bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decoding the complexity of delayed wound healing followingEnterococcus faecalisinfection
Authors: Celik Cenk , Lee Stella Yue Ting , Tanoto Frederick Reinhart , Veleba Mark , Kline Kimberly A. , Thibault Guillaume 
Published: November 2023

ABSTRACTWound infections are highly prevalent, and can lead to delayed or failed healing, causing significant morbidity and adverse economic impacts. These infections occur in various contexts, including diabetic foot ulcers, burns, and surgical sites.Enterococcus faecalisis often found in persistent non-healing wounds, but its contribution to chronic wounds remains understudied. To address this, we employed single-cell RNA sequencing (scRNA-seq) on infected wounds in comparison to uninfected wounds in a mouse model. Examining over 23,000 cells, we created a comprehensive single-cell atlas that captures the cellular and transcriptomic landscape of these wounds. Our analysis revealed unique transcriptional and metabolic alterations in infected wounds, elucidating the distinct molecular changes associated with bacterial infection compared to the normal wound healing process. We identified dysregulated keratinocyte and fibroblast transcriptomes in response to infection, jointly contributing to an anti-inflammatory environment. Notably,E. faecalisinfection prompted a premature, incomplete epithelial-to-mesenchymal transition in keratinocytes. Additionally,E. faecalisinfection modulated M2-like macrophage polarization by inhibiting pro-inflammatory resolutionin vitro,in vivo,and in our scRNA-seq atlas. Furthermore, we discovered macrophage crosstalk with neutrophils, which regulates chemokine signaling pathways, while promoting anti-inflammatory interactions with endothelial cells. Overall, our findings offer new insights into the immunosuppressive role ofE. faecalisin wound infections.
The embryonic DNA methylation program modulates thecis-regulatory landscape via CTCF antagonism
Authors: Monteagudo-Sánchez Ana , Richard Albert Julien , Scarpa Margherita , Noordermeer Daan , Greenberg Maxim V.C. 
Published: November 2023

AbstractDuring mammalian embryogenesis, both the 5-cytosine DNA methylation (5meC) landscape and three-dimensional (3D) chromatin architecture are profoundly remodeled during a process known as “epigenetic reprogramming.” An understudied aspect of epigenetic reprogramming is how the 5meC flux,per se, affects the 3D genome. This is pertinent given the 5meC-sensitivity of DNA binding for a key regulator of chromosome folding: CTCF. We profiled the CTCF binding landscape using a mouse embryonic stem cell (ESC) differentiation protocol that models the exit of naïve pluripotency, wherein global DNA methylation levels start low and increase to somatic levels within four days. We took advantage of the fact that mouse ESCs lacking DNA methylation machinery exhibit globally similar differentiation dynamics, thus allowing for dissection of more subtle effects of CTCF misregulation on gene expression. We carried this out by performing CTCF HiChIP in both wild-type and mutant conditions to assess aberrant CTCF-CTCF contacts in the absence of 5meC. We went on to assess the impact that misregulated CTCF binding has oncis-regulatory contacts by performing H3K27ac HiChIP, given that H3K27ac is enriched on active promoters and enhancers. Using DNA methylation epigenome editing, we were able to directly demonstrate that the DNA methyl-mark is able to impact CTCF binding. Finally, a detailed dissection of the imprintedZdbf2gene showed how 5meC-antagonism of CTCF allows for proper gene regulation during differentiation. This work provides a comprehensive overview of how DNA methylation impacts the 3D genome in a relevant model for early embryonic events.
Fine-grained modelling of ATP dependence of decision-making capacity in genetic regulatory networks
Authors: Kumar Rajneesh , Johnston Iain G. 
Published: November 2023

