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Molecular model of TFIIH recruitment to the transcription-coupled repair machinery
Abstract Transcription-coupled repair (TCR) is a vital nucleotide excision repair sub-pathway that removes DNA lesions from actively transcribed DNA strands. Binding of CSB to lesion-stalled RNA Polymerase II (Pol II) initiates TCR by triggering the recruitment of downstream repair factors. Yet it remains unknown how transcription factor IIH (TFIIH) is recruited to the intact TCR complex. Combining existing structural data with AlphaFold predictions, we build an integrative model of the initial TFIIH-bound TCR complex. We show how TFIIH can be first recruited in an open repair-inhibited conformation, which requires subsequent CAK module removal and conformational closure to process damaged DNA. In our model, CSB, CSA, UVSSA, elongation factor 1 (ELOF1), and specific Pol II and UVSSA-bound ubiquitin moieties come together to provide interaction interfaces needed for TFIIH recruitment. STK19 acts as a linchpin of the assembly, orienting the incoming TFIIH and bridging Pol II to core TCR factors and DNA. Molecular simulations of the TCR-associated CRL4CSA ubiquitin ligase complex unveil the interplay of segmental DDB1 flexibility, continuous Cullin4A flexibility, and the key role of ELOF1 for Pol II ubiquitination that enables TCR. Collectively, these findings elucidate the coordinated assembly of repair proteins in early TCR.
A dynamic isotope effect in the nucleophilic substitution reaction between F− and CD3I
Longitudinal single cell profiling of epitope specific memory CD4+ T cell responses to recombinant zoster vaccine
GCN5-targeted dual-modal probe across the blood-brain barrier for borders display in invasive glioblastoma
Salmonella exploits LRRK2-dependent plasma membrane dynamics to invade host cells
Cartilage-bioinspired tenacious concrete-like hydrogel verified via in-situ testing
An atlas of RNA-dependent proteins in cell division reveals the riboregulation of mitotic protein-protein interactions
Abstract Ribonucleoprotein complexes are dynamic assemblies of RNA with RNA-binding proteins, which modulate the fate of RNA. Inversely, RNA riboregulates the interactions and functions of the associated proteins. Dysregulation of ribonucleoprotein functions is linked to diseases such as cancer and neurological disorders. In dividing cells, RNA and RNA-binding proteins are present in mitotic structures, but their impact on cell division remains unclear. By applying the proteome-wide R-DeeP strategy to cells synchronized in mitosis versus interphase integrated with the RBP2GO knowledge, we provided an atlas of RNA-dependent proteins in cell division, accessible at R-DeeP3.dkfz.de. We uncovered AURKA, KIFC1 and TPX2 as unconventional RNA-binding proteins. KIFC1 was identified as a new substrate of AURKA, and new TPX2-interacting protein. Their pair-wise interactions were RNA dependent. In addition, RNA stimulated AURKA kinase activity and stabilized its conformation. In this work, we highlighted riboregulation of major mitotic factors as an additional complexity level of cell division.
Reduced temporal and spatial stability of neural activity patterns predict cognitive control deficits in children with ADHD
Abstract This study investigates the neural underpinnings of cognitive control deficits in attention-deficit/hyperactivity disorder (ADHD), focusing on trial-level variability of neural coding. Using fMRI, we apply a computational approach to single-trial neural decoding on a cued stop-signal task, probing proactive and reactive control within the dual control model. Reactive control involves suppressing an automatic response when interference is detected, and proactive control involves implementing preparatory strategies based on prior information. In contrast to typically developing children (TD), children with ADHD show disrupted neural coding during both proactive and reactive control, characterized by increased temporal variability and diminished spatial stability in neural responses in salience and frontal-parietal network regions. This variability correlates with fluctuating task performance and ADHD symptoms. Additionally, children with ADHD exhibit more heterogeneous neural response patterns across individuals compared to TD children. Our findings underscore the significance of modeling trial-wise neural variability in understanding cognitive control deficits in ADHD.
Power-free knee rehabilitation robot for home-based isokinetic training
Abstract Robot-assisted isokinetic training has been widely adopted for knee rehabilitation. However, existing rehabilitation facilities are often heavy, bulky, and extremely energy-consuming, which limits the rehabilitation opportunities only at designated hospitals. In this study, we introduce a highly integrated and lightweight (52 kg) knee rehabilitation robot that can provide home-based isokinetic training without external power. By integrating a motor, torque/angle sensors, control circuit, and energy regeneration circuit into a single driver module, our robot can provide power-free isokinetic training by recycling mechanical work from the trainee. Ten postsurgical subjects were involved in an interventional randomized trial (ChiCTR2300076715, Part I) and the cross-sectional area of trained legs (experimental group) was significantly higher than that of untrained legs (control group). The primary outcomes, muscle growth (quadriceps: 5.93%, hamstrings: 10.27%) and strength improvements (quadriceps: 70%, hamstrings: 84%), achieved with our robots surpass those of existing commercial rehabilitation devices. These findings indicate that our robot presents a viable option for home-based knee rehabilitation, significantly enhancing the accessibility of effective treatment.
Self-supervised learning reveals clinically relevant histomorphological patterns for therapeutic strategies in colon cancer
Abstract Self-supervised learning (SSL) automates the extraction and interpretation of histopathology features on unannotated hematoxylin-eosin-stained whole slide images (WSIs). We train an SSL Barlow Twins encoder on 435 colon adenocarcinoma WSIs from The Cancer Genome Atlas to extract features from small image patches (tiles). Leiden community detection groups tiles into histomorphological phenotype clusters (HPCs). HPC reproducibility and predictive ability for overall survival are confirmed in an independent clinical trial ( N = 1213 WSIs). This unbiased atlas results in 47 HPCs displaying unique and shared clinically significant histomorphological traits, highlighting tissue type, quantity, and architecture, especially in the context of tumor stroma. Through in-depth analyses of these HPCs, including immune landscape and gene set enrichment analyses, and associations to clinical outcomes, we shine light on the factors influencing survival and responses to treatments of standard adjuvant chemotherapy and experimental therapies. Further exploration of HPCs may unveil additional insights and aid decision-making and personalized treatments for colon cancer patients.
Genome-wide profiling of highly similar paralogous genes using HiFi sequencing
Ultrafast phonon-mediated dephasing of color centers in hexagonal boron nitride probed by electron beams
Abstract Defect centers in hexagonal boron nitride (hBN) have been extensively studied as room-temperature single-photon sources. The electronic structure of these defects exhibits strong coupling to phonons, as evidenced by the observation of phonon sidebands in both photoluminescence and cathodoluminescence spectra. However, the dynamics of the electron-phonon coupling as well as phonon-mediated dephasing of the color centers in hBN remain unexplored. Here, we apply a novel time-resolved CL spectroscopy technique to explore the population decay to phonon states and the dephasing time T 2 with sub-femtosecond time resolution. We demonstrate an ultrafast dephasing time of only 200 fs and a radiative decay of about 585 fs at room temperature, in contrast with all-optical time-resolved photoluminescence techniques that report a decay of a few nanoseconds. This behavior is attributed to efficient electron-beam excitation of coherent phonon-polaritons in hBN, resulting in faster dephasing of electronic transitions. Our results demonstrate the capability of our sequential cathodoluminescence spectroscopy technique to probe the ultrafast dephasing time of single emitters in quantum materials with 1.5 fs time resolution, heralding access to quantum-path interferences in single emitters coupled to their complex environment.