Search

Tenosynovial giant cell tumor (TGCT) is a rare type of tumor that originates from the synovium of joints and tendon sheaths. It is characterized by recurring genetic abnormalities, often involving the CSF1 gene. Common symptoms include pain and swelling, which are not specific to TGCT, so MRI and a pathological biopsy are needed for an accurate diagnosis. We report the case of a 45-year-old man who experienced painful swelling in his right hip for six months. Initially, this was diagnosed as Erdheim-Chester disease. However, whole exome sequencing (WES) and RNA-Sequencing revealed a CSF1::GAPDHP64 fusion, leading to a revised diagnosis of TGCT. The patient was treated with pegylated interferon and imatinib, which resulted in stable disease after three months. Single-cell transcriptome analysis identified seven distinct cell clusters, revealing that neoplastic cells expressing CSF1 attract macrophages. Analysis of ligand-receptor interactions showed significant communication between neoplastic cells and macrophages mediated by CSF1 and CSF1R. Our findings emphasize the importance of comprehensive molecular analysis in diagnosing and treating rare malignancies like TGCT. [ABSTRACT FROM AUTHOR]

Background: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co‐occurring movement disorders such as Parkinson's disease (PD). Objectives: To screen >2000 patients with dystonia or PD for rare variants in known dystonia‐causing genes. Methods: We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next‐generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature. Results: We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic. Conclusion: This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT‐KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The present work aimed to study the mainstream feasibility of the deammonifying sludge of side stream of municipal wastewater treatment plant (MWWTP) in Kaster, Germany. For this purpose, the deammonifying sludge available at the side stream was investigated for nitrogen (N) removal with respect to the operational factors temperature (15–30°C), pH value (6.0–8.0) and chemical oxygen demand (COD)/N ratio (≤1.5–6.0). The highest and lowest N‐removal rates of 0.13 and 0.045 kg/(m3 d) are achieved at 30 and 15°C, respectively. Different conditions of pH and COD/N ratios in the SBRs of Partial nitritation/anammox (PN/A) significantly influenced both the metabolic processes and associated N‐removal rates. The scientific insights gained from the current work signifies the possibility of mainstream PN/A at WWTPs. The current study forms a solid basis of operational window for the upcoming semi‐technical trails to be conducted prior to the full‐scale mainstream PN/A at WWTP Kaster and WWTPs globally. [ABSTRACT FROM AUTHOR]

Background: Protein synthesis is a tightly controlled process, involving a host of translation‐initiation factors and microRNA‐associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental‐delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability. Objective: We sought to characterize the role of EIF4A2 variants in dystonic conditions. Methods: We undertook an unbiased search for likely deleterious variants in mutation‐constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient‐derived fibroblasts. Results: We report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence‐ to adulthood‐onset dystonia with tremor. In patient‐derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4‐Not, the complex that interacts with eIF4A2 to mediate microRNA‐dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4‐Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia‐affected pedigrees. Conclusions: Our findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia‐tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later‐onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Air quality monitoring using airborne platforms is rapidly gaining ground as unmanned aerial vehicles (UAVs) are becoming easier, less expensive, and safer to operate on a routine basis. To facilitate measurements of key atmospheric properties, however, efforts are still required in developing/testing miniaturized instruments for use onboard UAVs. Here, we test two commercially available cost-effective/lightweight optical particle counters (OPCs; Alphasense Model N2) capable of measuring the size distributions of airborne particles having diameters from 380 nm to 17 mm. Tests were made against a reference and recently calibrated OPC (Grimm Model 1.109) using monodisperse polystyrene spheres. All instruments were placed in a chamber in which the temperature and pressure varied in the ranges of -5 to 23°C and 0.7 to 1.0 atm, respectively; conditions typically encountered during UAV flights. Agreement in the particle number concentrations measured by the Alphasense and the Grimm OPCs was within 40%, under all experimental conditions used in this work, when particles having sizes >1 μm were employed during the tests. Deviations higher than 50%, however, were observed when the instruments were tested with 1.0- and 0.8-μm polysterene spheres. The particle sizes reported by both Alphasense OPCs were within ± 5% with respect to the nominal polysterene spheres' size under all operating pressures and temperatures down to 5°C. At lower temperatures, the sizing accuracy of one of the two Alphasense OPCs degraded significantly. While our findings support that the Alphasense OPCs can be used at low temperature/pressure conditions, they should be carefully tested prior the measurements to ensure good performance. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (M pro ) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M pro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the M pro -induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19., (© 2021. The Author(s).)