bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism-guided quantification of LINE-1 reveals p53 regulation of both retrotransposition and transcription
Authors: Solovyov Alexander , Behr Julie M. , Hoyos David , Banks Eric , Drong Alexander W. , Zhong Jimmy Z. , Garcia-Rivera Enrique , McKerrow Wilson , Chu Chong , Zaller Dennis M. , Fromer Menachem , Greenbaum Benjamin D. 
Published: May 2023

AbstractSomatic activity of LINE-1 (L1) mobile elements has been implicated in cancer etiology, which may be related to the loss of p53-mediated regulation as a result ofTP53mutations. Quantifying the mechanisms of L1 regulation in cancer has been challenging. Here, we build a statistical model of L1 regulation by simultaneously quantifying L1 retrotransposition, L1 expression, and the fitness costs of mutatedTP53with precision. We first developed Total ReCall, an algorithm specifically tailored to the mechanisms of L1 reintegration, to detect L1 insertions from short-read whole-genome sequencing. Applying Total ReCall to high-quality data consisting of >750 paired tumor and normal samples from The Cancer Genome Atlas (TCGA) shows high L1 insertion heterogeneity among tumor types, with increased retrotransposition burden in lung squamous cell carcinoma, head and neck, and colon cancers. We next assessed the active RNA expression of intact L1 in >9,000 TCGA tumor samples, establishing, for the first time, a clear correlation between L1 expression and retrotransposition. Finally, we integrated the number of L1 insertions, L1 expression and a mathematical model ofTP53fitness into a multi-modal model of p53- mediated mechanisms of L1 regulation. We show thatTP53mutations enable retrotransposition both by disinhibiting L1 expression and enabling its reintegration and quantify the relative weights of this dual regulatory role. We demonstrate how mechanism-based multi-modal modeling applied at scale can statistically disentangle the complex interplay between canonical driver events in tumor evolution and retrotransposon activity.
Elevated nuclear TDP-43 induces constitutive exon skipping
Authors: Carmen-Orozco Rogger P. , Tsao William , Ye Yingzhi , Sinha Irika R. , Chang Koping , Trinh Vickie , Chung William , Bowden Kyra , Troncoso Juan C. , Blackshaw Seth , Hayes Lindsey R. , Sun Shuying , Wong Philip C. , Ling Jonathan P. 
Published: May 2023

AbstractCytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generatein vitroandin vivomodel systems. Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43. Our findings emphasize the need for caution in interpreting TDP-43 overexpression data, and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy. Understanding the subtle aspects of TDP-43 toxicity within different subcellular locations is essential for the development of therapies targeting neurodegenerative disease.
Automatic Auditory Streaming Restores Missing Temporal Modulations in Echoic Speech
Authors: Gao Jiaxin , Fang Mingxuan , Chen Honghua , Ding Nai 
Published: May 2023

SummaryHuman listeners can reliably recognize speech in adverse listening environments, and previous studies have identified that reliable neural encoding of slow temporal modulations in speech is essential for speech recognition. Recent behavioral studies demonstrate that long-delay echoes, which are rare in physical environments but common during online conferencing, can eliminate critical temporal modulations. These echoes, however, barely affect speech intelligibility, and here we investigate the underlying neural mechanisms. MEG experiments demonstrate that cortical activity can effectively track the temporal modulations eliminated by an echo, which cannot be explained by basic neural adaptation mechanisms such as synaptic depression, gain control, and adaptive filtering. Instead, the cortical response to echoic speech is better explained by a model that segregates speech from its echo than a model that encodes echoic speech as a whole. The speech segregation effect is observed even when attention is diverted, but disappears when speech segregation cues in the spectro-temporal fine structure are degraded. Altogether, these results strongly suggest that the auditory system can automatically segregate speech and its echo and encode them as two auditory streams, providing a potential neural basis for reliable speech recognition in echoic environments.
Dog population estimates and rabies vaccination optimization using the High-Resolution Settlement Layer (HRSL) – a proof of principle for the Oshana region, Namibia
Authors: Freuling Conrad M. , Czaja Eva-Maria , Wysocki Patrick , Athingo Rauna , Tenzin Tenzin , Müller Thomas 
Published: May 2023

