The 2016 revised fourth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors incorporated molecular features with histologic grading, revolutionizing ...how oncologists conceptualize primary brain and spinal cord tumors as well as providing new insights into their management and prognosis. The 2021 revised fifth edition of the WHO classification further integrates molecular alterations for CNS tumor categorization, updating current understanding of the pathophysiology of many of these disease entities. Here, the authors review changes in the new classification for the most common primary adult tumors—gliomas (including astrocytomas, oligodendrogliomas, and ependymomas) and meningiomas—highlighting the key genomic alterations for each group classification to help clinicians interpret them as they consider therapeutic options—including clinical trials and targeted therapies—and discuss the prognosis of these tumors with their patients. The revised, updated 2021 WHO classification also further integrates molecular alterations in the classification of pediatric CNS tumors, but those are not covered in the current review.
The 2021 World Health Organization classification of tumors of the central nervous system increasingly relies on molecular alterations for central nervous system tumor categorization. The new classification will help improve diagnosis, prognosis, and treatment selection (including enrollment into relevant clinical trials) for patients with brain tumors.
We describe sleuth (http://pachterlab.github.io/sleuth), a method for the differential analysis of gene expression data that utilizes bootstrapping in conjunction with response error linear modeling ...to decouple biological variance from inferential variance. sleuth is implemented in an interactive shiny app that utilizes kallisto quantifications and bootstraps for fast and accurate analysis of data from RNA-seq experiments.
We present kallisto, an RNA-seq quantification program that is two orders of magnitude faster than previous approaches and achieves similar accuracy. Kallisto pseudoaligns reads to a reference, ...producing a list of transcripts that are compatible with each read while avoiding alignment of individual bases. We use kallisto to analyze 30 million unaligned paired-end RNA-seq reads in <10 min on a standard laptop computer. This removes a major computational bottleneck in RNA-seq analysis.
Delirium is a common and costly complication of hospitalization. Although medications are a known cause of delirium, antibiotics are an underrecognized class of medications associated with delirium. ...In this article, we comprehensively review the clinical, radiologic, and electrophysiologic features of antibiotic-associated encephalopathy (AAE). AAE can be divided into 3 unique clinical phenotypesencephalopathy commonly accompanied by seizures or myoclonus arising within days after antibiotic administration (caused by cephalosporins and penicillin); encephalopathy characterized by psychosis arising within days of antibiotic administration (caused by quinolones, macrolides, and procaine penicillin); and encephalopathy accompanied by cerebellar signs and MRI abnormalities emerging weeks after initiation of antibiotics (caused by metronidazole). We correlate these 3 clinical phenotypes with underlying pathophysiologic mechanisms of antibiotic neurotoxicity. Familiarity with these types of antibiotic toxicity can improve timely diagnosis of AAE and prompt antibiotic discontinuation, reducing the time patients spend in the delirious state.
The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect ...glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived oncostatin M (OSM) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.
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•Macrophages induce the MES-like state of glioblastoma cells•Induction is mediated by macrophage-derived OSM interacting with OSMR/LIFR-GP130•Subsets of glioblastoma-associated macrophages express a related MES-like program•The MES-like state in glioblastoma is associated with cytotoxic T cells programs
Hara et al. combine single-cell RNA sequencing and functional experiments to explore the crosstalk between glioblastoma and the microenvironment, revealing that macrophage-derived OSM induces the mesenchymal-like state of glioblastoma, a state associated with upregulation of major histocompatibility complex genes, and with potential implications for immunotherapy.
Technology is widely considered the main source of economic progress, but it has also generated cultural anxiety throughout history. The developed world is now suffering from another bout of such ...angst. Anxieties over technology can take on several forms, and we focus on three of the most prominent concerns. First, there is the concern that technological progress will cause widespread substitution of machines for labor, which in turn could lead to technological unemployment and a further increase in inequality in the short run, even if the long-run effects are beneficial. Second, there has been anxiety over the moral implications of technological process for human welfare, broadly defined. While, during the Industrial Revolution, the worry was about the dehumanizing effects of work, in modern times, perhaps the greater fear is a world where the elimination of work itself is the source of dehumanization. A third concern cuts in the opposite direction, suggesting that the epoch of major technological progress is behind us. Understanding the history of technological anxiety provides perspective on whether this time is truly different. We consider the role of these three anxieties among economists, primarily focusing on the historical period from the late 18th to the early 20th century, and then compare the historical and current manifestations of these three concerns.
Phase-separated states of proteins underlie ribonucleoprotein (RNP) granules and nuclear RNA-binding protein assemblies that may nucleate protein inclusions associated with neurodegenerative ...diseases. We report that the N-terminal low-complexity domain of the RNA-binding protein Fused in Sarcoma (FUS LC) is structurally disordered and forms a liquid-like phase-separated state resembling RNP granules. This state directly binds the C-terminal domain of RNA polymerase II. Phase-separated FUS lacks static structures as probed by fluorescence microscopy, indicating they are distinct from both protein inclusions and hydrogels. We use solution nuclear magnetic resonance spectroscopy to directly probe the dynamic architecture within FUS liquid phase-separated assemblies. Importantly, we find that FUS LC retains disordered secondary structure even in the liquid phase-separated state. Therefore, we propose that disordered protein granules, even those made of aggregation-prone prion-like domains, are dynamic and disordered molecular assemblies with transiently formed protein-protein contacts.
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•N-terminal prion-like low-complexity domain of FUS is disordered in solution•FUS LC phase separates to recruit RNA polymerase II C-terminal domain•Droplet granule models are viscous but dynamic assemblies lacking static structures•Local structure of phase-separated FUS LC remains disordered
The structure of RNA-binding proteins low-complexity domains within eukaryotic RNA processing granule assemblies is not known. Burke et al. show that the low-complexity domain of Fused in Sarcoma phase-separates into liquid droplets and retains disordered structure within these granules.
Liquid-liquid phase separation (LLPS) of proteins and nucleic acids is a phenomenon that underlies membraneless compartmentalization of the cell. The underlying molecular interactions that underpin ...biomolecular LLPS have been of increased interest due to the importance of membraneless organelles in facilitating various biological processes and the disease association of several of the proteins that mediate LLPS. Proteins that are able to undergo LLPS often contain intrinsically disordered regions and remain dynamic in solution. Solution-state NMR spectroscopy has emerged as a leading structural technique to characterize protein LLPS due to the variety and specificity of information that can be obtained about intrinsically disordered sequences. This review discusses practical aspects of studying LLPS by NMR, summarizes recent work on the molecular aspects of LLPS of various protein systems, and discusses future opportunities for characterizing the molecular details of LLPS to modulate phase separation.
The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid-liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that ...stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp
, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.
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