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Studying the neural basis of human dynamic visual perception requires extensive experimental data to evaluate the large swathes of functionally diverse brain neural networks driven by perceiving visual events. Here, we introduce the BOLD Moments Dataset (BMD), a repository of whole-brain fMRI responses to over 1,000 short (3s) naturalistic video clips of visual events across ten human subjects. We use the videos’ extensive metadata to show how the brain represents word- and sentence-level descriptions of visual events and identify correlates of video memorability scores extending into the parietal cortex. Furthermore, we reveal a match in hierarchical processing between cortical regions of interest and video-computable deep neural networks, and we showcase that BMD successfully captures temporal dynamics of visual events at second resolution. With its rich metadata, BMD offers new perspectives and accelerates research on the human brain basis of visual event perception.
The ubiquitin (Ub) code denotes the complex Ub architectures, including Ub chains of different length, linkage-type and linkage combinations, which enable ubiquitination to control a wide range of protein fates. Although many linkage-specific interactors have been described, how interactors are able to decode more complex architectures is not fully understood. We conducted a Ub interactor screen, in humans and yeast, using Ub chains of varying length, as well as, homotypic and heterotypic branched chains of the two most abundant linkage types – K48- and K63-linked Ub. We identified some of the first K48/K63 branch-specific Ub interactors, including histone ADP-ribosyltransferase PARP10/ARTD10, E3 ligase UBR4 and huntingtin-interacting protein HIP1. Furthermore, we revealed the importance of chain length by identifying interactors with a preference for Ub3 over Ub2 chains, including Ub-directed endoprotease DDI2, autophagy receptor CCDC50 and p97-adaptor FAF1. Crucially, we compared datasets collected using two common DUB inhibitors – Chloroacetamide and N-ethylmaleimide. This revealed inhibitor-dependent interactors, highlighting the importance of inhibitor consideration during pulldown studies. This dataset is a key resource for understanding how the Ub code is read.
Zinc finger (ZnF) domains appear in a pool of structural contexts and despite their small size achieve varying target specificities, covering single-stranded and double-stranded DNA and RNA as well as proteins. Combined with other RNA-binding domains, ZnFs enhance affinity and specificity of RNA-binding proteins (RBPs). The ZnF-containing immunoregulatory RBP Roquin initiates mRNA decay, thereby controlling the adaptive immune system. Its unique ROQ domain shape-specifically recognizes stem-looped cis-elements in mRNA 3’-untranslated regions (UTR). The N-terminus of Roquin contains a RING domain for protein-protein interactions and a ZnF, which was suggested to play an essential role in RNA decay by Roquin. The ZnF domain boundaries, its RNA motif preference and its interplay with the ROQ domain have remained elusive, also driven by the lack of high-resolution data of the challenging protein. We provide the solution structure of the Roquin-1 ZnF and use an RBNS-NMR pipeline to show that the ZnF recognizes AU-rich elements (ARE). We systematically refine the contributions of adenines in a poly(U)-background to specific complex formation. With the simultaneous binding of ROQ and ZnF to a natural target transcript of Roquin, our study for the first time suggests how Roquin integrates RNA shape and sequence specificity through the ROQ-ZnF tandem.
G protein-coupled receptors (GPCRs) play a crucial role in modulating physiological responses and serve as the main drug target. Specifically, salmeterol and salbutamol which are used for the treatment of pulmonary diseases, exert their effects by activating the GPCR β2-adrenergic receptor (β2AR). In our study, we employed coarse-grained molecular dynamics simulations with the Martini 3 force field to investigate the dynamics of drug molecules in membranes in presence and absence of β2AR. Our simulations reveal that in more than 50% of the flip-flop events the drug molecules use the β2AR surface to permeate the membrane. The pathway along the GPCR surface is significantly more energetically favorable for the drug molecules, which was revealed by umbrella sampling simulations along spontaneous flip-flop pathways. Furthermore, we assessed the behavior of drugs with intracellular targets, such as kinase inhibitors, whose therapeutic efficacy could benefit from this observation. In summary, our results show that β2AR surface interactions can significantly enhance membrane permeation of drugs, emphasizing their potential for consideration in future drug development strategies.