AbstractDespite being vaccine preventable, dog-mediated rabies continues unabated in low-resourced countries in Africa and Asia. For interventions into dog rabies control, an estimate of the dog population is a prerequisite. Here we used a High-Resolution Settlement Layer (HRSL) with an unprecedented resolution of 30m grid length that is Open Source for dog populations estimates and studies on vaccination coverages, with the Oshana region of Namibia as an example. Our analyses show that the average dog density per km2is 8.15 but ranges between 0 and 40 per constituency, with individual densities being as high as 551.Spatial analyses for different settings of static vaccination points indicate that the previously used vaccination points during the pilot phase and cattle crush-pens are insufficient for reaching a 70% vaccination level in the Oshana region. Based on cost calculations, between US$5.29 and US$7.77 are needed to parenterally vaccinate dogs in this region, suggesting that oral rabies vaccination may be a cost-effective supplement or even replacement. The high-resolution spatial analyses are exemplified for rabies, but any other One Health intervention, particularly for Neglected tropical diseases in highly heterogenous and remote areas could use our approach as a template.Author SummaryHere, we used high-resolution geospatial data for demonstrating and validating its utility to assist veterinary authorities in their fight against dog-mediated rabies on the example of the Oshana region in Namibia. With such detailed data it is possible estimate the dog population and to analyse and optimize vaccination strategies in dog rabies endemic areas. Such analyses are exemplified for rabies, but any other One Health intervention, particularly for Neglected tropical diseases in highly heterogenous and remote areas could use our approach as a template.
Abnormal behavioral episodes associated with sleep and quiescence in Octopusinsularis: Possible nightmares in a cephalopod?
Authors: Ramos Eric A. , Steinblatt Mariam , Demsey Rachel , Reiss Diana , Magnasco Marcelo O. 
Published: May 2023

ABSTRACTThis paper presents some unusual behaviors observed in one single specimen ofO. insularis. While nothing can be concluded rigorously from such data, we share the data and our analysis with the community, in the hope that others will be on the lookout for such rare events. Sleep is a fundamental biological function that is present in all tested vertebrates and most invertebrates.Cephalopods, such as octopuses, are cognitively complex animals that display active and inactive sleep states similar to those of vertebrates. In particular, octopuses have active sleep states during which they display sequences of camouflage patterns and modulation of basal rhythms, while remaining relatively unresponsive to outside stimuli. Some scientists have speculated that these states could be analogous to dreaming in mammals, involving episodic recall with a narrative structure. The convergent evolution of sleep in neurologically complex animals is a striking possibility, but its demonstration requires overcoming significant challenges. Towards this end, capturing abnormal sleep-associated episodes and other parasomnias in cephalopods can provide further insight into the biology of their sleep. This study reports abnormal behavioral episodes associated with transitions between activity states and sleep states observed in a maleOctopus insularis. The study used continuous video monitoring to characterize the animal’s activity patterns and detect rare behavioral episodes. Over the course of a month, four brief episodes (duration range: 44-290 seconds) were identified during which the octopus abruptly emerged from quiescent or active sleep, detached itself from its sleep position, and engaged in antipredator and predatory behaviors (with no predator present). The longest of these episodes resembled the species-typical response to a predatory attack, suggesting that the animal may have been responding to a negative episodic memory or exhibiting a form of parasomnia. These findings, in conjunction with recent evidence for sleep in octopuses, highlight the complexity of possible sleep-associated behavioral episodes. Investigating sleep in invertebrates is crucial to understanding the evolution of sleep across distantly related species.
Immunoprecipitation of RNA-DNA hybrid interacting proteins inTrypanosoma bruceireveals conserved and novel activities, including in host immune evasion by antigenic variation
Authors: Girasol Mark J. , Briggs Emma M. , Marques Catarina A. , Batista José M. , Beraldi Dario , Burchmore Richard , Lemgruber Leandro , McCulloch Richard 
Published: May 2023

