHA class and MHC2a (r = 0.47, P < 0.05) and MHC2b (r = 0.55, P < 0.01) and a negative correlation between NYHA class and MHC1 (r = -0.74, P < 0.001). Similarly, significant correlations were found for ejection fraction, diuretic consumption score, exercise test tolerance, and degree of muscle atrophy. CONCLUSIONS: The CHF myopathy appears to be specific and not related to detraining. The magnitude of MCH redistribution correlates with the severity of the disease. The electrophoretic micromethod used is very sensitive and reproducible. Biopsies are so well tolerated that can be repeated frequently, allowing thorough follow up. PMID: 8983681 [PubMed - indexed for MEDLINE

Circulating soluble-CD30 (sCD30) in patients with HCV-related chronic hepatitis and in patients with alcoholic liver diseases

Abstract: Background/Aims: Serum sCD30 (soluble CD30) is a marker of cells producing Th2-type (T-helper-2-type) cytokines. High levels of sCD30 have been found in the active phase of HBV infection. The Th2-type cytokine profile has been documented in alcoholic liver diseases, which have particularly high IgE and IgA serum levels. The aims were: 1) to evaluate sCD30 levels in patients with (a) alcoholic liver diseases and (b) HCV-related chronic hepatitis before and after interferon treatment; 2) to correlate sCD30 concentrations with IgE and IgA serum levels. Methodology: Serum samples from 34 HCV-related chronic hepatitis patients, before and after interferon treatment, and 17 alcoholic liver disease patients were tested for sCD30 using the ELISA method (Dako, CD30-Ki-1 Antigen, Denmark). Results: Significantly higher levels of sCD30 were found in alcoholic liver disease than in HCV-related chronic hepatitis patients (73.3+/-120 vs. 27.5+/-44 U/mL, P<0.05). Alcoholic liver disease patients also exhibited significantly higher levels of IgA. than HCV-related chronic hepatitis patients (P<0.0001). No correlation was found between sCD30 and serum IgA or IgE or response to interferon. Conclusions: Th2 cells are strongly expanded in alcoholic liver diseases, though the particular immunoglobulin profile observed in this condition has yet to be explained. Th2 function also plays a crucial part in chronic HCV infection, but seems unrelated to interferon response

[IgE levels in cord blood in an area of the Veneto region].

BACKGROUND: Cord blood IgE levels have been studied as a possible marker of allergy in infants but few studies are available in our Region. The aim of this paper was to test IgE levels in cord blood of 60 consecutive newborns in a restricted area of Veneto, to correlate cord blood IgE levels with family history of allergy and to verify the risk of contamination from mother's blood. METHODS: Cord blood was obtained from 60 consecutive newborns. Immunoglobulin levels (IgG, IgA, IgM, and IgE) were measured in cord blood of newborns and in serum of all mothers. Family history for allergy was previously investigated from the mothers. RESULTS: IgE were detectable in cord blood of 5 newborns but only 2 of them had positive family history for allergy which was pointed out in 11/60. In one of these cases the contamination of sample from mother's blood was postulated. IgG levels in newborn cord blood were higher than in mothers' blood and it was not related with IgE levels or other investigated factors. CONCLUSIONS: Only 6.6% of newborns in a restricted area of Veneto region have detectable IgE in cord blood whereas 18.3% of them have positive family history for allergy. Measurable levels of IgE in cord blood are not related with positive family history of allergy and are rarely influenced by mothers' blood contamination

Clinico-Genetic Characterization of a Large Italian Cohort with Primary Spastic Paraplegia

M1002. Clinico-Genetic Characterization of a Large Italian Cohort with Primary Spastic Paraplegia Andrea Martinuzzi, Mariateresa Bassi, Grazia D\u2019Angelo, Sara Bonato, Gabriella Paparella, Olimpia Musumeci, Mariagiovanna Rossetto, Marianna Fantin, Francesca Peruch, Alessia Arnoldi, Claudia Crimella, Erika Tenderini, Paolo Bonanni, Vanessa Casanova, Giovanni Meola, Giacomo Comi, Antonio Toscano and Nereo Bresolin; Conegliano, TV, Italy; Bosisio Parini, LC, Italy; Messina, Italy and Milano, Italy Background: Diagnostic definition of hereditary spastic paraplegias (HSPs) is complicated by the wide genetic heterogeneity. Objectives: Establish in a large cohort of Italian HSP patients the relative frequency of the various forms, provid- ing indications for an efficient diagnostic algorhythm. Methods: 478 index cases (72 familial, 98 pure, 380 complicated) HSP were clinically and molecularly assessed. Results: 80 cases were molecularly defined. SPG4 was the most frequent form (55%), followed by SPG11 (16.6%) SPG7 (9%), SPG10 (8,8% ) and 5 (5.1%). SPG3a and SPG31 were rarer (2.5%). No mutations were identified in SPG6, 8, 13, 20, 21, 35, 48. There was wide inter and intrafamilial variation. Neurophysiology showed invariably increased central conduction time at lower limbs. Axonal polyneuropathy was detected in some SPG3a, 5, 10, 11, 17 and SPG4 (15%). MRI showed abnormalities in SPG 5, 10, 11 and 15. Conclusion: Frequency of SPG forms within this cohort of Italian HSPs confirms the prevalence of SPG4, reveals the recurrence of SPG11 and 7 and the low frequency of SPG3a and 31. Once SPG4 and SPG11 are excluded, fam- ily history, neurophysiology and neuroimaging may direct the choice of genetic testing. Study supported by: Italian Ministry of Healt

From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures

Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay. © 2022 American Association for the Advancement of Science. All rights reserved