Motivated by the question of the impact of selective advantage in populations with skewed reproduction mechanims, we study a Moran model with selection. We assume that there are two types of individuals, where the reproductive success of one type is larger than the other. The higher reproductive success may stem from either more frequent reproduction, or from larger numbers of offspring, and is encoded in a measure Λ for each of the two types. Our approach consists of constructing a Λ-asymmetric Moran model in which individuals of the two populations compete, rather than considering a Moran model for each population. Under certain conditions, that we call the "partial order of adaptation", we can couple these measures. This allows us to construct the central object of this paper, the Λ−asymmetric ancestral selection graph, leading to a pathwise duality of the forward in time Λ-asymmetric Moran model with its ancestral process. Interestingly, the construction also provides a connection to the theory of optimal transport. We apply the ancestral selection graph in order to obtain scaling limits of the forward and backward processes, and note that the frequency process converges to the solution of an SDE with discontinous paths. Finally, we derive a Griffiths representation for the generator of the SDE and use it to find a semi-explicit formula for the probability of fixation of the less beneficial of the two types.
The ALICE Collaboration reports a differential measurement of inclusive jet suppression using pp and Pb−Pb collision data at a center-of-mass energy per nucleon-nucleon collision sNN−−−√=5.02 TeV. Charged-particle jets are reconstructed using the anti-kT algorithm with resolution parameters R= 0.2, 0.3, 0.4, 0.5, and 0.6 in pp collisions and R= 0.2, 0.4, 0.6 in central (0−10%), semi-central (30−50%), and peripheral (60−80%) Pb−Pb collisions. A novel approach based on machine learning is employed to mitigate the influence of jet background. This enables measurements of inclusive jet suppression in new regions of phase space, including down to the lowest jet pT≥40 GeV/c at R=0.6 in central Pb−Pb collisions. This is an important step for discriminating different models of jet quenching in the quark-gluon plasma. The transverse momentum spectra, nuclear modification factors, derived cross section, and nuclear modification factor ratios for different jet resolution parameters of charged-particle jets are presented and compared to model predictions. A mild dependence of the nuclear modification factor ratios on collision centrality and resolution parameter is observed. The results are compared to a variety of jet-quenching models with varying levels of agreement.
The two-particle momentum correlation functions between charm mesons (D∗± and D±) and charged light-flavor mesons (π± and K±) in all charge-combinations are measured for the first time by the ALICE Collaboration in high-multiplicity proton-proton collisions at a center-of-mass energy of s√=13 TeV. For DK and D∗K pairs, the experimental results are in agreement with theoretical predictions of the residual strong interaction based on quantum chromodynamics calculations on the lattice and chiral effective field theory. In the case of Dπ and D∗π pairs, tension between the calculations including strong interactions and the measurement is observed. For all particle pairs, the data can be adequately described by Coulomb interaction only, indicating a shallow interaction between charm and light-flavor mesons. Finally, the scattering lengths governing the residual strong interaction of the Dπ and D∗π systems are determined by fitting the experimental correlation functions with a model that employs a Gaussian potential. The extracted values are small and compatible with zero.
Here, we introduce racoon_clip, a sustainable and fully automated pipeline for the complete processing of iCLIP and eCLIP data to extract RNA binding signal at single-nucleotide resolution. racoon_clip is easy to install and execute, with multiple pre-settings and fully customizable parameters, and outputs a conclusive summary report with visualizations and statistics for all analysis steps.
For genus g=r(r+1)2+1, we prove that via the forgetful map, the universal Prym-Brill-Noether locus Rrg has a unique irreducible component dominating the moduli space Rg of Prym curves.
Can prediction error explain predictability effects on the N1 during picture-word verification?
(2024)
Do early effects of predictability in visual word recognition reflect prediction error? Electrophysiological research investigating word processing has demonstrated predictability effects in the N1, or first negative component of the event-related potential (ERP). However, findings regarding the magnitude of effects and potential interactions of predictability with lexical variables have been inconsistent. Moreover, past studies have typically used categorical designs with relatively small samples and relied on by-participant analyses. Nevertheless, reports have generally shown that predicted words elicit less negative-going (i.e., lower amplitude) N1s, a pattern consistent with a simple predictive coding account. In our preregistered study, we tested this account via the interaction between prediction magnitude and certainty. A picture-word verification paradigm was implemented in which pictures were followed by tightly matched picture-congruent or picture-incongruent written nouns. The predictability of target (picture-congruent) nouns was manipulated continuously based on norms of association between a picture and its name. ERPs from 68 participants revealed a pattern of effects opposite to that expected under a simple predictive coding framework.