AbstractRNA-DNA hybrids are widespread epigenetic features of genomes that provide a growing range of activities in transcription, chromatin and DNA replication and repair. Understanding of these diverse functions has been advanced by characterising the proteins that interact with the hybrids, with all such studies revealing hundreds of potential interactors. However, all interaction analyses to date have focused on mammalian cells, and so it is unclear if a similar spectrum of RNA-DNA hybrid interactors is found in other eukaryotes, thus limiting our understanding of the conserved and lineage-specific activities linked to these genetic structures. The African trypanosome is a compelling organism in which to address these questions. As a divergent single-cell eukaryotic parasite of the Discoba grouping,Trypanosoma bruceidisplays substantial divergence in several aspects of core biology from its mammalian host and, unusually for a protist, has well-developed tools for molecular genetic analysis. For these reasons, we used DNA-RNA hybrid immunoprecipitation coupled with mass spectrometry to reveal 602 putative interactors inT. bruceimammal- or insect vector-infective stage cells. We show that the approach selects for a subset of the parasite proteome and reveals a range of predicted RNA-DNA hybrid associated activities, some overlapping with similar studies in mammals. We demonstrate that loss of three factors, two putative helicases and a RAD51 paralogue, impact onT. bruceinuclear RNA-DNA hybrid and DNA damage levels. Moreover, loss of each affects the operation of the crucial parasite immune survival mechanism of antigenic variation. Thus, our work reveals the broad range of activities contributed by RNA-DNA hybrids toT. bruceibiology, including new functions in host immune evasion as well as many conserved with mammals, and so likely fundamental to eukaryotic genome function.
Rapid processing of observed touch through social perceptual brain regions: an EEG-fMRI fusion study
Authors: Lee Masson Haemy , Isik Leyla 
Published: May 2023

AbstractSeeing social touch triggers a strong social-affective response that involves multiple brain networks, including visual, social perceptual, and somatosensory systems. Previous studies have identified the specific functional role of each system, but little is known about the speed and directionality of the information flow. Is this information extracted via the social perceptual system or from simulation from somatosensory cortex? To address this, we examined the spatiotemporal neural processing of observed touch. Twenty participants watched 500 ms video clips showing social and non-social touch during EEG recording. Visual and social-affective features were rapidly extracted in the brain, beginning at 90 and 150 ms after video onset, respectively. Combining the EEG data with fMRI data from our prior study with the same stimuli reveals that neural information first arises in early visual cortex (EVC), then in the temporoparietal junction and posterior superior temporal sulcus (TPJ/pSTS), and finally in the somatosensory cortex. EVC and TPJ/pSTS uniquely explain EEG neural patterns, while somatosensory cortex does not contribute to EEG patterns alone, suggesting that social-affective information may flow from TPJ/pSTS to somatosensory cortex. Together, these findings show that social touch is processed quickly, within the timeframe of feedforward visual processes, and that the social-affective meaning of touch is first extracted by a social perceptual pathway. Such rapid processing of social touch may be vital to its effective use during social interaction.Significance StatementSeeing physical contact between people evokes a strong social-emotional response. Previous research has identified the brain systems responsible for this response, but little is known about how quickly and in what direction the information flows. We demonstrated that the brain processes the social-emotional meaning of observed touch quickly, starting as early as 150 milliseconds after the stimulus onset. By combining EEG data with fMRI data, we show for the first time that the social-affective meaning of touch is first extracted by a social perceptual pathway and followed by the later involvement of somatosensory simulation. This rapid processing of touch through the social perceptual route may play a pivotal role in effective usage of touch in social communication and interaction.
Network and State Specificity in Connectivity-Based Predictions of Individual Behavior
Authors: Kraljević Nevena , Langner Robert , Küppers Vincent , Raimondo Federico , Patil Kaustubh R. , Eickhoff Simon B. , Müller Veronika I. 
Published: May 2023

