Single-cell sequencing of iPSC-Dopamine neurons reconstructs disease progression and identifies HDAC4 as a regulator of Parkinson cell phenotypes

Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson’s disease (PD), but neuronal cultures are confounded by asynchronous and heterogeneous appearance of disease phenotypes in vitro. Using high-resolution, single-cell transcriptomic analyses of iPSC-derived dopamine neurons carrying the GBA-N370S PD risk variant, we identified a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Pseudotime analysis of genes differentially expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with HDAC4-modulating compounds upregulated genes early in the DE axis and corrected PD-related cellular phenotypes. Our study demonstrates how single-cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets

Embracing monogenic Parkinson's disease: the MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Michael J. Fox Foundation for Parkinson's Research. Grant Number: ID 15015.02. NIHR Cambridge Biomedical Research Centre. Grant Number: BRC-1215-20014info:eu-repo/semantics/publishedVersio

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.[Background] As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited.[Objective] The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.[Methods] We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed.[Results] We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.[Conclusions] Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.This project was funded by The Michael J. Fox Foundation (ID 15015.02)Peer reviewe

Gender-specific Grading? The Influence of Behavioral Features as Evaluated by Teachers on Grading

Han M, Elsaesser S, Lang V, Ditton H. Geschlechtsspezifische Benotung? Der Einfluss der von Lehrkräften eingeschätzten Verhaltensmerkmale auf die Notengebung. Zeitschrift für Soziologie der Erziehung und Sozialisation. 2017;37(2):174-194.This paper investigates the role of teacher-rated work habits and social behavior on school grades during primary schooling. Based on the German school law it is shown that teachers' scope of discretion might be an indication for gender differences in grading. We use longitudinal data from the study "Competence development and educational trajectories within the school system" (KOALA-S). Our results show that in contrast to social behavior, work habits have a substantial positive effect on grades in both major subjects, German and mathematics. While gender differences for grades in German are completely mediated by work habits, there remains a gender gap to the disadvantage of girls for grades in mathematics. We discuss our results with regard to possible processes of gender-stereotyping in grading and related consequences for the subject-specific self-perception of girls

Effect of heat treatment on microstructures and mechanical properties in a full lamellar PM TiAl alloy

The effect of heat treatment on the microstructures and tensile properties of a powder metallurgical (PM) TiAl based alloy has been investigated in this paper. The near gamma (NG) microstructure is transformed to a full lamellar (FL) microstructure with an average grain size of 100 μm by heat treatments. The lamellar spacing of FL structure decreases with the increase of cooling rate. For cooling rates of 5, 10 and 50 °C/min, the lamellar spacing is 1.9, 1.0 and 0.8 μm respectively. The room temperature tensile properties exhibit an increasing trend with decrease of lamellar spacing

Central versus peripheral drug exposure ratio, a key differentiator for siponimod over fingolimod ?

Siponimod, a potent and selective sphingosine-1-phosphate (S1P1,5) agonist, is the only therapeutic agent that has shown efficacy on disability progression, decline in cognitive processing speed, total brain volume loss, gray matter atrophy, and signs of demyelination in patients with secondary progressive multiple sclerosis (SPMS). Although the pathophysiology of progression in SPMS and primary progressive MS (PPMS) is thought to be similar, fingolimod, the prototype S1P1,3,45 agonist, failed to show efficacy on disability progression in PPMS. Differentiating the mechanisms of siponimod’s effects on progression from those of fingolimod is believed to be key to better understand the key characteristics that could make siponimod uniquely efficacious in progressive MS (PMS). Here, we compared the dose-dependent central vs peripheral drug exposure of siponimod and fingolimod in healthy mice and mice with experimental autoimmune encephalomyelitis (EAE). Siponimod treatment achieved dose-dependent efficacy and dose-proportional increases in steady state drug blood levels, with a similar central nervous system (CNS)/blood drug-exposure ratio (CNS/BloodDER) in both healthy and EAE mice. In contrast, fingolimod treatment achieved dose-proportional increases in fingolimod/fingolimod-P drug blood levels with a CNS/BloodDER that was markedly increased in EAE vs healthy mice. These results, taken together with recent preclinical observations implying a bell-shaped dose-effect relationship for S1P receptor-dependent central effects, suggest that at human-equivalent therapeutic doses an increase in CNS/BloodDER with loss of central efficacy for fingolimod/fingolimod-P but not for siponimod. Therefore, CNS/bloodDER is a potential new differentiator for siponimod over fingolimod, that warrants further investigation and clinical validation