The hippocampal-dependent memory system and striatal-dependent memory system modulate reinforcement learning depending on feedback timing in adults, but their contributions during development remain unclear. In a 2-year longitudinal study, 6-to-7-year-old children performed a reinforcement learning task in which they received feedback immediately or with a short delay following their response. Children’s learning was found to be sensitive to feedback timing modulations in their reaction time and inverse temperature parameter, which quantifies value-guided decision-making. They showed longitudinal improvements towards more optimal value-based learning, and their hippocampal volume showed protracted maturation. Better delayed model-derived learning covaried with larger hippocampal volume longitudinally, in line with the adult literature. In contrast, a larger striatal volume in children was associated with both better immediate and delayed model-derived learning longitudinally. These findings show, for the first time, an early hippocampal contribution to the dynamic development of reinforcement learning in middle childhood, with neurally less differentiated and more cooperative memory systems than in adults.
For genus g=2i≥4 and the length g−1 partition μ=(4,2,…,2,−2,…,−2) of 0, we compute the first coefficients of the class of D¯¯¯¯(μ) in PicQ(R¯¯¯¯g), where D(μ) is the divisor consisting of pairs [C,η]∈Rg with η≅OC(2x1+x2+⋯+xi−1−xi−⋯−x2i−1) for some points x1,…,x2i−1 on C. We further provide several enumerative results that will be used for this computation.
Upon infection of host cells, Legionella pneumophila releases a multitude of effector enzymes into the cells cytoplasm that hijack a plethora of cellular activities, including the hosts ubiquitination pathways. Effectors belonging to the SidE-family are involved in non-canonical serine phosphoribosyl ubiquitination of host substrate proteins contributing to the formation of a Legionella-containing vacuole that is crucial in the onset of Legionnaires’ disease. This dynamic process is reversed by effectors called Dups that hydrolyse the phosphodiester in the phosphoribosyl ubiquitinated protein. We installed reactive warheads on chemically prepared ribosylated ubiquitin to generate a set of probes targeting these Legionella enzymes. In vitro tests on recombinant DupA revealed that a vinyl sulfonate warhead was most efficient in covalent complex formation. Mutagenesis and x-ray crystallography approaches were used to identify the site of covalent crosslinking to be an allosteric cysteine residue. The subsequent application of this probe highlights the potential to selectively enrich the Dup enzymes from Legionella-infected cell lysates.
The epitranscriptome embodies many new and largely unexplored functions of RNA. A significant roadblock hindering progress in epitranscriptomics is the identification of more than one modification in individual transcript molecules. We address this with CHEUI (CH3 (methylation) Estimation Using Ionic current). CHEUI predicts N6-methyladenosine (m6A) and 5-methylcytidine (m5C) in individual molecules from the same sample, the stoichiometry at transcript reference sites, and differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals to achieve high single-molecule, transcript-site, and stoichiometry accuracies in multiple tests using synthetic RNA standards and cell line data. CHEUI’s capability to identify two modification types in the same sample reveals a co-occurrence of m6A and m5C in individual mRNAs in cell line and tissue transcriptomes. CHEUI provides new avenues to discover and study the function of the epitranscriptome.
Microbial rhodopsins are omnipresent on Earth, however the vast majority of them remain uncharacterized. Here we describe a new rhodopsin clade from cold-adapted organisms and cold environments, such as glaciers, denoted as CryoRhodopsins (CryoRs). Our data suggest that CryoRs have photosensory activity. A distinguishing feature of the clade is the presence of a buried arginine residue close to the cytoplasmic face of its members. Combining single-particle cryo-electron microscopy and X-ray crystallography with the rhodopsin activation by light, we demonstrate that the arginine stabilizes a strongly blue-shifted intermediate of an extremely slow CryoRhodopsin photocycle. Together with extensive spectroscopic characterization, our investigations on CryoR1 and CryoR2 proteins reveal mechanisms of photoswitching in the newly identified clade and demonstrate principles of the adaptation of these rhodopsins to low temperatures.