AbstractPredicting individual behavior from brain functional connectivity (FC) patterns can contribute to our understanding of human brain functioning. This may apply in particular if predictions are based on features derived from circumscribed,a prioridefined functional networks, which improves interpretability. Furthermore, some evidence suggests that task-based FC data may yield more successful predictions of behavior than resting-state FC data. Here, we comprehensively examined to what extent the correspondence of functional network priors and task states with behavioral target domains influences the predictability of individual performance in cognitive, social, and affective tasks. To this end, we used data from the Human Connectome Project for large-scale out-of-sample predictions of individual abilities in working memory (WM), theory-of-mind cognition (SOCIAL), and emotion processing (EMO) from FC of corresponding and non-corresponding states (WM/SOCIAL/EMO/resting-state) and networks (WM/SOCIAL/EMO/whole-brain connectome). Using root mean squared error and coefficient of determination to evaluate model fit revealed that predictive performance was rather poor overall. Predictions from whole-brain FC were slightly better than those from FC in task-specific networks, and a slight benefit of predictions based on FC from task versus resting state was observed for performance in the WM domain. Beyond that, we did not find any significant effects of a correspondence of network, task state, and performance domains. Together, these results suggest that multivariate FC patterns during both task and resting states contain rather little information on individual performance levels, calling for a reconsideration of how the brain mediates individual differences in mental abilities.HighlightsBetter prediction of behavior from task vs. resting-state FC only in a cognitive domainLittle evidence for specificity of state, network, or task similarityPredicting complex behavior based on FC remains a significant challengeWe extend research on brain-based behavior prediction beyond the cognitive domainAbstract Figure
Uncertainty-modulated prediction errors in cortical microcircuits
Authors: Wilmes Katharina A. , Petrovici Mihai A. , Sachidhanandam Shankar , Senn Walter 
Published: May 2023

AbstractUnderstanding the variability of the environment is essential to function in everyday life. The brain must hence take uncertainty into account when updating its internal model of the world. The basis for updating the model are prediction errors that arise from a difference between the current model and new sensory experiences. Although prediction error neurons have been identified in layer 2/3 of diverse brain areas, how uncertainty modulates these errors and hence learning is, however, unclear. Here, we use a normative approach to derive how uncertainty should modulate prediction errors and postulate that layer 2/3 neurons represent uncertainty-modulated prediction errors (UPE). We further hypothesise that the layer 2/3 circuit calculates the UPE through the subtractive and divisive inhibition by different inhibitory cell types. By implementing the calculation of UPEs in a microcircuit model, we show that different cell types can compute the means and variances of the stimulus distribution. With local activity-dependent plasticity rules, these computations can be learned context-dependently, and allow the prediction of upcoming stimuli and their distribution. Finally, the mechanism enables an organism to optimise its learning strategy via adaptive learning rates.
Dissociating instructive from permissive roles of brain circuits with reversible neural activity manipulations
Authors: Quintana Daniel , Bounds Hayley A. , Brown Jennifer , Wang May , Bhatla Nikhil , Wiegert J. Simon , Adesnik Hillel 
Published: May 2023

