title: STORM: spectral sparsification helps restore the spatial structure at single-cell resolution

abstract: Single-cell RNA sequencing thoroughly quantifies the individual cell transcriptomes but renounces the spatial structure. Conversely, recently emerged spatial transcriptomics technologies capture the cellular spatial structure but skimp cell or gene resolutions. Cell-cell affinity estimated by ligand-receptor interactions can partially reconstruct the quasi-structure of cells but falsely include the pseudo affinities between distant or indirectly interacting cells. Here, we develop a software package, STORM, to reconstruct the single-cell resolution quasi-structure from the spatial transcriptome with diminished pseudo affinities. STORM first curates the representative single-cell profiles for each spatial spot from a candidate library, then reduces the pseudo affinities in the intercellular affinity matrix by partial correlation, spectral graph sparsification, and spatial coordinates refinement. STORM embeds the estimated interactions into a low-dimensional space with the cross-entropy objective to restore the intercellular quasi-structures, which facilitates the discovery of dominant ligand-receptor pairs between neighboring cells at single-cell resolution. STORM reconstructed structures achieved shape Pearson correlations ranging from 0.91 to 0.97 on the mouse hippocampus and human organ tumor microenvironment datasets. Furthermore, STORM can solely de novo reconstruct the quasi-structures at single-cell resolution, i.e., reaching the cell-type proximity correlations 0.68 and 0.89 between reconstructed and immunohistochemistry-informed spatial structures on a human developing heart dataset and a tumor microenvironment dataset, respectively.


title: LmTag: functional-enrichment and imputation-aware tag SNP selection for population-specific genotyping arrays

abstract: Despite the rapid development of sequencing technology, single-nucleotide polymorphism (SNP) array is still the most cost-effective genotyping solutions for large-scale genomic research and applications. Recent years have witnessed the rapid development of numerous genotyping platforms of different sizes and designs, but population-specific platforms are still lacking, especially for those in developing countries. We aim to develop methods to design SNP arrays for thse countries, so the arrays should be cost-effective (small size), yet can still generate key information needed to associate genotypes with traits. A key design principle for most current platforms is to improve genome-wide imputation so that more SNPs (imputed tag SNPs) not included in the array can be predicted. However, current tag SNP selection methods mostly focus on imputation accuracy and coverage, but not the functional content of the measured and imputed SNPs. It is those functional SNPs that are most likely associated to traits. Here, we propose LmTag, a novel method for tag SNP selection that not only improves imputation performance but also prioritizes highly functional SNP markers. We apply LmTag on a wide range of populations using both public and in-house whole genome sequencing databases. Our results showed that LmTag improved both functional marker prioritization and genome-wide imputation accuracy compared to existing methods. This novel approach could contribute to the next generation genotyping arrays that provide excellent imputation capability as well as facilitate array-based functional genetic studies. Such arrays are particularly suitable for under-represented populations in developing countries or non-model species, where little genomics data are available while investment in genome sequencing or high-density SNP arrays is limited.

category: bioinformatics


title: What stabilizes pre-folded structures in the intrinsically disordered α-helical binding motifs?

abstract: Many examples are known of regions of intrinsically disordered proteins (IDPs) that fold into -helices upon binding their globular protein targets. In their unbound state these regions possess a small amount of residual helicity, referred to as pre-folded structure, which has been studied on case by case basis. In order to investigate what determines these pre-folded structures we compiled a database of peptides that fold-upon-binding, and experimentally characterized their helicity in the unbound and target-bound state. These regions are more hydrophobic and lack proline residues compared to IDPs in general. On average they possess about 17% helicity in the pre-folded state and gain 40% of helicity upon target binding. We observe that the locations of pre-folded helical regions strongly overlap with those in the targetbound IDPs. To understand this correlation, we analyzed per-residue energetic contributions stabilizing helical structure and found that target-interacting IDP have higher helix propensity. Notably, leucine is the most common residue involved in IDP-target interactions and, due to its high helix propensity, it strongly stabilizes pre-folded helical structures. For many IDP binding motifs, particularly those enriched in leucine, we observe that they not only mediate target-interactions but also confer stability to the pre-folded structure. Collectively, this shows that the formation of pre-folded helical elements is coupled to the IDP-target interactions, explaining why such elements are a common feature of -helical binding motifs. Moreover, it probably explains the preference for leucine among IDP-target hotspots, even though this residue is underrepresented among hotspots in the interfaces between globular proteins.


title: TissUUmaps 3: Interactive visualization and quality assessment of large-scale spatial omics data

abstract: TissUUmaps is a browser-based tool for GPU-accelerated visualization and interactive exploration of 107+ datapoints overlaying tissue samples. Users can visualize markers and regions, explore spatial statistics and quantitative analyses of tissue morphology, and assess the quality of decoding in situ transcriptomics data. TissUUmaps provides instant multi-resolution image viewing, can be customized, shared, and also integrated in Jupyter Notebooks. We envision TissUUmaps to contribute to broader dissemination and flexible sharing of large-scale spatial omics data.


title: Differential cellular stiffness contributes to tissue elongation on an expanding surface

abstract: Pattern formation and morphogenesis of cell populations is essential for successful embryogenesis. Steinberg proposed the differential adhesion hypothesis (DAH), and differences in cell-cell adhesion and interfacial tension have proven to be critical for cell sorting. Standard theoretical models such as the vertex model consider not only cell-cell adhesion/tension but also area elasticity of apical cell surfaces and viscous friction forces. However, the potential contributions of the latter two parameters to pattern formation and morphogenesis remain to be determined. In this theoretical study, we analyzed the effect of both area elasticity and the coefficient of friction on pattern formation and morphogenesis. We assumed the presence of two cell populations, one population of which is surrounded by the other. Both populations were placed on the surface of a uniformly expanding environment analogous to growing embryos, in which friction forces are exerted between cell populations and their expanding environment. When the area elasticity or friction coefficient in the cell cluster was increased relative to that of the surrounding cell population, the cell cluster was elongated. In comparison with experimental observations, elongation of the notochord in mice is consistent with the hypothesis based on the difference in area elasticity but not the difference in friction coefficient. Because area elasticity is an index of cellular stiffness, we propose that differential cellular stiffness may contribute to tissue elongation within an expanding environment.

category: biophysics


title: INFLAMMATORY BOWEL DISEASE INDUCES α-SYNUCLEIN AGGREGATION IN GUT AND BRAIN

abstract: According to Braaks hypothesis, it is plausible that Parkinso[n]s disease (PD) starts in the enteric nervous system (ENS) to spread the brain via the vagus nerve. Thus, we were wondering whether human inflammatory bowel diseases (IBD) can progress with appearance of pathogenic -synuclein (-syn) in the gastrointestinal tract and midbrain dopaminergic neurons. Analysis of human gastrointestinal tract sections from IBD patients demonstrated the presence of pathogenic phosphorylated -syn in both myenteric (Auerbachs) and submucosal (Meissners) plexuses. Remarkably, PD subjects exhibit -syn pathology in identical gastrointestinal locations. Analysis of human midbrain sections from IBD subjects revealed a clear displacement of neuromelanin in some nigral neurons from the ventral mesencephalon, which were inherently associated with presence of -syn aggregates reminiscent of pale bodies. We also used different dextran sodium sulfate (DSS)-based rat models of gut inflammation (subchronic and chronic) to study the appearance of phosphorylated -syn inclusions in both Auerbachs and Meissners plexuses (gut), and in dopaminergic neuritic processes (brain) along with degeneration of nigral dopaminergic neurons, which are considered classical hallmarks of PD. Vagotomized DSS-treated animals exhibited pathological -syn in the gut but failed to show dopaminergic cells degeneration and -syn aggregation in the ventral mesencephalon. Taken together, these results strongly suggest that Braaks hypothesis is plausible.

