Ten months after her diagnosis and following five surgical excisions, the patient was diagnosed with metastatic melanoma to the brain and succumbed to intracranial hemorrhage. We present a case in which paracicatricial melanoma may simulate benign paracicatricial melanocytic hyperplasia. These findings have significant therapeutic and prognostic implications for the practicing dermatologist and dermatopathologist.Gene expression is controlled and regulated by interactions between cis-regulatory DNA elements (CREs) and regulatory proteins. Enhancers are one of the most important classes of CREs in eukaryotes. Eukaryotic genes, especially those related to development or responses to environmental cues, are often regulated by multiple enhancers in different tissues and/or at different developmental stages. Remarkably, little is known about the molecular mechanisms by which enhancers regulate gene expression in plants. We identified a distal enhancer, CREβ, which regulates the expression of AtDGK7, which encodes a diacylglycerol kinase in Arabidopsis. We developed a transgenic line containing the luciferase reporter gene (LUC) driven by CREβ fused with a minimal cauliflower mosaic virus (CaMV) 35S promoter. The CREβ enhancer was shown to play a role in the response to osmotic pressure of the LUC reporter gene. A forward genetic screen pipeline based on the transgenic line was established to generate mutations associated with altered expression of the LUC reporter gene. We identified a suite of mutants with variable LUC expression levels as well as different segregation patterns of the mutations in populations. We demonstrate that this pipeline will allow us to identify trans-regulatory factors associated with CREβ function as well as those acting in the regulation of the endogenous AtDGK7 gene. With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PD ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement. To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI). We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PD patients compared to PD patients. Cross-sectionally in both cohorts and longitudinally in PPMI (1) glucocerebrosidase activity was significantly lower in PD compared to PD . (2) CSF levels of upstream substrates (glucosylceramides species) were hdging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PDGBA with severe variants. © 2021 International Parkinson and Movement Disorder Society.Intracellular protein trafficking via the endosomes plays a key role in the maintenance of normal neuronal function. Although many diseases of the central nervous system exhibit specific pathological hallmarks, abnormalities of the endosome system are common traits for several of them, including Alzheimer disease (AD). Three main routes originate from the endosomes the recycling, degradation, and retrograde pathways. Studies have shown that the majority of Down syndrome subjects develop AD pathology and manifest altered morphology and number of endosomes, and abnormalities in lysosome acidification and exosome secretion, suggesting that dysfunction of one of these pathways could play a functional role in the AD-like phenotype of the syndrome. Two of the major endosomal routes are mediated by the retromer complex, a multimeric system responsible for transport of cargo from the endosome to the trans-Golgi network or to the cell membrane. Recently, a new endosome system structurally related to the retromer, called "retriever," has been reported. ER stress inhibitor Whereas we know a great deal about the neuropathophysiology of the retromer complex, no precise pathogenic role for the retriever has yet been identified. Here, we will review the neurobiology of the endosome system and its role as key player in the development of AD-like pathology in Down syndrome. Additionally, we will discuss current knowledge on these two main endosome systems, retromer and retriever, and their potential as novel therapeutic targets. ANN NEUROL 2021.Polyploidization is a well-known speciation and adaptation mechanism. Traces of former polyploidization events were discovered within many genomes, and especially in plants. Allopolyploidization by interspecific hybridization between two species is common. Among hybrid plants, many are domesticated species of agricultural interest and many of their genomes and of their presumptive parents have been sequenced. Hybrid genomes remain challenging to analyse because of the presence of multiple subgenomes. The genomes of hybrids often undergo rearrangement and degradation over time. Based on 10 hybrid plant genomes from six different genera, with hybridization dating from 10,000 to 5 million years ago, we assessed subgenome degradation, subgenomic intermixing and biased subgenome fractionation. The restructuring of hybrid genomes does not proceed proportionally with the age of the hybrid. The oldest hybrids in our data set display completely different fates whereas the subgenomes of the tobacco plant Nicotiana benthamiana are in an advanced stage of degradation, the subgenomes of quinoa (Chenopodium quinoa) are exceptionally well conserved by structure and sequence. We observed statistically significant biased subgenome fractionation in seven out of 10 hybrids, which had different ages and subgenomic intermixing levels. Hence, we conclude that no correlation exists between biased fractionation and subgenome intermixing. Lastly, domestication may encourage or hinder subgenome intermixing, depending on the evolutionary context. In summary, comparative analysis of hybrid genomes and their presumptive parents allowed us to determine commonalities and differences between their evolutionary fates. In order to facilitate the future analysis of further hybrid genomes, we automated the analysis steps within manticore, which is publicly available at https//github.com/MatteoSchiavinato/manticore.git.