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Mashup Score: 0The invasion phenotypes of glioblastoma depend on plastic and reprogrammable cell states - 8 hour(s) ago
Glioblastoma (GBM), the most common brain cancer in adults, is characterized by rapid local invasion, along diverse routes such as infiltration of white matter tracts and penetration of perivascular spaces. We investigate the hypothesis that GBM invasion routes correlate with the transcriptional states of individual cells and identify route-specific master regulator genes. Utilizing patient-derived GBM xenograft models, we integrate single-cell transcriptomics and spatial proteomics, revealing that mesenchymal and oligodendrocyte progenitor-like GBM cells migrate perivascularly, while neural progenitor and astrocyte-like GBM cells invade diffusively. Computational reconstruction identifies ANXA1 as a perivascular invasion driver and lineage-restricted transcription factors RFX4 and HOPX as drivers of diffuse invasion, predictive of patient survival. Genetic ablation of these genes alters invasion phenotypes and extends survival in xenografted mice, clarifying the role of cell states in
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Mashup Score: 0Peristromal niches protect lung cancers from targeted therapies through a combined effect of multiple molecular mediators - 8 hour(s) ago
Targeted therapies directed against oncogenic signaling addictions, such as inhibitors of ALK in ALK+ NSCLC often induce strong and durable clinical responses. However, they are not curative in metastatic cancers, as some tumor cells persist through therapy, eventually developing resistance. Therapy sensitivity can reflect not only cell-intrinsic mechanisms but also inputs from stromal microenvironment. Yet, the contribution of tumor stroma to therapeutic responses in vivo remains poorly defined. To address this gap of knowledge, we assessed the contribution of stroma-mediated resistance to therapeutic responses to the frontline ALK inhibitor alectinib in xenograft models of ALK+ NSCLC. We found that stroma-proximal tumor cells are partially protected against cytostatic effects of alectinib. This effect is observed not only in remission, but also during relapse, indicating the strong contribution of stroma-mediated resistance to both persistence and resistance. This therapy-protective
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Mashup Score: 3Inferring gene regulatory networks using DNA methylation data - 9 hour(s) ago
We show much-improved accuracy of inference of GRN (gene regulatory network) structure resulting from the use of an epigenomic prior network. We also find that DNAme data are very effective for inferring the epigenomic prior network, recapitulating known epigenomic network structure found previously from chromatin accessibility data, and in some cases providing potential TF cis-regulations for eight times as many genes compared to chromatin accessibility data. When our proposed methodology is applied to real datasets from human embryonic development and from women at risk of breast cancer, we find patterns of differential cis-regulation that are in line with expectations under appropriate biological models. ### Competing Interest Statement The authors have declared no competing interest.
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Mashup Score: 0Models optimized for real-world tasks reveal the necessity of precise temporal coding in hearing - 9 hour(s) ago
Neurons encode information in the timing of their spikes in addition to their firing rates. Spike timing is particularly precise in the auditory nerve, where action potentials phase lock to sound with sub- millisecond precision, but its behavioral relevance is uncertain. To investigate the role of this temporal coding, we optimized machine learning models to perform real-world hearing tasks with simulated cochlear input. We asked how precise auditory nerve spike timing needed to be to reproduce human behavior. Models with high-fidelity phase locking exhibited more human-like sound localization and speech perception than models without, consistent with an essential role in human hearing. Degrading phase locking produced task-dependent effects, revealing how the use of fine-grained temporal information reflects both ecological task demands and neural implementation constraints. The results link neural coding to perception and clarify conditions in which prostheses that fail to restore hi
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Mashup Score: 0
Plasticity in the subcortical motor basal ganglia-thalamo-cerebellar network plays a key role in the acquisition and control of long-term memory for new procedural skills, from the formation of population trajectories controlling trained motor skills in the striatum to the adaptation of sensorimotor maps in the cerebellum. However, recent findings demonstrate the involvement of a wider cortical and subcortical brain network in the consolidation and control of well-trained actions, including an area traditionally associated with declarative memory – the hippocampus. Here, we probe which role these subcortical areas play in skilled motor sequence control, from sequence feature selection during planning to their integration during sequence execution. An fMRI dataset collected after participants learnt to produce four finger sequences entirely from memory with high accuracy over several days was examined for both changes in BOLD activity and their informational content in subcortical regio