category: neuroscience


title: Nucleoside reverse transcriptase inhibitors are the major class of HIV antiretroviral therapeutics that induce neuropathic pain in Mice

abstract: AO_SCPLOWBSTRACTC_SCPLOWThe development of combination antiretroviral therapy (cART) has transformed human immunodeficiency virus (HIV) infection from a lethal diagnosis into a chronic disease, and people living with HIV on cART can experience an almost normal life expectancy. However, these individuals often develop various complications that lead to decreased quality of life, one of the most significant of which is neuropathic pain and development of painful peripheral sensory neuropathy (PSN). Critically, although cART is thought to induce pain pathogenesis, the relative contribution of different classes of antiretrovirals has not been systematically investigated. In this study, we measured development of pathological pain and peripheral neuropathy in mice orally treated with distinct antiretrovirals at their translational dosages. Our results show that only nucleoside reverse transcriptases (NRTIs), but not other types of antiretrovirals, such as proteinase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, and CCR5 antagonists, induce pathological pain and PSN. Thus, these findings suggest that NRTIs are the major class of antiretrovirals in cART that promote development of neuropathic pain. As NRTIs form the essential backbone of multiple different current cART regimens, it is of paramount clinical importance to better understand the underlying mechanism to facilitate design of less toxic forms of these drugs and or potential mitigation strategies.


title: Breadth of SARS-CoV-2 Neutralization and Protection Induced by a Nanoparticle Vaccine

abstract: Coronavirus vaccines that are highly effective against SARS-CoV-2 variants are needed to control the current pandemic. We previously reported a receptor-binding domain (RBD) sortase A-conjugated ferritin nanoparticle (RBD-scNP) vaccine that induced neutralizing antibodies against SARS-CoV-2 and pre-emergent sarbecoviruses and protected monkeys from SARS-CoV-2 WA-1 infection. Here, we demonstrate SARS-CoV-2 RBD-scNP immunization induces potent neutralizing antibodies in non-human primates (NHPs) against all eight SARS-CoV-2 variants tested including the Beta, Delta, and Omicron variants. The Omicron variant was neutralized by RBD-scNP-induced serum antibodies with a mean of 10.6-fold reduction of ID50 titers compared to SARS-CoV-2 D614G. Immunization with RBD-scNPs protected NHPs from SARS-CoV-2 WA-1, Beta, and Delta variant challenge, and protected mice from challenges of SARS-CoV-2 Beta variant and two other heterologous sarbecoviruses. These results demonstrate the ability of RBD-scNPs to induce broad neutralization of SARS-CoV-2 variants and to protect NHPs and mice from multiple different SARS-related viruses. Such a vaccine could provide the needed immunity to slow the spread of and reduce disease caused by SARS-CoV-2 variants such as Delta and Omicron.

category: immunology


title: Existence of blood circulating immune-cell clusters (CICs) comprising antigen-presenting cells and B cells

abstract: Cell-to-cell physical interactions are involved in almost every physiological processes in multicellular organisms. Although the dynamics of these interactions could be highly diverse and complex in many circumstances, certain cell-to-cell interactions among immune cells have been well studied due importance in understanding disease pathogenesis and immune therapy development1. Dendritic cells (DCs) and B cells are directly involved in adaptive immune response against pathogens. Interaction mechanism between these two celltypes is well-known to occur in germinal centers either indirectly via helper T (Th) cells or directly via cell contact. However, there are animal in vitro and in vivo evidence that such direct DC-to-B cell contact can occur outside germinal centers like in peripheral blood or collagen matrix and display antiviral immune-related activity2,3. Here, we provide evidence that certain types of antigen presenting cells (APCs) can form robust cell clusters with B cells and circulate in blood. From healthy human blood immune single cell RNA-seq datasets, we detected APC subpopulations (0.34{+/-}0.19% of total PBMCs) that were also enriched with well-known naive B cell markers. We visually observed DC:B doublets and multiplets ([~]0.69% of total live PBMCs) in wildtype mouse blood using flow cytometry and microscopic imaging, thus proving the existence of circulating immune-cell clusters (CICs) composed of APCs and B cells. BCR repertoire of these healthy mouse CICs were similar to circulating B cells. Noticeably, frequency of these APC:B CICs were higher COVID-19 patients than healthy donors and their B cell subtype composition (e.g. naive, plasmablast, IgM+, IgG+) varied with disease severity.


title: WAT3R: Recovery of T-Cell Receptor Variable Regions From 3' Single-Cell RNA-Sequencing

abstract:
SummaryDiversity of the T-cell receptor (TCR) repertoire is central to adaptive immunity. The TCR is composed of  and {beta} chains, encoded by the TRA and TRB genes, of which the variable regions determine antigen specificity. To generate novel biological insights into the complex functioning of immune cells, combined capture of variable regions and single-cell transcriptomes provides a compelling approach. Recent developments enable the enrichment of TRA and TRB variable regions from widely used technologies for 3-biased single-cell RNA-sequencing (scRNA-seq). However, a comprehensive computational pipeline to process TCR-enriched data from 3 scRNA-seq is not available. Here we present an analysis pipeline to process TCR variable regions enriched from 3 scRNA-seq cDNA. The tool reports TRA and TRB nucleotide and amino acid sequences linked to cell barcodes, enabling the reconstruction of T-cell clonotypes with associated transcriptomes. We demonstrate the software using peripheral blood mononuclear cells (PBMCs) from a healthy donor and detect TCR sequences in a high proportion of single T-cells. Detection of TCR sequences is negligible in non-T-cell populations, demonstrating specificity. Finally, we show that TCR clones are larger in CD8 Memory T-cells than other T-cell types, indicating an association between T-cell clonotypes and differentiation states.

Availability and implementationThe Workflow for Association of T-cell receptors from 3 single-cell RNA-seq (WAT3R), including test data, is available on GitHub (https://github.com/mainciburu/WAT3R), Docker Hub (https://hub.docker.com/r/mainciburu/wat3r), and a workflow on the Terra platform (https://app.terra.bio). The test dataset is available on GEO (accession number pending).


title: mucG, mucH,and mucI modulate production of mutanocyclin and reutericyclins in Streptococcus mutans B04Sm5

abstract:
Streptococcus mutans is considered a primary etiologic agent of dental caries, which is the most common chronic infectious disease worldwide. S. mutans B04Sm5 was recently shown to produce reutericyclins and mutanocyclin through the muc biosynthetic gene cluster, and to utilize reutericyclins to inhibit the growth of neighboring commensal Streptococci. In this study, examination of S. mutans and muc phylogeny suggested evolution of an ancestral S. mutans muc into three lineages within one S. mutans clade, and then horizontal transfer of muc to other S. mutans clades. The roles of the mucG and mucH transcriptional regulators, and the mucI transporter, were also examined. mucH was demonstrated to encode a transcriptional activator of muc. mucH deletion reduced production of mutanocyclin and reutericyclins, and eliminated the impaired growth and inhibition of neighboring Streptococci phenotypes which are associated with reutericyclin production. {Delta}mucG had increased mutanocyclin and reutericyclin production, which impaired growth and increased the ability to inhibit neighboring Streptococci. However, deletion of mucG also caused reduced expression of mucD, mucE, and mucI. Deletion of mucI reduced mutanocyclin and reutericylin production, but enhanced growth, suggesting that mucI may not transport reutericyclin as its homolog does in Limosilactobacillus reuteri. Further research is needed to determine the roles of mucG and mucI, and to identify any co-factors affecting the activity of the mucG and mucH regulators. Overall, this study provided pangenome and phylogenetic analysis that serves as a resource for S. mutans research, and began elucidation of the regulation of reutericyclins and mutanocyclin production in S. mutans.