AbstractCellular decision-making is fundamental to life, from developmental biology to environmental responses and antimicrobial resistance. Many regulatory processes that drive cellular decisions rely on gene expression, which requires energy in the form of ATP. As even genetically identical cells can have dramatically different ATP levels, bioenergetic status can be an important source of variability in cellular decision-making. Existing studies have investigated this energy dependence but often use coarse-grained modelling approaches (which are not always readily connected to the underlying molecular processes of gene regulation). Here we use a fine-grained mathematical model of gene expression in a two-gene decision-making regulatory network to explore cellular decision-making capacity as energy availability varies. We simulate both a deterministic model, to explore the emergence of different cell fate attractors as ATP levels vary, and a stochastic case to explore how ATP influences the noisy dynamics of stochastic cell decision-making. Higher energy levels typically support increased decision-making capacity (higher numbers of, and more separated, cell states that can be selected), and the fine-grained modelling reveals some differences in behaviour from previous coarse-grained modelling approaches.
Contrasting segregation patterns among endogenous retroviruses across the koala population
Authors: Lillie Mette , Pettersson Mats , Jern Patric 
Published: November 2023

AbstractKoalas (Phascolarctos cinereus) are subject to retroviral infections by the koala retrovirus (KoRV), resulting in accumulation of heritable endogenous KoRV in the koala germline. Like other vertebrates, koalas have experienced a history of retroviral epidemics leaving marks as endogenous retroviruses (ERVs) in their genomes; another recently identified ERV lineage, namedphaCin-β, shows a pattern of recent, possibly current, activity with high insertional polymorphism in the koala population that predates the establishment of endogenous KoRV. We investigate geographic patterns of retrovirus activity, focusing on three distinct ERV lineages of increasing estimated ages from KoRV tophaCin-βand tophaCin-β-like, using a whole-genome sequencing dataset of 430 koalas produced by the Koala Genome Survey. We find thousands of ERV loci across the koala population and identify contrasting patterns of polymorphism. In the youngest established ERV-lineage (KoRV), we identify thousands of integrations among northern individuals. In thephaCin-βERV lineage, which is slightly older yet with overlapping time of activity with KoRV, we observe hundreds of integrations in northern individuals. In southern koalas, however,phaCin-βloci are found at higher frequencies possibly reflecting a bottleneck effect. Overall, the findings suggest high ERV burden in koalas that represent historic retrovirus-host interactions. Importantly, the ERV catalogue supplies improved markers for population conservation genetics of this endangered species.
Autapses enable temporal pattern recognition in spiking neural networks
Authors: Yaqoob Muhammad , Steuber Volker , Wróbel Borys 
Published: November 2023

ABSTRACTMost sensory stimuli are temporal in structure. How action potentials encode the information incoming from sensory stimuli remains one of the central research questions in neuroscience. Although there is evidence that the precise timing of spikes represents information in spiking neuronal networks, information processing in spiking networks is still not fully understood. One feasible way to understand the working mechanism of a spiking network is to associate the structural connectivity of the network with the corresponding functional behaviour. This work demonstrates the structure-function mapping of spiking networks evolved (or handcrafted) for a temporal pattern recognition task. The task is to recognise a specific order of the input signals so that theOut putneurone of the network spikes only for the correct placement and remains silent for all others. The minimal networks obtained for this task revealed the twofold importance of autapses in recognition; first, autapses simplify the switching among different network states. Second, autapses enable a network to maintain a network state, a form of memory. To show that the recognition task is accomplished by transitions between network states, we map the network states of a functional spiking neural network (SNN) onto the states of a finite-state transducer (FST, a formal model of computation that generates output symbols, here: spikes or no spikes at specific times, in response to input, here: a series of input signals). Finally, based on our understanding, we define rules for constructing the topology of a network handcrafted for recognising a subsequence of signals (pattern) in a particular order. The analysis of minimal networks recognising patterns of different lengths (two to six) revealed a positive correlation between the pattern length and the number of autaptic connections in the network. Furthermore, in agreement with the behaviour of neurones in the network, we were able to associate specific functional roles of ‘locking,’ ‘switching,’ and ‘accepting’ to neurones.
oncotree2vec – A method for embedding and clustering of tumor phylogenetic trees
Authors: Baciu-Drăgan Monica-Andreea , Beerenwinkel Niko 
Published: November 2023

