Schwartzvinther5193

Rett syndrome (RTT), a severe postnatal neurodevelopmental disorder, is caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). MeCP2 is a chromatin organizer regulating gene expression. RTT-causing mutations have been shown to affect this function. However, the mechanism by which MeCP2 organizes chromatin is unclear. In this study, we found that MeCP2 can induce compaction and liquid-liquid phase separation of nucleosomal arrays in vitro, and DNA methylation further enhances formation of chromatin condensates by MeCP2. Interestingly, RTT-causing mutations compromise MeCP2-mediated chromatin phase separation, while benign variants have little effect on this process. Moreover, MeCP2 competes with linker histone H1 to form mutually exclusive chromatin condensates in vitro and distinct heterochromatin foci in vivo. RTT-causing mutations reduce or even abolish the ability of MeCP2 to compete with histone H1 and to form chromatin condensates. this website Together, our results identify a novel mechanism by which phase separation underlies MeCP2-mediated heterochromatin formation and reveal the potential link between this process and the pathology of RTT.Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is associated with a remarkably poor prognosis and with no treatment consensus. The identification of relevant therapeutic targets is challenging. Here, we investigated the immune functions, antileukemia efficacy and safety of CD28/4-1BB CAR T cells targeting CD123 the interleukin (IL)-3 receptor alpha chain which is overexpressed on BPDCN. We demonstrated that both retroviral and lentiviral engineering CD28/4-1BB CD123 CAR T cells exhibit effector functions against BPDCN cells through CD123 antigen recognition and that they efficiently kill BPDCN cell lines and BPDCN-derived PDX cells. In vivo, CD28/4-1BB CD123 CAR T-cell therapy displayed strong efficacy by promoting a decrease of BPDCN blast burden. Furthermore we showed that T cells from BPDCN patient transduced with CD28/4-1BB CD123 CAR successfully eliminate autologous BPDCN blasts in vitro. Finally, we demonstrated in humanized mouse models that these effector CAR T cells exert low or no cytotoxicity against various subsets of normal cells with low CD123 expression, indicating a potentially low on-target/off-tumor toxicity effect. Collectively, our data support the further evaluation for clinical assessment of CD28/4-1BB CD123 CAR T cells in BPDCN neoplasm.Torulaspora microellipsoides is an under-characterized budding yeast of the Saccharomycetaceae family that is primarily associated with viticulture. Here we report for the first time to our knowledge that T. microellipsoides undergoes a low-frequency morphological switch from small budding haploid (white) yeast to larger, higher ploidy (opaque) yeast. Comparison of transcriptomes by mRNA-seq revealed 511 differentially regulated genes, with white cells having greater expression of genes involved in stress resistance and complex carbohydrate utilization, and opaque cells up-regulating genes involved in ribosome biogenesis. Growth assays showed that white cells are physiologically more resistant to stationary-phase conditions and oxidative stress, whereas opaque cells exhibited greater cold tolerance. We propose that phenotypic switching in T. microellipsoides is an ecological adaptation, as has been suggested for similar morphological switching in distantly related species like Candida albicans, and we propose that this switching is a more broadly utilized biological strategy among yeasts than previously thought.Potassium channels form physical complexes with solute transporters in vivo, yet little is known about their range of possible signaling modalities and the underlying mechanisms. The KCNQ2/3 potassium channel, which generates neuronal M-current, is voltage-gated and its activity is also stimulated by binding of various small molecules. KCNQ2/3 forms reciprocally regulating complexes with sodium-coupled myo-inositol transporters (SMITs) in mammalian neurons. Here, we report that the neurotransmitter γ-aminobutyric acid (GABA) and other small molecules directly regulate myo-inositol transport in rat dorsal root ganglia, and by human SMIT1-KCNQ2/3 complexes in vitro, by inducing a distinct KCNQ2/3 pore conformation. Reciprocally, SMIT1 tunes KCNQ2/3 sensing of GABA and related metabolites. Ion permeation and mutagenesis studies suggest that SMIT1 and GABA similarly alter KCNQ2/3 pore conformation but via different KCNQ subunits and molecular mechanisms. KCNQ channels therefore act as chemosensors to enable co-assembled myo-inositol transporters to respond to diverse stimuli including neurotransmitters, metabolites and drugs.We present a cross-modality generation framework that learns to generate translated modalities from given modalities in MR images. Our proposed method performs Image Modality Translation (abbreviated as IMT) by means of a deep learning model that leverages conditional generative adversarial networks (cGANs). Our framework jointly exploits the low-level features (pixel-wise information) and high-level representations (e.g. brain tumors, brain structure like gray matter, etc.) between cross modalities which are important for resolving the challenging complexity in brain structures. Our framework can serve as an auxiliary method in medical use and has great application potential. Based on our proposed framework, we first propose a method for cross-modality registration by fusing the deformation fields to adopt the cross-modality information from translated modalities. Second, we propose an approach for MRI segmentation, translated multichannel segmentation (TMS), where given modalities, along with translated modalities, are segmented by fully convolutional networks (FCN) in a multichannel manner. Both of these two methods