ImportanceS. mutans must be able to outcompete neighboring organisms in its ecological niche in order to cause dental caries. S. mutans B04Sm5 inhibited the growth of neighboring commensal Streptococci through production of reutericyclins via the muc biosynthetic gene cluster. In this study, carriage of muc was examined across S. mutans, which showed that 35 of 244 RefSeq S. mutans genomes encoded muc and provided a valuable update to the S. mutans pangenome and phylogeny. The roles of the mucG and mucH transcriptional regulators, and the mucI transporter, were also examined. All 3 genes impacted production of mutanocyclin and reutericyclins, which affected the growth rates, transcriptomes, and the ability of the S. mutans strains to inhibit the growth of neighboring commensals.

category: microbiology


title: The Vibrio vulnificus stressosome is dispensable in nutrient-replete conditions.

abstract:
The stressosome is a protein complex that has been demonstrated to sense environmental stresses and mediate the stress response in several Gram-positive bacteria, through the activation of the alternative sigma factor SigB. The in vivo characterisation of this complex has never been performed in Vibrio vulnificus or any other bacteria that do not possess SigB. The elucidation of the role of the stressosome in V. vulnificus would provide elements to elaborate a functional model of the complex in a Gram-negative bacterium and identify the regulatory output in the absence of SigB. The stressosome locus is only found in 44% of Vibrio vulnificus isolates raising the question as to whether the role of stressosome is essential or modulatory in this bacterial species.

In this work, the expression of the stressosome genes was proven in nutrient-replete conditions and the co-transcription as one operonic unit of the stressosome locus and its putative downstream regulatory locus was demonstrated.

Moreover, the construction of a stressosome mutant lacking the four genes constituting the stressosome complex allowed us to examine the role of this complex in vivo. The initial established mutagenesis strategy relied on rifampicin-resistant V. vulnificus to select recombinant bacteria. Our data clearly showed that the influence of the RifR allele on stress and virulence characteristics overshadowed any effects of the stressosome. Therefore, we established an alternative mutagenesis strategy with a non-modified V. vulnificus parental strain and a DAP auxotrophic E. coli donor strain. Extensive phenotypic characterisation of the successfully-generated mutant in nutrient-replete conditions showed that the stressosome does not significantly contribute to the growth, of V. vulnificus. The stressosome did not modulate the response of V. vulnificus to the range of stresses tested - Ethanol, osmolarity, temperature, and salinity. Furthermore, the stressosome is dispensable for motility and exoenzyme production of V. vulnificus.


title: Common and lifestyle-specific traits of mycorrhiza-associated metabolite alterations in plant roots reflects strategies of root-mycorrhizal interactions

abstract: Convergent patterns in morphological and genetic traits of mycorrhizas have been well-documented and reflect common selection forces that define mycorrhizas. However, generalizable patterns of mycorrhiza-associated chemical alterations, which are immediately linked to plant and fungal strategies for successful symbiosis, have yet to be emerged. Comparing root metabolomes of phylogenetically-diverse plants inoculated by mycorrhizal fungi across two major lifestyles (arbuscular- vs. ecto-mycorrhizas), our study uncovers metabolite changes unique to each mycorrhizal lifestyle and those common across plant-mycorrhizal combinations irrespective of lifestyles. Arbuscular and ecto- mycorrhizal colonized roots accumulated different sets of carbohydrates, indicating unique carbon partitioning strategies: particularly, arbuscular mycorrhizal roots accumulated cyclic polyols inaccessible for symbionts, suggesting tighter regulation of plants in carbon partitioning. Mycorrhizas also altered specialized metabolism, featuring frequent increases of flavan-3-ols and decreases of flavanols irrespective of mycorrhizal lifestyles, suggesting tactical reconfiguration of specialized metabolites to facilitate/contain symbiosis. Our data show for the first time, to our knowledge, that part of the root metabolite alterations by mycorrhizas were relatively common across plant-mycorrhizal systems, highlighting their potentially critical regulatory and evolutionary role for successful symbiosis. This commonality appears robust to phylogenetic diversity of host plants and thus may be widespread in land plants. Our findings offer future research venues to elucidate the finer roles of these common traits of mycorrhiza-associated metabolite alterations and thus help to eventually develop a comprehensive understanding of this omnipresent plant-fungus partnership.

category: ecology


title: The genomic basis of the plant island syndrome in Darwin's giant daisies

abstract: Oceanic archipelagos comprise multiple disparate environments over small geographic areas and are isolated from other biotas. These conditions have led to some of the most spectacular adaptive radiations, which have been key to our understanding of evolution, and offer a unique chance to characterise the genomic basis underlying rapid and pronounced phenotypic changes. Repeated patterns of evolutionary change in plants on oceanic archipelagos, i.e. the plant island syndrome, include changes in leaf morphology, acquisition of perennial life-style, and change of ploidy. Here, we describe the genome of the critically endangered and Galapagos endemic Scalesia atractyloides Arnot., obtaining a chromosome-resolved 3.2-Gbp assembly with 43,093 candidate gene models. Using a combination of fossil transposable elements, k-mer spectra analyses and orthologue assignment, we identify the two ancestral subgenomes and date their divergence and the polyploidization event, concluding that the ancestor of all Scalesia species on the Galapagos was an allotetraploid. There are a comparable number of genes and transposable elements across the two subgenomes, and while their synteny has been mostly conserved, we find multiple inversions that may have facilitated adaptation. We identify clear signatures of selection across genes associated with vascular development, life-growth, adaptation to salinity and changes in flowering time, thus finding compelling evidence for a genomic basis of island syndrome in Darwins giant daisy radiation. This work advances understanding of factors influencing subgenome divergence in polyploid genomes, and characterizes the quick and pronounced genomic changes in a specular and diverse radiation of an iconic island plant radiation.

category: evolutionary biology


title: The histone code of the fungal genus Aspergillus uncovered by evolutionary and proteomic analyses

abstract:
Chemical modifications of DNA and histone proteins impact the organization of chromatin within the nucleus. Changes in these modifications, catalyzed by different chromatin-modifying enzymes, influence chromatin organization, which in turn is thought to impact the spatial and temporal regulation of gene expression. While combinations of different histone modifications, the histone code, have been studied in several model species, we know very little about histone modifications in the fungal genus Aspergillus, whose members are generally well-studied due to their importance as models in cell and molecular biology as well as their medical and biotechnological relevance. Here, we used phylogenetic analyses in 94 Aspergilli as well as other fungi to uncover the occurrence and evolutionary trajectories of enzymes and protein complexes with roles in chromatin modifications or regulation. We found that these enzymes and complexes are highly conserved in Aspergilli, pointing towards a complex repertoire of chromatin modifications. Nevertheless, we also observed few recent gene duplications or losses, highlighting Aspergillus species to further study the roles of specific chromatin modifications. SET7 and other components of PRC2 (Polycomb Repressive Complex 2), which is responsible for trimethylation on histone H3 at lysine 27 in many eukaryotes including fungi, are absent in Aspergilli as well as in closely related Penicillium species, suggesting that these lost the capacity for this histone modification. We corroborated our computational predictions by performing untargeted mass spectrometry analysis of histone post-translational modifications in Aspergillus nidulans. This systematic analysis will pave the way for future research into the complexity of the histone code and its functional implications on genome architecture and gene regulation in fungi.

Data SummaryThe predicted proteomes used in this study are publicly available at the JGI (Joint Genome Institute) MycoCosm repository (1); the species names and abbreviations are listed in Table S1. To evaluate the completeness of the predicted proteomes and to obtain a species phylogeny, 758 fungal BUSCO (Benchmarking Universal Single-Copy Ortholog) genes were used, and their names are listed in Table S2. The fasta, trimmed alignment, and maximum-likelihood phylogenetic tree files can be found in Supplementary Data 1 and 2 deposited at Zenodo (doi:10.5281/zenodo.5907090), as well as the mass spectrometry results are mentioned in Table S4.