Complement Activation and Organ Damage After Trauma—Differential Immune Response Based on Surgical Treatment Strategy

Background: The complement system is part of the innate immunity, is activated immediately after trauma and is associated with adult respiratory distress syndrome, acute lung injury, multiple organ failure, and with death of multiply injured patients. The aim of the study was to investigate the complement activation in multiply injured pigs as well as its effects on the heart in vivo and in vitro. Moreover, the impact of reamed vs. non-reamed intramedullary nailing was examined with regard to the complement activation after multiple trauma in pigs. Materials and Methods: Male pigs received multiple trauma, followed by femoral nailing with/without prior conventional reaming. Systemic complement hemolytic activity (CH-50 and AH-50) as well as the local cardiac expression of C3a receptor, C5a receptors1/2, and the deposition of the fragments C3b/iC3b/C3c was determined in vivo after trauma. Human cardiomyocytes were exposed to C3a or C5a and analyzed regarding calcium signaling and mitochondrial respiration. Results: Systemic complement activation increased within 6 h after trauma and was mediated via the classical and the alternative pathway. Furthermore, complement activation correlated with invasiveness of fracture treatment. The expression of receptors for complement activation were altered locally in vivo in left ventricles. C3a and C5a acted detrimentally on human cardiomyocytes by affecting their functionality and their mitochondrial respiration in vitro. Conclusion: After multiple trauma, an early activation of the complement system is triggered, affecting the heart in vivo as well as in vitro, leading to complement-induced cardiac dysfunction. The intensity of complement activation after multiple trauma might correlate with the invasiveness of fracture treatment. Reaming of the femoral canal might contribute to an enhanced “second hit” response after trauma. Consequently, the choice of fracture treatment might imply the clinical outcome of the critically injured patients and might be therefore crucial for their survival

Canakinumab Lacks Efficacy in Treating Adult Patients with Moderate to Severe Chronic Spontaneous Urticaria in a Phase II Randomized Double-Blind Placebo-Controlled Single-Center Study

Chronic idiopathic/spontaneous urticaria (CSU) is a common disease with a significant proportion of patients who do not respond to standard therapy with antihistamines and optionally corticosteroids/immunosuppressants.; The IL-1β antagonist canakinumab is effective in cryopyrin-associated periodic syndromes associated with urticarial symptoms and urticarial vasculitis, and so it was suspected that it could also be effective in patients with CSU.; The effect of canakinumab was investigated in 20 patients with moderate to severe CSU in a 1:1 randomization to either canakinumab or placebo in a double-blind single-dose crossover design. The verum group received 150 mg canakinumab subcutaneously once at baseline. Patients who had received placebo were able to switch to canakinumab at week 4 if they did not improve. The primary end point was clinical improvement at week 4 compared with baseline in sum of urticaria activity scores over 7 consecutive days. Secondary end points were the clinical improvement at week 8 compared with baseline in sum of urticaria activity scores over 7 consecutive days and the clinical improvement measured by the Physician Score and Dermatology Life Quality Index at week 1, 2, 4, and 8.; At week 4, 2 patients with canakinumab and 3 with placebo met the primary end point, and so canakinumab failed the significant superiority to the placebo (P = 1.0). An inclusion of the patients who switched to canakinumab after 4 weeks did not alter the result. There was also no significant difference between the verum and placebo groups for all secondary end points. The therapy was well tolerated, and mild adverse events were equally distributed between verum and placebo groups.; Because of this clinical trial with 20 patients, it must be assumed that canakinumab has no effect on lesions of CSU. This suggests that IL-1β may not play a crucial role in pathology of patients with CSU, unlike, for example, in hereditary fevers or urticarial vasculitis, where targeting IL-1 is a main treatment option. However, the good tolerability of canakinumab could be confirmed