Miracle-dz/UniFAR-FTUs huggingface dataset:
Multimodal mapping of neural activity and cerebral blood flow reveals long-lasting neurovascular dissociations after small-scale strokes

Neurovascular coupling, the close spatial and temporal relationship between neural activity and hemodynamics, is disrupted in pathological brain states. To understand the altered neurovascular relationship in brain disorders, longitudinal, simultaneous mapping of neural activity and hemodynamics is critical yet challenging to achieve. Here, we employ a multimodal neural platform in a mouse model of stroke and realize long-term, spatially-resolved tracking of intracortical neural activity and cerebral blood flow in the same brain regions. We observe a pronounced neurovascular dissociation that occurs immediately after small-scale strokes, becomes the most severe a few days after, lasts into chronic periods, and varies with the level of ischemia. Neuronal deficits extend spatiotemporally whereas restoration of cerebral blood flow occurs sooner and reaches a higher relative value. Our findings reveal the neurovascular impact of mini-strokes and inform the limitation of neuroimaging techniques that infer neural activity from hemodynamic responses.
Testing the pathogenic potential of Cryphonectria parasitica and related species on three common European Fagaceae

Invasions by non-native pathogens represent a major threat to managed and natural ecosystems worldwide. Although necessary for adopting preventive strategies, the identification of invasive species before they are introduced is particularly difficult. Indeed, most pathogenic species that have become established in the last decades were first described only after they became invasive. To prevent further biological invasions, not only the early identification of potential new invasive plant pathogens is crucial, but also the assessment of their potential host range. In this study, we determined the pathogenicity and the saprotrophic ability of three Cryphonectria species towards three potential hosts in the family Fagaceae. For this, seedlings and dormant stems of European chestnut (Castanea sativa), pedunculate oak (Quercus robur) and European beech (Fagus sylvatica) were inoculated with different genotypes of C. parasitica (Asian species, invasive in Europe), C. naterciae (European species), and C. japonica (Asian species, not present in Europe). Lesion growth was measured and mortality assessed for four months. The highest damage was caused by C. parasitica on European chestnut, while C. japonica and C. naterciae induced significantly smaller lesions on this host species. All three Cryphonectria species did not grow saprophytically on F. sylvatica and Q. robur, but successfully colonized dormant stems of C. sativa. In the context of biological invasions, our study shows that the Asian C. japonica most likely represents a much less severe threat than C. parasitica for the tested European host species. Nonetheless, the ability of C. naterciae and C. japonica to saprotrophically colonize fresh chestnut wood may suggest that they could become established in chestnut forests and eventually infect weakened chestnut trees or other hosts not tested in this study.
Dispersal ability of Neophilaenus campestris, a vector of Xylella fastidiosa, from olive groves to over-summering hosts

Neophilaenus campestris is one of the recently identified spittlebugs (Hemiptera: Cercopoidea) able to transmit Xylella fastidiosa to olive trees. Considering its vector ability and the wide distribution of this species in Spain, N. campestris should be considered a serious threat to key crops that are vital for Spanish agriculture such as olive, almonds and grapevines. Migration and dispersal abilities of insect vectors have profound implications in the spread of vector-borne diseases. Thus, knowledge on the dispersal ability of N. campestris is essential to model, predict and limit the spread of the diseases caused by X. fastidiosa. A mark-release-recapture technique was developed to track between-field movements of N. campestris during its late spring migration from the ground cover grasses within olive groves to sheltered areas dominated by pine trees. An indoor assay showed that the fluorescent dust used for marking did not affect the survival nor the flying ability of N. campestris. Spittlebug adults captured in olive groves at Los Santos de la Humosa (Madrid, Spain) during late spring, 2019 were dusted with four fluorescent colours and released in four different locations. Six recapture samplings were performed 23 to 42 days after release in 12 different sites located within a maximum distance of 2.8 km from the release point. Results indicated that N. campestris was able to disperse a maximum distance of 2473 m in 35 days from the olive groves to areas dominated by pine trees. Furthermore, our flight mill studies also showed that N. campestris was able to fly long distances, reaching almost 1.4 km in an 82 minutes’ single flight. Moreover, we carried out a survey of directional movement of potential vectors of X. fastidiosa in an olive grove located in Villa del Prado (Madrid). We used yellow sticky bands, a Malaise trap and a vertical yellow sticky net to assess the directional movement from olive groves to surrounding managed and unmanaged areas. The captures obtained in the yellow sticky bands showed that spittlebugs dispersal from the olive grove to surrounding vegetation matched with the time when the ground cover dried out. The highest number of spittlebugs was captured in the border between the olive grove and a vineyard close by. Altogether, our findings suggest that eradication measures by rooting-up X. fastidiosa-infected and non-infected trees in a radius of 100 m are of limited value because vectors are able to disperse rapidly over distances much longer than expected.
Mechanism of Dynamic Binding of Replication Protein A to ssDNA