Impact StatementUncovering how fungi regulate gene expression and genome organization is an important step to understand how they control biological processes such as growth or biosynthesis of bioactive molecules. Despite the known importance of chromatin modifications in controlling a plethora of biological processes across eukaryotes, they remain particularly poorly understood in filamentous fungi, even in model organisms like Aspergilli. Our systematic evolutionary analysis provides a robust framework for the functional analysis of chromatin modifications in Aspergillus species and other fungi. Our results do not only implicate candidate enzymes to play a role in new chromatin modifications, but they also point at species that have experienced duplications or losses of genes encoding enzymes for specific chromatin modifications. We therefore expect that this work will set the stage for future research into the complexity of the histone code and its functional implications on gene regulation and genome organization in fungi.


title: Antagonistic regulation of Drosophila mitochondrial uncoupling protein UCP4b by cold and BMP signaling

abstract:
Regulation of energy metabolism and response to cold are intimately linked in mammals. Central to these two processes are the mitochondrial uncoupling proteins (UCPs), which by promoting proton leakage across the inner mitochondrial membrane lead to the generation of heat instead of ATP synthesis. In addition to heat generation, UCPs also influence energy storage and can protect against obesity and diabetes. Cold-blooded animals like flies also contain UCPs that protect from cold, however their regulations are poorly understood. We find that Drosophila UCP4b is induced by cold in a cell-intrinsic manner and protects against cold and obesity in fly models. Mechanistically, cold regulates UCP4b expression through calcium signaling and Spargel (Srl), the Drosophila ortholog of mammalian PGC1. To the opposite, MAD, acting downstream of the BMP branch of the TGF{beta} signaling pathway, represses UCP4b expression independently of cold. Interestingly, the two mechanisms of UCP4b regulation are integrated as MAD binding to the UCP4b promoter is displaced by cold in a Srl-dependent manner. We discuss the similarities between the regulation of mammalian and Drosophila UCPs.

SignificanceMitochondrial uncoupling proteins (UCPs) that uncouple the mitochondrial respiration from ATP synthesis regulate energy metabolism, non-shivering thermogenesis, and redox balance in vertebrates and invertebrates. However, their regulation in Drosophila is poorly understood. We found that Drosophila uncoupling protein UCP4b is induced by cold in a cell-autonomous fashion. Conversely, MAD, acting downstream of BMP signaling, inhibits UCP4b expression. MAD is displaced from the upstream regions of the UCP4b gene by cold. UCP4b protects Drosophila against cold and diet-induced obesity. The regulation of UCP4b by cold and BMP signaling is reminiscent of the regulation of mammalian uncoupling protein UCP1. Altogether, we discovered an important regulator of Drosophila energy metabolism which is controlled by regulatory processes that are similar between Drosophila and mammals.

category: genetics


title: Fast and accurate joint inference of coancestry parameters for populations and/or individuals

abstract:
We introduce a fast, new algorithm for inferring jointly the FST parameters describing genetic distances among a set of populations and/or unrelated diploid individuals, and a tree representing their genetic structure, from allele count data. While the inferred tree typically reflects historical processes of splitting and divergence, its aim is to represent the actual genetic variance, with FST values specified by branch lengths. We generalise two major approaches to defining FST, via correlations and mismatch probabilities of sampled allele pairs, which measure shared and non-shared components of genetic variance. A diploid individual can be treated as a population of two gametes, which allows inference of coancestry coefficients for individuals as well as for populations, or a combination of the two. A simulation study illustrates that our fast method-of-moments estimation of FST values, simultaneously for multiple populations/individuals, gains statistical efficiency over pairwise approaches by pooling information about ancestral allele frequencies. We apply our approach to genome-wide genotypes from the 26 worldwide human populations of the 1000 Genomes Project. We first analyse at the population level, then a subset of individuals and in a final analysis we pool individuals from the more homogeneous populations. This flexible analysis approach gives many advantages over traditional approaches to population structure/coancestry, including visual and quantitative assessments of long-standing questions about the relative magnitudes of within- and between-population genetic differences.

Author summaryWe propose new ways to measure, and visualise in a tree, the genetic distances among a set of populations using allele frequency data. The two genomes within a diploid individual can be treated as a small population, which allows a flexible framework for investigating genetic variation within and between populations. Genetic structure can be accurately and efficiently represented in a tree with nodes representing either homogeneous populations or genetically diverse individuals, for example due to admixture. We first generalise the long-established measure of genetic distance, FST, to tree-structured populations and individuals, finding that two measures are required for each pair of populations, corresponding to their shared and and non-shared genetic variation. We show using a simulation study that our novel tree-based estimators are more efficient than current pairwise estimators, and we illustrate the potential for novel ways to explore and visualise genetic variation within and between populations using a worldwide human genetic dataset.


title: The thresholding problem and variability in the EEG graph network parameters

abstract: The graph thresholding is a frequently used practice of eliminating the weak connections in brain functional connectivity graphs. The main aim of the procedure is to delete the spurious connections in the data. However, the choice of the threshold is arbitrary and the effect of the threshold choice in not fully understood. Here we present the description of the changes in the global measures of a functional connectivity graph depending on the different proportional thresholds based on the 146 resting-state EEG recordings. The dynamics is presented in five different synchronization measures (wPLI, ImCoh, Coherence, ciPLV, PPC) in sensors and source spaces. The analysis shows significant changes in the graphs global connectivity measures as a function of the chosen threshold which may influence on the outcome of the study. The choice of the threshold could lead to the different study conclusions, thus it is necessary to improve the reasoning behind the choice of the different analytic options and consider adoption of different analytic approaches.


title: Position- and scale-invariant object-centered spatial selectivity in monkey frontoparietal cortex dynamically adapts to task demand

abstract:
Humans utilize egocentric and allocentric spatial information to guide goal-directed movements. Egocentric encoding is a well-known property of brain areas along the dorsal pathway. We ask if dorsal stream reach planning areas like parietal reach region (PRR) and dorsal premotor cortex (PMd) also encode object-centered (allocentric) information. During two consecutive instructed delay periods, rhesus monkeys first memorized an object-relative target position and then planned a reach to this position after the object re-occurred at variable positions with potentially different size. In both areas, we find predominant object-centered encoding during visual memory, which is invariant to object position and object size, and predominant egocentric encoding during reach planning. Such dynamic transition from allo- to egocentric encoding within individual dorsal stream areas contrasts the idea of task-independent functional segregation between processing pathways. Instead, demand-specific local computations might facilitate spatial cognition in dynamic environments to facilitate motor planning towards objects changing their location.

Significance statementHuman and non-human primates interact with their environment by manipulating objects. This requires planning and executing reaches to transport the hand to object-relative positions close to or on the object. Previous studies showed that frontal and parietal lobe areas encode reach goals in coordinate systems anchored to different parts of the subjects body, such as hand position or gaze direction, and modulated by pose. We show that neurons in the same areas can encode object-centered allocentric spatial information, independent of object location and object size, or egocentric information, depending on dynamically changing task demands. Such dynamic adaptation seems inconsistent with a functional segregation for ego- and allocentric encoding between processing streams.


title: Decoding the temporal dynamics of affective scene processing

abstract: Natural images containing affective scenes are used extensively to investigate the neural mechanisms of visual emotion processing. Functional fMRI studies have shown that these images activate a large-scale distributed brain network that encompasses areas in visual, temporal, and frontal cortices. The underlying spatial and temporal dynamics among these network structures, however, remain to be characterized. We recorded simultaneous EEG-fMRI data while participants passively viewed affective images from the International Affective Picture System (IAPS). Applying multivariate pattern analysis to decode EEG data, and representational similarity analysis to fuse EEG data with simultaneously recorded fMRI data, we found that: (1) ~100 ms after picture onset, perceptual processing of complex visual scenes began in early visual cortex, proceeding to ventral visual cortex at ~160 ms, (2) between ~200 and ~300 ms (pleasant pictures: ~200 ms; unpleasant pictures: ~260 ms), affect-specific neural representations began to form, supported mainly by areas in occipital and temporal cortices, and (3) affect-specific neural representations, lasting up to ~2 s, were stable and exhibited temporally generalizable activity patterns. These results suggest that affective scene representations in the brain are formed in a valence-dependent manner and are sustained by recurrent neural interactions among distributed brain areas.