successfully adopt the cross-modality information to improve the performance without adding any extra data. Experiments demonstrate that our proposed framework advances the state-of-the-art on five brain MRI datasets. We also observe encouraging results in cross-modality registration and segmentation on some widely adopted brain datasets. Overall, our work can serve as an auxiliary method in medical use and be applied to various tasks in medical fields.Studies on the expression of cellular glycans are limited by a lack of sensitive tools that can discriminate specific structural features. Here we describe the development of a robust platform using immunized lampreys (Petromyzon marinus), which secrete variable lymphocyte receptors called VLRBs as antibodies, for generating libraries of anti-glycan reagents. We identified a wide variety of glycan-specific VLRBs detectable in lamprey plasma after immunization with whole fixed cells, tissue homogenates, and human milk. The cDNAs from lamprey lymphocytes were cloned into yeast surface display (YSD) libraries for enrichment by multiple methods. We generated VLRB-Ig chimeras, termed smart anti-glycan reagents (SAGRs), whose specificities were defined by microarray analysis and immunohistochemistry. 15 VLRB antibodies were discovered that discriminated between linkages, functional groups and unique presentations of the terminal glycan motif. The development of SAGRs will enhance future studies on glycan expression by providing sequenced, defined antibodies for a variety of research applications.Hydrogen has the potential to play an important role in decarbonising our energy systems. Crucial to achieving this is the ability to produce clean sources of hydrogen using renewable energy sources. Currently platinum is commonly used as a hydrogen evolution catalyst, however, the scarcity and expense of platinum is driving the need to develop non-platinum-based catalysts. Here we report a protein-based hydrogen evolution catalyst based on a recombinant silk protein from honeybees and a metal macrocycle, cobalt protoporphyrin (CoPPIX). We enhanced the hydrogen evolution activity three fold compared to the unmodified silk protein by varying the coordinating ligands to the metal centre. Finally, to demonstrate the use of our biological catalyst, we built a proton exchange membrane (PEM) water electrolysis cell using CoPPIX-silk as the hydrogen evolution catalyst that is able to produce hydrogen with a 98% Faradaic efficiency. This represents an exciting advance towards allowing protein-based catalysts to be used in electrolysis cells.The incidence of intervertebral disc (IVD) degeneration disease, caused by changes in the osmotic pressure of nucleus pulposus (NP) cells, increases with age. In general, low back pain is associated with IVD degeneration. However, the mechanism and molecular target of low back pain have not been elucidated, and there are no data suggesting specific biomarkers of low back pain. Therefore, the research aims to identify and verify the significant gene biomarkers of low back pain. The differentially expressed genes (DEGs) were screened in the Gene Expression Omnibus (GEO) database, and the identification and analysis of significant gene biomarkers were also performed with various bioinformatics programs. A total of 120 patients with low back pain were recruited. Before surgery, the degree of pain was measured by the numeric rating scale (NRS), which enables comparison of the pain scores from individuals. After surgery, IVD tissues were obtained, and NP cells were isolated. The NP cells were cultured in two varioussion. The expression of CCL5 and OPRL1 might be correlated with low back pain in patients with IVD degeneration disease caused by changes in the osmotic pressure of NP cells.We suggest that the analytic dialogue develops as a continuous movement that we call "Dissociative Process", and that this process is the continuous oscillation between defensive positions (repression) and creative positions. Dissociation, as a defense, is a Freudian theoretical stance, while Dissociation, as a possibility for new and creative solutions, is a theory emanating from Janet and was adopted, especially, by relational and inter-subjective psychoanalysis. Through a clinical vignette we suggest how the attitude of an analyst, who is attentive to the Dissociative Process, will respect the Defensive Dissociations of the patient. But, at the same time, the analyst will be particularly careful to support potential solutions, never made real before, that emerge as new associative aggregates (Janet's Reaggrégation psychique) deriving from the dissociation of the frustrating or traumatic experience, which we propose calling "Creative Dissociations". The dissociative solutions (defensive and creative) are not sequential but simultaneous.In genome-wide association studies (GWAS), variants showing consistent effect directions across populations are considered as true discoveries. We model this information in an Effect Direction MEta-analysis (EDME) to quantify pleiotropy using GWAS of 34 Cholesky-decorrelated traits in 44,000+ cattle with sequence variants. The effect-direction agreement between independent bull and cow datasets was used to quantify the false discovery rate by effect direction (FDRed) and the number of affected traits for prioritised variants. Variants with multi-trait p  less then  1e-6 affected 1∼22 traits with an average of 10 traits. EDME assigns pleiotropic variants to each trait which informs the biology behind complex traits. New pleiotropic loci are identified, including signals from the cattle FTO locus mirroring its bystander effects on human obesity. When validated in the 1000-Bull Genome database, the prioritized pleiotropic variants consistently predicted expected phenotypic differences between dairy and beef cattle.