Replication protein A (RPA) serves as hub protein inside eukaryotic cells, where it coordinates crucial DNA metabolic processes and activates the DNA-damage response system. A characteristic feature of its action is to associate with ssDNA intermediates before handing over them to downstream proteins. The length of ssDNA intermediates differs for different pathways. This means RPA must have mechanisms for selective processing of ssDNA intermediates based on their length, the knowledge of which is fundamental to elucidate when and how DNA repair and replication processes are symphonized. By employing extensive molecular simulations, we investigated the mechanism of binding of RPA to ssDNA of different lengths. We show that the binding involves dynamic equilibrium with a stable intermediate, the population of which increases with the length of ssDNA. The vital underlying factors are decoded through collective variable principal component analysis. It suggests a differently orchestrated set of interactions that define the action of RPA based on the sizes of ssDNA intermediates. We further estimated the association kinetics and probed the diffusion mechanism of RPA to ssDNA. RPA diffuses on short ssDNA through progressive ‘bulge’ formation. With long ssDNA, we observed a conformational change in ssDNA coupled with its binding to RPA in a cooperative fashion. Our analysis explains how the ‘short-lived,’ long ssDNA intermediates are processed quickly in vivo. The study thus reveals the molecular basis of several recent experimental observations related to RPA binding to ssDNA and provides novel insights into the RPA functioning in DNA repair and replication. Significance Statement Despite ssDNA be the common intermediate to all pathways involving RPA, how does the latter function differently in the DNA processing events such as DNA repair, replication, and recombination just based on the length of ssDNA intermediates remains unknown. The major hindrance is the difficulty in capturing the transient interactions between the molecules. Even attempts to crystallize RPA complexes with 32nt and 62nt ssDNA have yielded a resolved structure of only 25nt ssDNA wrapped with RPA. Here, we used a state-of-the-art coarse-grained protein-ssDNA model to unravel the detailed mechanism of binding of RPA to ssDNA. Our study illustrates the molecular origin of variations in RPA action during various DNA processing events depending on the length of ssDNA intermediates.
Adaptive evolution of DNA methylation reshaped gene regulation in maize

ABSTRACT DNA methylation is a ubiquitous chromatin feature – in maize, more than 25% of cytosines in the genome are methylated. Recently, major progress has been made in describing the molecular mechanisms driving methylation, yet variation and evolution of the methylation landscape during maize domestication remain largely unknown. Here we leveraged whole-genome sequencing (WGS) and whole-genome bisulfite sequencing (WGBS) on populations of modern maize, landrace, and teosinte (Zea mays ssp. parviglumis) to investigate the adaptive and phenotypic consequences of methylation variations in maize. By using a novel estimation approach, we inferred the methylome site frequency spectrum (mSFS) to estimate forward and backward methylation mutation rates and selection coefficients. We only found weak evidence for direct selections on methylations in any context, but thousands of differentially methylated regions (DMRs) were identified in population-wide that are correlated with recent selections. Further investigation revealed that DMRs are enriched in 5’ untranslated regions, and that maize hypomethylated DMRs likely helped rewire distal gene regulation. For two trait-associated DMRs, vgt1-DMR and tb1-DMR, our HiChIP data indicated that the interactive loops between DMRs and respective downstream genes were present in B73, a modern maize line, but absent in teosinte. And functional analyses suggested that these DMRs likely served as cis-acting elements that modulated gene regulation after domestication. Our results enable a better understanding of the evolutionary forces acting on patterns of DNA methylation and suggest a role of methylation variation in adaptive evolution.
Anatomy and activity patterns in a multifunctional motor neuron and its surrounding circuits