title: Widespread alterations in microRNA biogenesis in human Huntington's disease putamen

abstract: Altered microRNA (miRNA) expression is a common feature of Huntingtons disease (HD) and could participate in disease onset and progression. However, little is known about the underlying causes of miRNA disruption in HD. We and others have previously shown that mutant Huntingtin (mHTT) binds to Ago2, a central component of miRNA biogenesis, and disrupts mature miRNA levels. In this study, we sought to determine if miRNA maturation per se was compromised in HD. Towards this end, we characterized t major miRNA biogenesis pathway components and miRNA maturation products (pri-miRNA, pre-miRNA, and mature) in human HD (N=41, Vonsattel grades HD2-4) and healthy control (N=25) subjects. Notably, the striatum (putamen) and cortex (BA39) from the same individuals were analyzed in parallel. We show that Ago2, Drosha, and Dicer were strongly downregulated in human HD at early stages of disease. Using a panel of HD-related miRNAs (miR-10b, miR-196b, miR-132, miR-212, miR-127, miR-128), we uncovered various types of maturation defects in HD brain, the most prominent occurring at the pre-miRNA to mature miRNA maturation step. Consistent with earlier findings, we provide evidence that alterations in autophagy could participate in miRNA maturation defects. Notably, most changes occurred in the striatum, which is more prone to HTT aggregation and neurodegeneration. Likewise, we observed no significant alterations in miRNA biogenesis in human HD cortex and blood, strengthening tissue-specific effects. Overall, these data provide important clues into the underlying mechanisms behind miRNA alterations in HD-susceptible tissues. Further investigations are now required to understand the biological, diagnostic, and therapeutic implications of miRNA/RNAi biogenesis defects in HD and related neurodegenerative disorders.


title: Predicting the Degree of Distracted Driving Based on fNIRS Functional Connectivity: A Pilot Study

abstract: Distracted driving is one of the main causes of traffic accidents. By predicting the attentional state of drivers, it is possible to prevent distractions and promote safe driving. In this study, we developed a model that could predict the degree of distracted driving based on brain activity. Changes in oxyhemoglobin concentrations were measured in drivers while driving a real car using functional near-infrared spectroscopy (fNIRS). A regression model was constructed for each participant using functional connectivity as an explanatory variable and break reaction time to random beeps while driving as an objective variable. As a result, we were able to construct a prediction model for 11 of the 12 participants. Furthermore, the regression model with the highest prediction accuracy for each participant was analyzed to gain a better understanding of the neural basis of distracted driving. The 11 models were classified into five clusters by hierarchical clustering based on their functional connectivity edges used in each cluster. The results showed that the combinations of the dorsal attention network (DAN)-sensory motor network (SMN) and DAN-ventral attention network (VAN) connections were common in all clusters and that these networks were essential to predict the degree of distraction in complex multitask driving. They also confirmed the existence of multiple types of prediction models with different within- and between-network connectivity patterns. These results indicate that it is possible to predict the degree of distracted driving based on the brain activity of the driver during actual driving. These results are expected to contribute to the development of safe driving systems and elucidation of the neural basis of distracted driving.


title: Anterior insular cortex inputs to the dorsolateral striatum govern the maintenance of binge alcohol drinking

abstract: How does binge drinking alcohol change synaptic function, and do these changes maintain binge consumption? The anterior insular cortex (AIC) and dorsolateral striatum (DLS) are brain regions implicated in alcohol use disorder. In mice, we found that binge drinking alcohol produced glutamatergic synaptic adaptations selective to AIC inputs within the DLS. Photoexciting AIC[->]DLS circuitry during binge drinking decreased alcohol, but not water consumption and altered alcohol drinking mechanics. Further, drinking mechanics alone from drinking session data predicted alcohol-related circuit changes. AIC[->]DLS manipulation did not alter operant, valence, or anxiety-related behaviors. These findings suggest that alcohol-mediated changes in AIC inputs govern behavioral sequences that maintain binge drinking and may serve as a circuit-based biomarker for the development of alcohol use disorder.


title: Encoding and decoding analysis of music perception using intracranial EEG

abstract: Music perception engages multiple brain regions, however the neural dynamics of this core human experience remains elusive. We applied predictive models to intracranial EEG data from 29 patients listening to a Pink Floyd song. We investigated the relationship between the song spectrogram and the elicited high-frequency activity (70-150Hz), a marker of local neural activity. Encoding models characterized the spectrotemporal receptive fields (STRFs) of each electrode and decoding models estimated the population-level song representation. Both methods confirmed a crucial role of the right superior temporal gyri (STG) in music perception. A component analysis on STRF coefficients highlighted overlapping neural populations tuned to specific musical elements (vocals, lead guitar, rhythm). An ablation analysis on decoding models revealed the presence of unique musical information concentrated in the right STG and more spatially distributed in the left hemisphere. Lastly, we provided the first song reconstruction decoded from human neural activity.


title: Resveratrol increases tear production and spontaneous ocular pain after corneal abrasion in male, but not female, rats using a preclinical model of photorefractive keratectomy (PRK)

abstract: Photorefractive keratectomy (PRK) is an alternative to LASIK and can cause intense acute pain that is often not relieved by standard treatments. To assess potential therapeutics for this type of acute pain, appropriate preclinical models are needed. Herein we describe a rodent preclinical model of PRK and a multi-faceted approach to determine the therapeutic potential of resveratrol, a natural phytoestrogen, on pain, tear production, and the corneal epithelium. Studies were conducted in male and female Sprague-Dawley rats. Heptanol was applied to one eye and the superficial corneal epithelium was removed, mimicking the abrasion seen in PRK. Spontaneous pain was assessed with orbital tightening (OT) scores for 7 days. Corneal abrasion increased OT scores in both male and female rats with peak responses at 24 - 48 hours. Topical application of resveratrol had a sex-specific effect on OT scores and tear production. Resveratrol increased OT scores in abraded males, but not females, at 72 hours and 1 week after abrasion. Resveratrol dose-dependently increased tear production in abraded males, but had no effect in abraded females. While there was no correlation between OT score at 1 week and tear production, CGRP content of corneal nerves was positively correlated with 1 week OT score. There was also a significant increase in CD68-labeled macrophages in resveratrol-treated abraded corneas as compared to naive corneas. These findings demonstrate the usefulness of our preclinical PRK model for the assessment of ocular pain therapeutics and indicate that topical resveratrol may not be useful for managing PRK-induced pain.


title: Cueing motor memory reactivation during NREM sleep engenders learning-related changes in precuneus and sensorimotor structures

abstract: Memory reactivation during Non-Rapid Eye Movement (NREM) sleep is important for memory consolidation but it remains unclear exactly how such activity promotes the development of a stable memory representation. We used Targeted Memory Reactivation (TMR) in combination with longitudinal structural and functional MRI to track the evolution of a motor memory trace over 20 days. We show that repeated reactivation of motor memory during sleep leads to increased precuneus activation 24 h post-TMR. Interestingly, a decrease in precuneus activity over the next 10 days predicts longer-term cueing benefit. We also find both functional and structural changes in sensorimotor cortex in association with effects of TMR 20 days post-encoding. These findings demonstrate that TMR can engage precuneus in the short-term while also impacting on task-related structure and function over longer timescales.


title: Static magnetic stimulation induces structural plasticity at the axon initial segment of inhibitory cortical neurons

abstract: Static magnetic stimulation (SMS) is a form of non-invasive brain stimulation that can alter neural activity and induce neural plasticity that outlasts the period of stimulation. While SMS is typically delivered for short periods (e.g., 10 minutes) to alter corticospinal excitability or motor behaviours, the plasticity mechanisms that can be induced with longer periods of stimulation have not been explored. In mammalian neurons, the axon initial segment (AIS) is the site of action potential initiation and undergoes structural plasticity as a homeostatic mechanism to counteract chronic changes in neuronal activity. Therefore, we investigated whether the chronic application of SMS would induce structural AIS plasticity in cortical neurons. SMS (0.5 Tesla in intensity) was delivered to postnatally derived mouse primary cortical neurons consisting of mainly inhibitory neurons, for 6 or 48 hours beginning from 7 days in vitro (DIV7). AIS structural plasticity (length and starting distance from the soma) was quantified immediately after and 24 hours post-stimulation. Following 6 hours of stimulation, we observed an immediate decrease in median AIS length compared to control, that persisted to 24 hours post stimulation. In addition, there was a distal shift in the AIS start position relative to the soma that was only observed 24 hours after the 6-hour stimulation. Following 48 hours of stimulation, we observed an immediate shortening of AIS length and a distal shift in AIS start position relative to the soma, however only the distal shift in AIS start position persisted to 24 hours post-stimulation. Our findings provide the foundation to expand the use of SMS to more chronic applications as a method to study or promote AIS plasticity non-invasively.