AbstractUnderstanding the genomic heterogeneity of tumors is an important task in computational oncology, especially in the context of finding personalized treatments based on the genetic profile of each patient’s tumor. Tumor clustering that takes into account the temporal order of genetic events, as represented by tumor mutation trees, is a powerful approach for grouping together patients with genetically and evolutionarily similar tumors and can provide insights into discovering tumor sub-types, for more accurate clinical diagnosis and prognosis. Here, we propose oncotree2vec, a method for clustering tumor mutation trees by learning vector representations of mutation trees that capture the different relationships between subclones in an unsupervised manner. Learning low-dimensional tree embeddings facilitates the visualization of relations between trees in large cohorts and can be used for downstream analyses, such as deep learning approaches for single-cell multi-omics data integration. We assessed the performance and the usefulness of our method in three simulation studies, and on two real datasets: a cohort of 43 trees from six cancer types with different branching patterns corresponding to different modes of spatial tumor evolution and a cohort of 123 AML mutation trees.
Live-cell imaging reveals the trade-off between target search flexibility and efficiency for Cas9 and Cas12a
Authors: Olivi Lorenzo , Bagchus Cleo , Pool Victor , Bekkering Ezra , Speckner Konstantin , Wu Wen , Martens Koen , van der Oost John , Staals Raymond , Hohlbein Johannes 
Published: November 2023

AbstractCRISPR-Cas systems have widely been adopted as genome editing tools, with two frequently employed Cas nucleases beingSpyCas9 andLbCas12a. Although both nucleases use RNA guides to find and cleave target DNA sites, the two enzymes differ in terms of protospacer-adjacent motif (PAM) requirements, guide architecture and cleavage mechanism. In the last years, rational engineering led to the creation of PAM-relaxed variantsSpRYCas9 and impLbCas12a to broaden the targetable DNA space. By employing their catalytically inactive variants (dCas9/dCas12a), we quantified how the protein-specific characteristics impact the target search process. To allow quantification, we fused these nucleases to the photoactivatable fluorescent protein PAmCherry2.1 and performed single-particle tracking in cells ofEscherichia coli. From our tracking analysis, we derived kinetic parameters for each nuclease with a non-targeting RNA guide, strongly suggesting that interrogation of DNA byLbdCas12a variants proceeds faster than that ofSpydCas9. In the presence of a targeting RNA guide, both simulations and imaging of cells confirmed thatLbdCas12a variants are faster and more efficient in finding a specific target site. Our work demonstrates the trade-off of relaxing PAM requirements inSpydCas9 andLbdCas12a using a powerful framework, which can be applied to other nucleases to quantify their DNA target search.
Presaccadic attention enhances and reshapes the Contrast Sensitivity Function differentially around the visual field
Authors: Kwak Y. , Zhao Y. , Lu Z-L. , Hanning N.M. , Carrasco M. 
Published: November 2023