Dorsal Excitor motor neuron DE-3 in the medicinal leech plays three very different dynamical roles in three different behaviors. In swimming, it oscillates at a relatively rapid 2 Hz in antiphase to its Ventral Excitor counterpart (VE-4) and controls the local dorsal flexion phase of the swim rhythm. In crawling, it is active in phase with VE-4 and controls the contraction phase of the crawl rhythm. In “local bending” it operates in tight concert with its contralateral homolog as well as VE-4 to precisely deform the local body wall away from a mechanical stimulus. Without rewiring its anatomical connectivity, how can a motor neuron dynamically switch roles to play its appropriate role in various behaviors? We used voltage-sensitive dye imaging to record from DE-3 and most other neurons in the segmental ganglion of the leech during fictive versions of the three behaviors. Then we re-imaged the same ganglion using serial blockface electron microscopy and traced all of DE-3’s processes. Further, we traced back the processes of all of DE-3’s presynaptic partners to their respective somata. This allowed us to analyze the relationship between circuit anatomy and the activity patterns it sustains. We found that input synapses important for all of the behaviors were widely distributed over DE-3’s branches, yet that functional clusters were different during (fictive) swimming vs. crawling. One-sentence summary Voltage-dye imaging followed by serial blockface electron microscopy of the same ganglion reveals structure-function relationships of leech motor behaviors. Graphical abstract Approach. Several fictive behaviors were induced in the isolated nervous system of a medicinal leech while one segmental ganglion was imaged using a voltage-sensitive dye. After fixation and resin embedding, the ganglion was x-ray-imaged to verify that the geometry of somata was preserved. Finally, the neuropil was imaged at nanometer resolution with serial blockface electron microscopy and selected neurons were manually traced.
A modeling framework for adaptive lifelong learning with transfer and savings through gating in the prefrontal cortex

Significance The prefrontal cortex (PFC) enables humans’ ability to flexibly adapt to new environments and circumstances. Disruption of this ability is often a hallmark of prefrontal disease. Neural network models have provided tools to study how the PFC stores and uses information, yet the mechanisms underlying how the PFC is able to adapt and learn about new situations without disrupting preexisting knowledge remain unknown. We use a neural network architecture to show how hierarchical gating can naturally support adaptive learning while preserving memories from prior experience. Furthermore, we show how damage to our network model recapitulates disorders of the human PFC. The prefrontal cortex encodes and stores numerous, often disparate, schemas and flexibly switches between them. Recent research on artificial neural networks trained by reinforcement learning has made it possible to model fundamental processes underlying schema encoding and storage. Yet how the brain is able to create new schemas while preserving and utilizing old schemas remains unclear. Here we propose a simple neural network framework that incorporates hierarchical gating to model the prefrontal cortex’s ability to flexibly encode and use multiple disparate schemas. We show how gating naturally leads to transfer learning and robust memory savings. We then show how neuropsychological impairments observed in patients with prefrontal damage are mimicked by lesions of our network. Our architecture, which we call DynaMoE, provides a fundamental framework for how the prefrontal cortex may handle the abundance of schemas necessary to navigate the real world.
How genetic disease risks can be misestimated across global populations

Background Accurate assessment of health disparities requires unbiased knowledge of genetic risks in different populations. Unfortunately, most genome-wide association studies use genotyping arrays and European samples. Here, we integrate whole genome sequence data from global populations, results from thousands of GWAS, and extensive computer simulations to identify how genetic disease risks can be misestimated. Results In contrast to null expectations, we find that risk allele frequencies at known disease loci are significantly different for African populations compared to other continents. Strikingly, ancestral risk alleles are found at 9.51% higher frequency in Africa and derived risk alleles are found at 5.40% lower frequency in Africa. By simulating GWAS with different study populations, we find that non-African cohorts yield disease associations that have biased allele frequencies and that African cohorts yield disease associations that are relatively free of bias. We also find empirical evidence that genotyping arrays and SNP ascertainment bias contribute to continental differences in risk allele frequencies. Because of these causes, polygenic risk scores can be grossly misestimated for individuals of African descent. Importantly, continental differences in risk allele frequencies are only moderately reduced if GWAS use whole genome sequences and hundreds of thousands of cases and controls. Finally, comparisons between uncorrected and corrected genetic risk scores reveal the benefits of considering whether risk alleles are ancestral or derived. Conclusions Our results imply that caution must be taken when extrapolating GWAS results from one population to predict disease risks in another population.
Application of the radial distribution function for quantitative analysis of neuropil microstructure in stratum radiatum of CA1 region in hippocampus

Various structures in the brain contain many important clues to the brain? s development and function. Among these, the microscopic organization of neural tissue is of particular interest since such organization has direct potential to affect the formation of local synaptic connectivity between axons and dendrites, serving as an important factor affecting the brain? s development. While the organization of the brain at large and intermediate scales had been well studied, the organization of neural tissue at micrometer scales remains largely unknown. In particular, at present it is not known what specific structures exist in neuropil at micrometer scales, what effect such structures have on formation of synaptic connectivity, and what processes shape the micrometer-scale organization of neuropil. In this work, we present an analysis of recent electron microscopy reconstructions of blocks of neuropil tissue from rat s. radiatum of hippocampal CA1 to provide insights into these questions. We propose a new statistical method for systematically analyzing the small-scale organization of neuropil based on an adaptation of the approach of radial distribution functions from statistical physics. Our results show that the micrometer-scale organization of hippocampal CA1 neuropil can be viewed as a disordered arrangement of axonal and dendritic processes without significant small-scale positional coordinations. We observe several deviations from this picture in the distributions of glia and dendritic spines. Finally, we study the relationship between local synaptic connectivity and the small-scale organization of neuropil.
An Unsupervised Deep Neural Network for Image Completion Resembles Early Visual Cortex fMRI Activity Patterns for Occluded Scenes