title: Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types

abstract: Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains following parabiosis. For each cell type, we catalogued alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions, and senescence status. Our analyses identified gene signatures demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest novel strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors.


title: An endogenous Rtn4/Nogo-interacting micropeptide that modulates synaptic plasticity with age.

abstract: Micropeptides, encoded from small open reading frames of 300 nucleotides or less, are hidden throughout mammalian genomes, though few functional studies of micropeptides in the brain are published. Here, we describe a micropeptide known as the Plasticity -Associated Neural Transcript Short (Pants), located in the 22q11.2 region of the human genome, the microdeletion of which conveys a high risk for schizophrenia. Our data show that Pants is upregulated in early adulthood in the mossy fiber circuit of the hippocampus, where it exerts a powerful negative effect on long-term potentiation (LTP). Further, we find that Pants is secreted from neurons, where it associates with synapses but is rapidly degraded with stimulation. Pants dynamically interacts with Rtn4/Nogo-A, a well-studied regulator of adult plasticity. Pants interaction with Nogo-A augments its influence over postsynaptic AMPA receptor clustering, thus gating plasticity at adult synapses. This work shows that neural micropeptides can act as architectural modules that increase the functional diversity of the known proteome.


title: An Rtn4/Nogo-A-interacting micropeptide modulates synaptic plasticity with age.


title: Penalized Decomposition Using Residuals (PeDecURe) for Nuisance Variable Adjustment in Multivariate Pattern Analysis

abstract: SO_SCPLOWUMMARYC_SCPLOWIn neuroimaging studies, multivariate methods provide a framework for studying associations between complex patterns distributed throughout the brain and neurological, psychiatric, and behavioral phenotypes. However, mitigating the influence of nuisance variables, such as confounders, remains a critical challenge in multivariate pattern analysis (MVPA). In studies of Alzheimers Disease, for example, imbalance in disease rates across age and sex may make it difficult to distinguish between structural patterns in the brain (as measured by neuroimaging scans) attributable to disease progression and those characteristic of typical human aging or sex differences. Concerningly, when not properly adjusted for, nuisance variables can obscure interpretations and preclude the generalizability of findings from neuroimaging studies. Motivated by this critical issue, in this work we examine the impact of nuisance variables on features extracted from image decomposition methods and propose Penalized Decomposition Using Residuals (PeDecURe), a new MVPA method for obtaining nuisance variable-adjusted features. PeDecURe estimates primary directions of variation which maximize covariance between residualized imaging features and a variable of interest (e.g., Alzheimers diagnosis) while simultaneously mitigating the influence of nuisance variation through a penalty on the covariance between residualized imaging features and those variables. Using features estimated using PeDecURes first direction of variation, we train an accurate and generalizable predictive model, as evidenced by its robustness in testing samples with different underlying nuisance variable distributions. We compare PeDecURe to commonly used decomposition methods (principal component analysis (PCA) and partial least squares) as well as a confounder-adjusted variation of PCA. We find that features derived from PeDecURe offer greater accuracy and generalizability and lower partial correlations with nuisance variables compared with the other methods. While PeDecURe is primarily motivated by MVPA in the context of neuroimaging, it is broadly applicable to datasets where the dimensionality or complexity of the covariance structure calls for novel methods to handle sources of nuisance variation.


title: Structural covariance and heritability of the optic tract and primary visual cortex in living human brains

abstract:
Individual differences among human brains exist at many scales, spanning gene expression, white matter tissue properties, and the size and shape of cortical areas. One notable example is an approximately 3-fold range in the size of human primary visual cortex (V1), a much larger range than is found in overall brain size. A previous study (Andrews et al., 1997) reported a correlation between optic tract cross-section area and V1 size in post-mortem human brains, suggesting that there may be a common developmental mechanism for multiple components of the visual pathways. We evaluated the relationship between properties of the optic tract and V1 in a much larger sample of living human brains by analyzing the Human Connectome Project 7 Tesla Retinotopy Dataset. This dataset includes retinotopic maps measured with functional MRI (fMRI) and fiber tract data measured with diffusion MRI (dMRI). We found a negative correlation between optic tract fractional anisotropy and V1 surface area (r = -0.2). This correlation, though small, was consistent across multiple dMRI datasets differing in acquisition parameters. Further, we found that both V1 size and optic tract properties were correlated among twins, with higher correlations for monozygotic than dizygotic twins, indicating a high degree of heritability for both properties. Together, these results demonstrate covariation across individuals in properties of the retina (optic tract) and cortex (V1) and show that each is influenced by genetic factors.

Significance statementThe size of human primary visual cortex (V1) has large inter-individual differences. These differences cannot be explained by differences in overall brain size. A previous post-mortem study reported a correlation between the size of the human optic tract and V1. In this study, we evaluated the relationship between the optic tract and V1 in living humans by analyzing a neuroimaging dataset that included functional and diffusion MRI data. We found a small, but robust correlation between optic tract tissue properties and V1 size, supporting the existence of structural covariance between the optic tract and V1 in living humans. The results suggest that characteristics of retinal ganglion cells, reflected in optic tract measurements, are related to individual differences in human V1.


title: Cross-modality supervised image restoration enables nanoscale tracking of synaptic plasticity in living mice

abstract: Synaptic plasticity encodes learning as changes in the strength of synapses, sub-micron structures that mediate communication between brain cells. Due to their small size and high density, synapses are extremely difficult to image in vivo, limiting our ability to directly relate synaptic plasticity with behavior. Here, we developed a combination of computational and biological methods to overcome these challenges. First, we trained a deep learning image restoration algorithm that combines the advantages of ex vivo super-resolution and in vivo imaging modalities to overcome limitations specific to each optical system. Applied to in vivo images from transgenic mice expressing fluorescently labeled synaptic proteins, this restoration algorithm super-resolved diffraction-limited synapses, enabling identification and logitudinal tracking of synaptic plasticity underlying behavior with unprecedented spatial resolution. More generally, our method demonstrates the capabilities of image enhancement to learn from ex vivo data and imaging techniques to improve in vivo imaging resolution.


title: High spatial overlap but diverging age-related trajectories of cortical MRI markers aiming to represent intracortical myelin and microstructure

abstract:
Cortical thickness (CT), gray-white matter contrast (GWC), boundary sharpness coefficient (BSC), and T1-weighted/T2-weighted ratio (T1w/T2w) are cortical metrics derived from standard T1- and T2-weighted magnetic resonance imaging (MRI) images that are often interpreted as representing or being influenced by intracortical myelin content. However, there is little empirical evidence to justify these interpretations nor have the homologies or differences between these measures been examined. We examined differences and similarities in group mean and age-related trends with the underlying hypothesis that different measures sensitive to similar changes in underlying myelo- and microstructural processes should be highly related. We further probe their sensitivity to cellular organization using the BigBrain, a high-resolution digitized volume stemming from a whole human brain histologically stained for cell bodies with the Merker stain.

The measures were generated on both the MRI-derived images of 127 healthy subjects, aged 18 to 81, and on the BigBrain volume using cortical surfaces that were generated with the CIVET 2.1.0 pipeline. Comparing MRI markers between themselves, our results revealed generally high overlap in spatial distribution (i.e., group mean), but mostly divergent age trajectories in the shape, direction, and spatial distribution of the linear age effect. Significant spatial relationships were found between the BSC and GWC and their BigBrain equivalent, as well as a correlation approaching significance between the BigBrain intensities and the T1w/T2w ratio in gray matter (GM) both sampled at half cortical depth.