ABSTRACTNeuroscientists rely on targeted perturbations and lesions to causally map functions in the brain1. Yet, since the brain is highly interconnected, manipulation of one area can impact behavior through indirect effects on many other brain regions, complicating the interpretation of such results2,3. On the other hand, the often-observed recovery of behavior performance after lesion can cast doubt on whether the lesioned area was ever directly involved4,5. Recent studies have highlighted how the results of acute and irreversible inactivation can directly conflict4-6, making it unclear whether a brain area is instructive or merely permissive in a specific brain function. To overcome this challenge, we developed a three-stage optogenetic approach which leverages the ability to precisely control the temporal period of regional inactivation with either brief or sustained illumination. Using a visual detection task, we found that acute optogenetic inactivation of the primary visual cortex (V1) suppressed task performance if cortical inactivation was intermittent across trials within each behavioral session. However, when we inactivated V1 for entire behavioral sessions, animals quickly recovered performance in just one to two days. Most importantly, after returning these recovered animals to intermittent cortical inactivation, they quickly reverted to failing on optogenetic inactivation trials. These data support a revised model where the cortex is the default circuit that instructs perceptual performance in basic sensory tasks. More generally, this novel, temporally controllable optogenetic perturbation paradigm can be broadly applied to brain circuits and specific cell types to assess whether they are instructive or merely permissive in a brain function or behavior.
Histone H3 tail modifications regulate structure and dynamics of the H1 C-terminal domain within nucleosomes
Authors: Das Subhra Kanti , Kumar Ashok , Hao Fanfan , DiPiazza Amber R. Cutter , Lee Tae-Hee , Hayes Jeffrey J. 
Published: May 2023

SummaryDespite their importance, how linker histone H1s interact in chromatin and especially how the highly positively charged and intrinsically disordered H1 C-terminal domain (CTD) binds and stabilizes nucleosomes and higher-order chromatin structures remains unclear. Using single-molecule FRET we found that about half of the H1 CTDs in H1-nucleosome complexes exhibit well-defined FRET values indicative of distinct, static conformations, while the remainder of the population exhibits dynamically changing values, similar to that observed for H1 in the absence of nucleosomes. We also find that the first 30 residues of the CTD participate in relatively localized interactions with the first ∼20 bp of linker DNA, and that two separate regions in the CTD contribute to H1-dependent organization of linker DNA, consistent with some non-random CTD-linker DNA interactions. Finally, our data show that acetylation mimetics within the histone H3 tail induce decondensation and enhanced dynamics of the nucleosome-bound H1 CTD. (148 words)
Antibodies Raised Against an Aβ Oligomer Mimic Recognize Pathological Features in Alzheimer’s Disease and Associated Amyloid-Disease Brain Tissue
Authors: Kreutzer Adam G. , Parrocha Chelsea Marie T. , Haerianardakani Sepehr , Guaglianone Gretchen , Nguyen Jennifer T. , Diab Michelle N. , Yong William , Perez-Rosendahl Mari , Head Elizabeth , Nowick James S. 
Published: May 2023

ABSTRACTAntibodies that target the β-amyloid peptide (Aβ) and its associated assemblies are important tools in Alzheimer’s disease research and have emerged as promising Alzheimer’s disease therapies. This paper reports the creation and characterization of a triangular Aβ trimer mimic composed of Aβl7-36β-hairpins, and the generation and study of polyclonal antibodies raised against the Aβ trimer mimic. The Aβ trimer mimic is covalently stabilized by three disulfide bonds at the corners of the triangular trimer to create a homogeneous oligomer. Structural, biophysical, and cell-based studies demonstrate that the Aβ trimer mimic shares characteristics with oligomers of full-length Aβ: X-ray crystallography elucidates the high-resolution structure of the trimer and reveals that four copies of the trimer assemble to form a dodecamer; SDS-PAGE, size exclusion chromatography, and dynamic light scattering reveal that the trimer also forms higher-order assemblies in solution; cell-based toxicity assays show that the trimer elicits LDH release, decreases ATP levels, and activates caspase-3/7 mediated apoptosis. Tmmunostaining studies on brain slices from people who lived with Alzheimer’s disease as well as people who lived with Down syndrome reveal that the polyclonal antibodies raised against the Aβ trimer mimic recognize pathological features including different types of Aβ plaques and cerebral amyloid angiopathy. These findings suggest that the triangular trimer structural motif is important in Alzheimer’s disease and may thus constitute a new structurally defined molecular target for diagnostic and therapy development.SYNOPSISA structurally defined Aβ oligomer mimic is created and studied, and antibodies raised against the Aβ oligomer mimic are used to investigate its relevance to Alzheimer’s disease.