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Mashup Score: 0Hierarchical cortical entrainment orchestrates the multisensory processing of biological motion - 9 hour(s) ago
When observing others’ behaviors, we continuously integrate their movements with the corresponding sounds to achieve efficient perception and develop adaptive responses. However, how human brains integrate these complex audiovisual cues based on their natural temporal correspondence remains unknown. Using electroencephalogram, we demonstrated that cortical oscillations entrained to hierarchical rhythmic structures in audiovisually congruent human walking movements and footstep sounds. Remarkably, the entrainment effects at different time scales exhibit distinct modes of multisensory integration, i.e., an additive integration effect at a basic-level integration window (step-cycle) and a super-additive multisensory enhancement at a higher-order temporal integration window (gait-cycle). Moreover, only the cortical tracking of higher-order rhythmic structures is specialized for the multisensory integration of human motion signals and correlates with individuals’ autistic traits, suggesting
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Mashup Score: 0
The neocortex constructs an internal representation of the world, but the underlying circuitry and computational principles remain unclear. Inspired by self-supervised learning algorithms, we introduce a computational model wherein layer 2/3 (L2/3) learns to predict incoming sensory stimuli by comparing previous sensory inputs, relayed via layer 4, with current thalamic inputs arriving at layer 5 (L5). We demonstrate that our model accurately predicts sensory information in a contextual temporal task, and that its predictions are robust to noisy or partial sensory input. Additionally, our model generates layer-specific sparsity and latent representations, consistent with experimental observations. Next, using a sensorimotor task, we show that the model’s L2/3 and L5 prediction errors mirror mismatch responses observed in awake, behaving mice. Finally, through manipulations, we offer testable predictions to unveil the computational roles of various cortical features. In summary, our fin
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Mashup Score: 1A look beyond the QR code of SNARE proteins - 15 hour(s) ago
Soluble N-ethylmaleimide-sensitive factor Attachment protein REceptor (SNARE) proteins catalyze the fusion process of vesicles with target membranes in eukaryotic cells. To do this, they assemble in a zipper-like fashion into stable complexes between the membranes. Structural studies have shown that the complexes consist of four different helices, which we subdivide into Qa-, Qb-, Qc-, and R-helix on the basis of their sequence signatures. Using a combination of biochemistry, modeling and molecular dynamics, we investigated how the four different types are arranged in a complex. We found that there is a matching pattern in the core of the complex that dictates the position of the four fundamental SNARE types in the bundle, resulting in a QabcR complex. In the cell, several different cognate QabcR-SNARE complexes catalyze the different transport steps between the compartments of the endomembrane system. Each of these cognate QabcR complexes is compiled from a repertoire of about 20 SNAR
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Mashup Score: 0Biochemical and structural insights into a 5' to 3' RNA ligase reveal a potential role in tRNA ligation - 15 hour(s) ago
ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here we identify C12orf29 as an atypical ATP-grasp enzyme that ligates RNA. Human C12orf29 and its homologs auto-adenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5′-phosphate and a 3′-hydroxyl. C12orf29 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro. Genetic depletion of c12orf29 in female mice alters global tRNA levels in brain. Furthermore, crystal structures of a C12orf29 homolog from Yasminevirus bound to nucleotides reveal a minimal and atypical RNA ligase fold with a unique active site architecture that participates in catalysis. Collectively, our results identify C12orf29 as an RNA ligase and sugg
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Mashup Score: 1Enigmatic missense mutations can cause disease via creation of de novo nuclear export signals - 15 hour(s) ago
Disease-causing missense mutations that occur within structurally and functionally unannotated protein regions can guide researchers to new mechanisms of protein regulation and dysfunction. Here, we report that the thrombocytopenia-, myelodysplastic syndromes-, and leukemia-associated P214L mutation in the transcriptional regulator ETV6 creates an XPO1-dependent nuclear export signal to cause protein mislocalization. Strategies to disrupt XPO1 activity fully restore ETV6 P214L protein nuclear localization and transcription regulation activity. Mechanistic insight inspired the design of humanized ETV6 mice, which we employ to demonstrate that the germline P214L mutation is sufficient to elicit severe defects in thrombopoiesis and hematopoietic stem cell maintenance. Beyond ETV6, we employed computational methods to uncover rare disease-associated missense mutations in unrelated proteins that create a nuclear export signal to disrupt protein function. Thus, missense mutations that operat
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The invasion phenotypes of glioblastoma depend on plastic and reprogrammable cell states https://t.co/AGucTjTk4K #bioRxiv