Nuclear pore complexes (NPCs) constitute giant channels within the nuclear envelope that mediate nucleocytoplasmic exchange. NPC diameter is thought to be regulated by nuclear envelope tension, but how such diameter changes are physiologically linked to cell differentiation, where mechanical properties of nuclei are remodeled and nuclear mechanosensing occurs, remains unstudied. Here we used cryo-electron tomography to show that NPCs dilate during differentiation of mouse embryonic stem cells into neural progenitors. In Nup133-deficient cells, which are known to display impaired neural differentiation, NPCs however fail to dilate. By analyzing the architectures of individual NPCs with template matching, we revealed that the Nup133-deficient NPCs are structurally heterogeneous and frequently disintegrate, resulting in the formation of large nuclear envelope openings. We propose that the elasticity of the NPC scaffold mechanically safeguards the nuclear envelope. Our studies provide a molecular explanation for how genetic perturbation of scaffolding components of macromolecular complexes causes tissue-specific phenotypes.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Background: Trauma-related guilt and shame are crucial for the development and maintenance of PTSD (posttraumatic stress disorder). We developed an intervention combining cognitive techniques with loving-kindness meditations (C-METTA) that specifically target these emotions. C-METTA is an intervention of six weekly individual treatment sessions followed by a four-week practice phase.
Objective: This study examined C-METTA in a proof-of-concept study within a randomized wait-list controlled trial.
Method: We randomly assigned 32 trauma-exposed patients with a DSM-5 diagnosis to C-METTA or a wait-list condition (WL). Primary outcomes were clinician-rated PTSD symptoms (CAPS-5) and trauma-related guilt and shame. Secondary outcomes included psychopathology, self-criticism, well-being, and self-compassion. Outcomes were assessed before the intervention phase and after the practice phase.
Results: Mixed-design analyses showed greater reductions in C-METTA versus WL in clinician-rated PTSD symptoms (d = −1.09), guilt (d = −2.85), shame (d = −2.14), psychopathology and self-criticism.
Conclusion: Our findings support positive outcomes of C-METTA and might contribute to improved care for patients with stress-related disorders. The study was registered in the German Clinical Trials Register (DRKS00023470).
HIGHLIGHTS
C-METTA is an intervention that addresses trauma-related guilt and shame and combines cognitive interventions with loving-kindness meditations.
A proof-of-concept study was conducted examining C-METTA in a wait-list randomized controlled trial
C-METTA led to reductions in trauma-related guilt and shame and PTSD symptoms.
The intense photon fluxes from relativistic nuclei provide an opportunity to study photonuclear interactions in ultraperipheral collisions. The measurement of coherently photoproduced π+π−π+π− final states in ultraperipheral Pb-Pb collisions at sNN−−−√=5.02 TeV is presented for the first time. The cross section, dσ/dy, times the branching ratio (ρ→π+π+π−π−) is found to be 47.8±2.3 (stat.)±7.7 (syst.) mb in the rapidity interval |y|<0.5. The invariant mass distribution is not well described with a single Breit-Wigner resonance. The production of two interfering resonances, ρ(1450) and ρ(1700), provides a good description of the data. The values of the masses (m) and widths (Γ) of the resonances extracted from the fit are m1=1385±14 (stat.)±3 (syst.) MeV/c2, Γ1=431±36 (stat.)±82 (syst.) MeV/c2, m2=1663±13 (stat.)±22 (syst.) MeV/c2 and Γ2=357±31 (stat.)±49 (syst.) MeV/c2, respectively. The measured cross sections times the branching ratios are compared to recent theoretical predictions.
Measurements of the pT-dependent flow vector fluctuations in Pb-Pb collisions at sNN−−−√=5.02 TeV using azimuthal correlations with the ALICE experiment at the LHC are presented. A four-particle correlation approach [1] is used to quantify the effects of flow angle and magnitude fluctuations separately. This paper extends previous studies to additional centrality intervals and provides measurements of the pT-dependent flow vector fluctuations at sNN−−−√=5.02 TeV with two-particle correlations. Significant pT-dependent fluctuations of the V⃗ 2 flow vector in Pb-Pb collisions are found across different centrality ranges, with the largest fluctuations of up to ∼15% being present in the 5% most central collisions. In parallel, no evidence of significant pT-dependent fluctuations of V⃗ 3 or V⃗ 4 is found. Additionally, evidence of flow angle and magnitude fluctuations is observed with more than 5σ significance in central collisions. These observations in Pb-Pb collisions indicate where the classical picture of hydrodynamic modeling with a common symmetry plane breaks down. This has implications for hard probes at high pT, which might be biased by pT-dependent flow angle fluctuations of at least 23% in central collisions. Given the presented results, existing theoretical models should be re-examined to improve our understanding of initial conditions, quark--gluon plasma (QGP) properties, and the dynamic evolution of the created system.