AbstractContrast sensitivity, which constrains our vision, decreases from fovea to periphery, from the horizontal to the vertical meridian, and from the lower vertical to the upper vertical meridian. The Contrast Sensitivity Function (CSF) depicts how contrast sensitivity varies with spatial frequency (SF). To overcome these visual constraints, we constantly make saccadic eye movements to foveate on relevant objects in the scene. Already before saccade onset,presaccadic attentionshifts to the saccade target and enhances perception. However, it is unknown whether and how it modulates the interplay between contrast sensitivity and SF, and if this effect varies around polar angle locations. Contrast sensitivity enhancement may result from a horizontal or vertical shift of the CSF, increase in bandwidth, or any combination. Here, we investigated these possibilities by extracting key attributes of the CSF using Hierarchical Bayesian Modeling, which enables precise estimation of the CSF parameters by decomposing the variability of the dataset into multiple levels. The results reveal that presaccadic attention (1) enhances contrast sensitivity across SF, (2) increases the most preferred and the highest discernable SF, and (3) narrows the bandwidth. Therefore, presaccadic attention bridges the gap between presaccadic and post-saccadic input by increasing visibility at the saccade target. Counterintuitively, the presaccadic enhancement in contrast sensitivity was more pronounced where perception is better –along the horizontal than the vertical meridian– exacerbating polar angle asymmetries. Our results call for an investigation of the differential neural modulations underlying presaccadic perceptual changes for different saccade directions.Significance statementThe contrast sensitivity function (CSF) describes how our ability to perceive contrast depends on spatial frequency. Contrast sensitivity is highest at the fovea and decreases in the periphery, especially at vertical locations. We thus make saccadic eye movements to view objects in detail. Already before moving our eyes,presaccadic attentionenhances perception at the target location. But how does it influence the interplay between spatial frequency and contrast sensitivity, and does its effect vary around the visual field? Using Hierarchical Bayesian Modeling, we show that presaccadic attention enhances and reshapes the CSF to prepare the periphery for upcoming fixation. Counterintuitively, it does so more at horizontal locations where vision is stronger, suggesting smoother perception across horizontal than vertical eye movements.
Post-stroke rapamycin treatment improves post-recanalization cerebral blood flow and outcome in rats
Authors: Schneider Anna M , Couch Yvonne , Larkin James , Buchan Alastair M , Beard Daniel J 
Published: November 2023

AbstractIschaemic stroke treatment is limited to recanalizing the occluded vessel, while there is no approved adjunctive cerebroprotective therapy to protect either the neurons and parenchyma or the neurovascular unit. Pharmacological inhibition of mammalian target of rapamycin-1 (mTORC1) with rapamycin has shown promise in reducing infarct volume and improving functional outcomes. However, previous studies that investigated the effects of rapamycin on the vasculature and cerebral blood flow (CBF), administered rapamycin prior to or during stroke induction, thus limiting the potential for clinical translation. Therefore we investigated whether rapamycin maintains its cerebrovascular protective effect when administered immediately after recanalization following 90 minutes stroke in Wistar rats. We show, that rapamycin significantly improved post-recanalization cerebral blood flow (CBF), suggesting a beneficial neurovascular effect of rapamycin. Rats treated with rapamycin had smaller infarct volumes and improved functional outcomes compared to the control animals at three days post-stroke. The mechanisms of the overall positive effects seen in this study are likely due to rapamycin’s hyperacute effects on the neurovasculature, as shown with increased CBF during this phase. This paper shows that rapamycin treatment is a promising adjunct cerebroprotective therapy option for ischemic stroke.
Natural killer cell cytotoxicity shapes the clonal evolution of B cell leukaemia
Authors: Buri Michelle C. , Shoeb Mohamed R. , Bykov Aleksandr , Repiscak Peter , Baik Hayeon , Dupanovic Alma , David Faith O. , Kovacic Boris , Hall-Glenn Faith , Dopa Sara , Urbanus Jos , Sippl Lisa , Stofner Susanne , Emminger Dominik , Cosgrove Jason , Schinnerl Dagmar , Poetsch Anna R. , Lehner Manfred , Koenig Xaver , Perié Leïla , Schumacher Ton N. , Gotthardt Dagmar , Halbritter Florian , Putz Eva M. 
Published: November 2023