The promise of artificial intelligence in understanding biological vision relies on the comparison of computational models with brain data that captures functional principles of visual information processing. Deep neural networks (DNN) have successfully matched the transformations in hierarchical processing occurring along the brain’s feedforward visual pathway extending into ventral temporal cortex. However, we are still to learn if DNNs can successfully describe feedback processes in early visual cortex. Here, we investigated similarities between human early visual cortex and a DNN with encoder/decoder architecture, trained in an unsupervised fashion to fill occlusions and reconstruct an unseen image. Using Representational Similarity Analysis (RSA), we compared 3T fMRI data from a non-stimulated patch of early visual cortex in human participants viewing partially occluded images, with the different DNN layer activations from the same images. Results show that our network outperforms a classical supervised network (VGG16) in terms of similarity to fMRI data, meaning that improved neural network models of vision need to incorporate architectures capturing cortical feedback processing. We also find that DNN decoder pathway activations are more similar to brain processing compared to encoder activations, suggesting an integration of mid- and low/middle-level features in early visual cortex. Challenging an AI model and the human brain to solve the same task offers a valuable way to compare DNNs with brain data and helps to constrain our understanding of information processing such as neuronal predictive coding.
BK polyomavirus evades innate immune sensing by disrupting the mitochondrial network and membrane potential and by promoting mitophagy

Immune escape contributes to viral persistence, yet little is known about human polyomaviruses. BK-polyomavirus (BKPyV) asymptomatically infects 90% of the human population, but causes early allograft failure in 10% of kidney transplants. Despite inducing potent virus-specific T-cells and neutralizing antibodies, BKPyV persists in the kidneys and regularly escapes from immune control as indicated by urinary shedding in immunocompetent individuals. Here, we report that BKPyV disrupts the mitochondrial network and its membrane potential when expressing the 66aa-long agnoprotein during late replication. Agnoprotein impairs nuclear IRF3-translocation, interferon-β expression, and promotes p62-mitophagy in vitro and in kidney transplant biopsies. Agnoprotein-mutant viruses unable to disrupt mitochondria show reduced replication, which can be rescued by type-I-interferon-blockade, TBK1-inhibition, or CoCl2 treatment. Agnoprotein is necessary and sufficient, using its amino-terminal and central domain for mitochondrial targeting and disruption, respectively. JCPyV- and SV40-infection similarly disrupt the mitochondrial network indicating a conserved mechanism facilitating polyomavirus persistence and post-transplant disease.
Novel bir’s-foot trefoil RNA viruses provide insights into a clade of legume associated enamoviruses

Bird’s-foot trefoil (Lotus corniculatus) is a nutritious forage crop, employed for livestock foraging around the world. Here, we report the identification and characterization of two novel viruses associated with bird’s-foot trefoil. Virus sequences with affinity to enamoviruses (ssRNA (+); Luteoviridae; Enamovirus) and nucleorhabdoviruses (ssRNA (-); Rhabdoviridae; Nucleorhabdovirus) were detected in L. corniculatus transcriptome data. The tentatively named birds-foot trefoil associated virus 1 (BFTV-1) genome organization is characterized by 13,626 nt long negative-sense ssRNA. BFTV-1 presents in its antigenome orientation six predicted gene products in the canonical order 3′-N-P-P3-M-G-L-5′. The proposed birds-foot trefoil associated virus 2 (BFTV-2) 5,736 nt virus sequence presents a typical 5′-PO-P1-2-IGS-P3-P5-3′ enamovirus genome structure. Phylogenetic analysis suggests that BFTV-1 is closely related to Datura yellow vein nucleorhabdovirus, and that BFTV-2 clusters into a monophyletic cluster of legumes-associated enamoviruses. This sub-clade of highly related and co-divergent legume associated viruses provides insights on the evolutionary history of the enamoviruses. The bioinformatic reanalysis of SRA libraries deposited in the NCBI database constitutes an emerging approach to the discovery of novel plant viruses which should be important for both quarantine purposes and disease management.