We conclude that the microstructural properties at the source of spatial distributions of MRI cortical markers (e.g. GM myelin) can be different from microstructural changes that affect these markers in aging. While our findings highlight a discrepancy in the interpretation of the biological underpinnings of the cortical markers, they also highlight their potential complementarity, as they are largely independent in aging. Our BigBrain results indicate a general trend of GM T1w signal and myelin being spatially related to the density of cells, which is possibly more pronounced in superficial cortical layers.

Highlights- Different MRI cortical markers aim to represent myelin and microstructure
- These markers show high spatial overlap, but mostly divergent age trajectories
- It is unlikely that myelin changes are the source of the age effect for all markers
- Trend of MRI signal being related to cell density in more superficial cortical layers


title: Connectivity dynamics and cognitive variability during aging

abstract: Aging is accompanied by cognitive changes but strong variations across individuals exists. One of the ways to characterize this individual variability is to use techniques such as magnetoencephalography (MEG) to measure the dynamics of synchronization between brain regions and the variability of this connectivity over time. Indeed, few studies have focused on the fluctuations in the dynamics of brain networks over time and their evolution with age. We therefore used this method on the Cam-CAN database. We show here that with age an increase in the variability of brain synchronization, as well as a reversal of the direction of information transfer in the default mode network (DMN), in delta frequency band takes place. These changes in functional connectivity were associated with cognitive decline. These results suggest that advancing age is accompanied by a functional disorganization of dynamic networks with a loss of communication stability and a decrease in the information transmitted. This could be partly due to the loss of integrity of the network structure.


title: Probabilistic forward replay of anticipated stimulus sequences in human primary visual cortex and hippocampus

abstract: The ability to recognize and predict future spatiotemporal sequences is vital for perception. It has been proposed that the brain makes  intelligent guesses about future inputs by forward replaying these events. However, it is unknown whether and how this mechanism incorporates the probabilistic structure that is inherent to naturalistic environments. Here we tested forward replay in human V1 and hippocampus using a probabilistic cueing paradigm. Participants were exposed to two visual moving dot sequences (A and B) that shared the same starting point. Each stimulus sequence was paired with either a high or a low tone that predicted which sequence would follow with 80% cue validity (probabilistic context) or 50% cue validity (random context). We found that after exposure, the auditory cue together with the starting point triggered simultaneous forward replay of both the likely (A) and the less likely (B) stimulus sequence. Crucially, forward replay preserved the probabilistic relationship of the environment, such that the likely sequence was associated with greater anticipatory V1 activity compared to the less likely stimulus sequence. Analogous to V1, forward replay in hippocampus was also found to preserve the probabilistic cue-sequence relationship. Further, the anterior hippocampus was found to represent the predicted stimulus sequence, irrespective of the input, while the posterior hippocampus revealed a prediction error-like signal that was only observed when predictions were violated. These findings show how mnemonic and sensory areas coordinate predictive representations in probabilistic contexts to improve perceptual processing.


title: Extrinsic mortality and senescence: a guide for the perplexed

abstract: Do environments or species traits that lower the mortality of individuals create selection for delaying senescence? Reading the literature creates an impression that mathematically oriented biologists cannot agree on the validity of George Williams prediction (who claimed  yes). The abundance of models and opinions may bewilder those that are new to the field. Here we provide heuristics as well as simple models that outline when the Williams prediction holds, why there is a  null model where extrinsic mortality does not matter, and why it is also possible to expect the opposite of Williams prediction: increased extrinsic mortality favours slower senescence. While most existing theory focuses on interpreting differences in selection gradients, we hope to offer intuition by quantifying how much delaying the  placement of an offspring into the population reduces its expected contribution to the gene pool of the future. Our first example shows why the null result arises and why the null can stop being valid in models that consider population regulation. Thereafter, a model with 10 different choices for density dependence shows why extrinsic mortality has the power to favour slow life histories on the fast-slow continuum, but this requires that density-dependent effects harm juveniles.


title: mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder.

abstract:
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a devastating rare neurodevelopmental disease without a cure, caused by mutations of the serine/threonine kinase CDKL5 highly expressed in the forebrain. CDD is characterized by early-onset seizures, severe intellectual disabilities, autistic-like traits, sensorimotor and cortical visual impairments (CVI). The lack of an effective therapeutic strategy for CDD urgently demands the identification of novel druggable targets potentially relevant for CDD pathophysiology.

To this aim, we studied metabotropic glutamate receptors 5 (mGluR5) for their important role in critical mechanisms involved in CDD, i.e.: synaptogenesis, dendritic spines formation/maturation and synaptic plasticity, and because mGluR5 function depends on the postsynaptic protein Homer1bc that is downregulated in the cerebral cortex of CDKL5-/y mice. In this study, we reveal that CDKL5 loss tampers with (i) the strength of Homer1bc-mGluR5 binding, (ii) the synaptic localization of mGluR5 and (iii) the mGluR5-mediated enhancement of NMDA-induced neuronal responses. Importantly, we showed that the stimulation of mGluR5 activity by administering in mice specific positive-allosteric-modulators, i.e.: 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) or RO6807794, corrected the synaptic, functional and behavioural defects shown by CDKL5-/y mice. Notably, the cerebral cortex of 2 CDD patients show similar changes in the synaptic organization to mutant CDKL5 mice, including a reduced mGluR5 expression, suggesting that mGluR5 represent a promising therapeutic target for CDD patients.


title: Neuroprotective effects of Canagliflozin: lessons from aged genetically diverse UM-HET3 mice.

abstract: The aging brain is characterized by a progressive increase in neuroinflammation and central insulin resistance, which contribute to neurodegenerative diseases and cognitive impairment. Recently, the Interventions Testing Program (ITP) demonstrated that the anti-diabetes drug, Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor (SGLT2i), led to lower fasting glucose and improved glucose tolerance in both sexes, but extended median lifespan by 14% only in male mice. Here we show that Cana treatment significantly improved central insulin sensitivity in the hypothalamus and the hippocampus of 30-month-old male mice. Remarkably, Cana-treated mice showed significant reductions in age-associated hypothalamic gliosis with a decrease in inflammatory cytokine production by microglia in both sexes. In the hippocampus, Cana reduced microgliosis and astrogliosis in males, but not in female mice. The decrease in microgliosis was partially dependent on mTOR signaling, as evidenced by reduced phosphorylation of S6 kinase in microglia of Cana-treated aged male, but not female mice. Remarkably, Cana treatment improved exploratory and locomotor activity of 30-month-old male but not female mice. Taken together, our findings demonstrate sex-specific neuroprotective effects of Cana treatment, suggesting its application for the potential treatment of neurodegenerative diseases.


title: Mapping SARS-CoV-2 antigenic relationships and serological responses

abstract:
During the SARS-CoV-2 pandemic, multiple variants with differing amounts of escape from pre-existing immunity have emerged, causing concerns about continued protection. Here, we use antigenic cartography to quantify and visualize the antigenic relationships among 16 SARS-CoV-2 variants titrated against serum samples taken post-vaccination and post-infection with seven different variants. We find major antigenic differences caused by substitutions at positions 417, 452, 484, and possibly 501. B.1.1.529 (Omicron) showed the highest escape from all sera tested. Visualization of serological responses as antibody landscapes shows how reactivity clusters in different regions of antigenic space. We find changes in immunodominance of different spike regions depending on the variant an individual was exposed to, with implications for variant risk assessment and vaccine strain selection.