AbstractThe term cancer immunoediting describes the dual role by which the immune system can suppress and promote tumour growth and is divided into three phases: elimination, equilibrium and escape. The role of NK cells has mainly been attributed to the elimination phase. Here we show that NK cells play a role in all three phases of cancer immunoediting. Extended co-culturing of DNA barcoded mouse BCR/ABLp185+B acute lymphoblastic leukaemia (B-ALL) cells with NK cells allowed for a quantitative measure of NK cell-mediated immunoediting. Whereas most tumour cell clones were efficiently eliminated by NK cells, a certain fraction of tumour cells harboured an intrinsic primary resistance. Furthermore, DNA barcoding revealed tumour cell clones with secondary resistance, which stochastically acquired resistance to NK cells. NK cell cytotoxicity put a selective pressure on B-ALL cells, which led to an outgrowth of primary and secondary resistant tumour cell clones, which were characterised by an IFN-γ signature. Besides well-known regulators of immune evasion, our analysis of NK cell resistant tumour cells revealed the upregulation of genes, includingLy6a, which we found to promote NK cell resistance in leukaemic cells. Translation of our findings to the human system showed that high expression ofLY6Eon tumour cells impaired the physical interaction with NK cells and led to worse prognosis in leukaemia patients. Our results demonstrate that tumour cells are actively edited by NK cells during the equilibrium phase and use different avenues to escape NK cell-mediated eradication.
Truly the best of both worlds: merging lineage-specific and universal baiting kits to maximize phylogenomic inference
Authors: Fonseca Luiz Henrique M. , Asselman Pieter , Goodrich Katherine R. , Nge Francis J. , Soulé Vincent , Mercier Kathryn , Couvreur Thomas L. P. , Chatrou Lars W. 
Published: November 2023

ABSTRACTPREMISEThe development of RNA baiting kits for reduced representation approaches of genomic sequencing is popularized, with universal and clade-specific kits for flowering plants available. Here, we provided an updated version of the Annonaceae bait kit targeting 799 low copy genes, known as Annonaceae799.METHODSThis new version of the kit combines the original 469 genes from the previous version of the Annonaceae kit with 334 genes from the universal Angiosperms353 kit. We also compared the results obtained using the Original Angiosperms353 kit with our custom approach. Parsimony informative sites (pis) were evaluated for all genes and combined matrices.RESULTSThe new version of the kit has extremely high rates of gene recovery. On average, 796 genes were recovered per sample, and 777.5 genes recovered with at least 50% of their size. Off-target reads were also obtained. Evaluating size, the proportion of on- and off-target regions, and the number of pis, the genes from the Angiosperms353 usually outperform the genes from the original Annonaceae bait kit.DISCUSSIONThe results obtained show that the new sequences from the Angiosperms353 aggregate variable and putative relevant bases for future studies on species-level phylogenomics, and within species studies. The merging of kits also creates a link between projects and makes available new genes for phylogenetic and populational studies.
Enhanced efficiency in the bilingual brain through the inter-hemispheric cortico-cerebellar pathway in early second language acquisition
Authors: Gracia-Tabuenca Zeus , Barbeau Elise B. , Kousaie Shanna , Chen Jen-Kai , Chai Xiaoqian , Klein Denise 
Published: November 2023

AbstractThe bilingual experience has a profound impact on the functional and structural organization of the brain, but it is not yet well known how this experience influences whole-brain functional network connectivity. We examined a well-characterized large sample (151 participants) of monolinguals and bilinguals with varied age of second language acquisition, who underwent resting-state functional magnetic brain imaging. We constructed comprehensive functional brain networks for each participant, encompassing cortical, subcortical, and cerebellar regions of interest. Whole-brain analyses revealed that bilingual individuals exhibit higher global efficiency than monolinguals, indicating enhanced functional integration in the brain. Moreover, the age at which the second language was acquired correlated with this increased efficiency, suggesting that earlier exposure to a second language has lasting positive effects on brain functional organization. Further investigation through the network-based statistics (NBS) approach indicates that this effect is primarily driven by heightened functional connectivity between association networks and the cerebellum. This work shows that early learning enhances global whole-brain efficiency and that the timing of learning of two languages has an impact on functional brain organization.Significance statementLong-term learning impacts brain organization at different spatial scales, and this may be particularly enhanced during early stages of life. Bilingualism offers a unique opportunity to test long-term learning effects in the human brain, given that exposure to a second language can occur from birth or later in life, and can be maintained over long periods of time. We found that second language acquisition in early childhood (before five years of age) enhances brain network efficiency, and that this effect goes beyond the language and cognitive control regions, in fact, the interhemispheric cortico-cerebellar circuit plays a key role. This work shows that the timing of bilingual learning experience alters the brain functional organization at the global and local levels.