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Chemoarchitecture, the heterogeneous distribution of neurotransmitter transporter and receptor molecules, is a relevant component of structure-function relationships in the human brain. Here, we studied the organization of the receptome, a measure of interareal chemoarchitectural similarity, derived from positron-emission tomography imaging studies of 19 different neurotransmitter transporters and receptors. Nonlinear dimensionality reduction revealed three main spatial gradients of cortical chemoarchitectural similarity - a centro-temporal gradient, an occipito-frontal gradient, and a temporo-occipital gradient. In subcortical nuclei, chemoarchitectural similarity distinguished functional communities and delineated a striato-thalamic axis. Overall, the cortical receptome shared key organizational traits with functional and structural brain anatomy, with node-level correspondence to functional, microstructural, and diffusion MRI-based measures decreasing along a primary-to-transmodal axis. Relative to primary and paralimbic regions, unimodal and heteromodal regions showed higher receptomic diversification, possibly supporting functional flexibility., Competing Interests: BH, JH, BB, SE, JD, BM, SV No competing interests declared, (© 2023, Hänisch et al.)

Variant surface glycoprotein (VSG) coats bloodstream form Trypanosoma brucei parasites, and monoallelic VSG expression underpins the antigenic variation necessary for pathogenicity. One of thousands of VSG genes is transcribed by RNA polymerase I in a singular nuclear structure called the expression site body (ESB), but how monoallelic VSG transcription is achieved remains unclear. Using a localization screen of 153 proteins we found one, ESB-specific protein 1 (ESB1), that localized only to the ESB and is expressed only in VSG-expressing life cycle stages. ESB1 associates with DNA near the active VSG promoter and is necessary for VSG expression, with overexpression activating inactive VSG promoters. Mechanistically, ESB1 is necessary for recruitment of a subset of ESB components, including RNA polymerase I, revealing that the ESB has separately assembled subdomains. Because many trypanosomatid parasites have divergent ESB1 orthologues yet do not undergo antigenic variation, ESB1 probably represents an important class of transcription regulators., (© 2022. The Author(s).)

Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A' (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of PLEC alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

When Alzheimer's disease (AD) disease-modifying therapies will be available, global healthcare systems will be challenged by a large-scale demand for clinical and biological screening. Validation and qualification of globally accessible, minimally-invasive, and time-, cost-saving blood-based biomarkers need to be advanced. Novel pathophysiological mechanisms (and related candidate biomarkers) - including neuroinflammation pathways (TREM2 and YKL-40), axonal degeneration (neurofilament light chain protein), synaptic dysfunction (neurogranin, synaptotagmin, α-synuclein, and SNAP-25) - may be integrated into an expanding pathophysiological and biomarker matrix and, ultimately, integrated into a comprehensive blood-based liquid biopsy, aligned with the evolving ATN + classification system and the precision medicine paradigm. Liquid biopsy-based diagnostic and therapeutic algorithms are increasingly employed in Oncology disease-modifying therapies and medical practice, showing an enormous potential for AD and other brain diseases as well. For AD and other neurodegenerative diseases, newly identified aberrant molecular pathways have been identified as suitable therapeutic targets and are currently investigated by academia/industry-led R&D programs, including the nerve-growth factor pathway in basal forebrain cholinergic neurons, the sigma1 receptor, and the GTPases of the Rho family. Evidence for a clinical long-term effect on cognitive function and brain health span of cholinergic compounds, drug candidates for repositioning programs, and non-pharmacological multidomain interventions (nutrition, cognitive training, and physical activity) is developing as well. Ultimately, novel pharmacological paradigms, such as quantitative systems pharmacology-based integrative/explorative approaches, are gaining momentum to optimize drug discovery and accomplish effective pathway-based strategies for precision medicine. This article is part of the special issue on 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Identifying master regulators that drive pathologic gene expression is a key challenge in precision oncology. Here, we have developed an analytic framework, named PRADA, that identifies oncogenic RNA-binding proteins through the systematic detection of coordinated changes in their target regulons. Application of this approach to data collected from clinical samples, patient-derived xenografts, and cell line models of colon cancer metastasis revealed the RNA-binding protein RBMS1 as a suppressor of colon cancer progression. We observed that silencing RBMS1 results in increased metastatic capacity in xenograft mouse models, and that restoring its expression blunts metastatic liver colonization. We have found that RBMS1 functions as a posttranscriptional regulator of RNA stability by directly binding its target mRNAs. Together, our findings establish a role for RBMS1 as a previously unknown regulator of RNA stability and as a suppressor of colon cancer metastasis with clinical utility for risk stratification of patients. SIGNIFICANCE: By applying a new analytic approach to transcriptomic data from clinical samples and models of colon cancer progression, we have identified RBMS1 as a suppressor of metastasis and as a post-transcriptional regulator of RNA stability. Notably, RBMS1 silencing and downregulation of its targets are negatively associated with patient survival. See related commentary by Carter, p. 1261 . This article is highlighted in the In This Issue feature, p. 1241 ., (©2020 American Association for Cancer Research.)

Background: Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive., Methods: A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder., Results: By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1., Conclusion: We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems., Trial Registration: Not applicable., Funding: Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.