One sentence summaryAntigenic Cartography of SARS-CoV-2 variants reveals amino acid substitutions governing immune escape and immunodominance patterns.


title: Ablation of colonic epithelial Reg4+ support cells induces Notch-independent regeneration and mesenchymal remodeling.

abstract:
The colonic epithelium harbors a complex network of adult stem cells that integrate signals from many supporting cells to assist in their decision making. In this study, we ablate an epithelial secretory support cell population characterized by Reg4 expression, to investigate the systemic impact on stemness-related cell signaling pathways. Ablation of these cells results in a hyperproliferative state as well as paradoxical activation of Notch signaling, with the proliferative effect continuing even during Notch inhibition. Reg4+ cell ablation also causes an unexpected remodeling of the mesenchyme. We observe increased presence of Pdgfra-high fibroblasts and an expanded network of smooth muscle myofibroblasts, suggesting that Reg4-ablation reorganizes signaling between epithelium and mesenchyme. These changes occur in the absence of any significant immunological inflammatory response. Our data demonstrate that Reg4+ cells are critical directors of homeostatic epithelial-mesenchymal signaling. Further, this ablation model is an in vivo system for probing cell-cell interactions in the colonic stem cell niche.

Graphical Abstract

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category: cell biology


title: Lymphatics constitute a novel component of the intestinal stem cell niche

abstract: Intestinal stem cells (ISCs) depend on niche factors for their proper function. However, the source of these ISC niche factors and how they support ISCs remain controversial due to their redundant expression patterns. Here, we report that the maintenance of ISCs depends on both lymphatic endothelial cells (LECs) and Rspo3+Grem1+ fibroblasts (RGFs). We found that LECs are surrounded by RGFs and located in close proximity to Lgr5+ ISCs. RSPO3 production is restricted to LECs and RGFs and they can partially compensate for each other; however, RSPO3 loss in both of LECs and RGFs drastically compromises ISC numbers, villi length, and repair after irradiation-induced injury. Mechanistically, irradiation-induced damage expands LEC and RGF numbers and enhances the latters generation of RSPO3 through IL-1 receptor activation. We propose that LECs represent a novel component of the ISC niche, which together with RGFs, provide essential RSPO3 to sustain ISCs in homeostasis and regeneration.


title: Hsp78-interaction proteome highlights chaperone role during protein aggregation in mitochondria under heat stress

abstract: Proteins of the Hsp100 chaperone family support protein homeostasis, the maintenance of protein activity under stress, by refolding aggregated proteins or targeting them for degradation. Hsp78, the ClpB-type mitochondrial member of the Hsp100 family, can be found in lower eukaryotes like yeast. Although Hsp78 has been shown to contribute to protection against elevated temperatures in yeast, the biochemical mechanisms underlying this mitochondria-specific thermotolerance are still largely unclear. To identify endogenous chaperone substrate proteins, we generated an Hsp78-ATPase mutant with a stabilized substrate binding behaviour. We used two SILAC-based quantitative mass spectrometry approaches to analyze the role of Hsp78 during heat stress-induced mitochondrial protein aggregation and disaggregation processes on a proteomic level. In the first setup, Hsp78-interacting polypeptides were identified to reveal the endogenous substrate spectrum of the chaperone. Our analysis revealed that Hsp78 is interacting with a wide variety of proteins related to metabolic functions including energy production and protein synthesis, as well as other chaperones, thus maintaining crucial functions for mitochondrial stress resistance. We compared these interaction data with a second experimental setup that focussed on the on overall aggregation and disaggregation processes in mitochondria under heat stress on a proteomic level. This revealed specific aggregation-prone protein populations and demonstrated the direct quantitative impact of Hsp78 on stress-dependent protein solubility under different conditions. We conclude that Hsp78 together with its cofactors represents a recovery system that protects major mitochondrial metabolic functions during heat stress as well restores protein biogenesis capacity after return to normal conditions.


title: Inserting Cre Recombinase into the Prolactin 8a2 gene for Decidua-Specific recombination in Mice

abstract: An estimated 75% of unsuccessful pregnancies are due to implantation failure. Investigating the causes of implantation failure is difficult as decidualization and embryo implantation is a dynamic process. Here we describe a new decidua specific iCre recombinase mouse strain. Utilizing CRISPR/Cas9-based genome editing, a mouse strain was developed that expresses iCre recombinase under the control of the endogenous prolactin family 8, subfamily a, member 2 (Prl8a2) promoter. iCre recombinase activity was examined by crossing with mTmG or Sun1-GFP reporter alleles. iCre activity initiated reporter expression at gestational day 5.5 in the primary decidual zone and continued into mid-gestation (gestational day 9.5), with expression highly concentrated in the anti-mesometrial region. No reporter expression was observed in the ovary, oviduct, pituitary, or skeletal muscle, supporting the tissue specificity of the Prl8a2iCre in the primary decidual zone. This novel iCre line will be a valuable tool for in vivo genetic manipulation and lineage tracing to investigate functions of genetic networks and cellular dynamics associated with decidualization and infertility.


title: Multimodal single cell sequencing of human diabetic kidney disease implicates chromatin accessibility and genetic background in disease progression

abstract: Multimodal single cell sequencing is a powerful tool for interrogating cell-specific changes in transcription and chromatin accessibility. We performed single nucleus RNA (snRNA-seq) and assay for transposase accessible chromatin sequencing (snATAC-seq) on human kidney cortex from donors with and without diabetic kidney disease (DKD) to identify altered signaling pathways and transcription factors associated with DKD. Both snRNA-seq and snATAC-seq had an increased proportion of VCAM1+ injured proximal tubule cells (PT_VCAM1) in DKD samples. PT_VCAM1 has a pro-inflammatory expression signature and transcription factor motif enrichment implicated NFkB signaling. We used stratified linkage disequilibrium score regression to partition heritability of kidney-function-related traits using publicly-available GWAS summary statistics. Cell-specific PT_VCAM1 peaks were enriched for heritability of chronic kidney disease (CKD), suggesting that genetic background may regulate chromatin accessibility and DKD progression. snATAC-seq found cell-specific differentially accessible regions (DAR) throughout the nephron that change accessibility in DKD and these regions were enriched for glucocorticoid receptor (GR) motifs. Changes in chromatin accessibility were associated with decreased expression of insulin receptor, increased gluconeogenesis, and decreased expression of the GR cytosolic chaperone, FKBP5, in the diabetic proximal tubule. Cleavage under targets and release using nuclease (CUT&RUN) profiling of GR binding in bulk kidney cortex and an in vitro model of the proximal tubule (RPTEC) showed that DAR co-localize with GR binding sites. CRISPRi silencing of GR response elements (GRE) in the FKBP5 gene body reduced FKBP5 expression in RPTEC, suggesting that reduced FKBP5 chromatin accessibility in DKD may alter cellular response to GR. We developed an open-source tool for single cell allele specific analysis (SALSA) to model the effect of genetic background on gene expression. Heterozygous germline single nucleotide variants (SNV) in proximal tubule ATAC peaks were associated with allele-specific chromatin accessibility and differential expression of target genes within cis-coaccessibility networks. Partitioned heritability of proximal tubule ATAC peaks with a predicted allele-specific effect was enriched for eGFR, suggesting that genetic background may modify DKD progression in a cell-specific manner.

category: genomics


title: A Chemical Mutagenesis Approach to Insert Post-Translational Modifications in Aggregation-Prone Proteins

abstract: Neurodegenerative diseases are a class of disorders linked to the formation in the nervous system of fibrillar protein aggregates called amyloids. This aggregation process is affected by a variety of post-translational modifications, whose specific mechanisms are not fully understood yet. Emerging chemical mutagenesis technology is currently striving to address the challenge of introducing protein post-translational modifications, while maintaining proteins stable and soluble during the modification reaction. Several amyloidogenic proteins are highly aggregation-prone, and current modification procedures lead to unexpected precipitation of these proteins, affecting their yield and downstream characterization. Here, we present a method for maintaining amyloidogenic proteins soluble during chemical mutagenesis. As proof-of-principle, we applied our method to mimic the phosphorylation of the serine 26 and the acetylation of the lysine 28 of the 40-residue long variant of amyloid-{beta} peptide, whose aggregation is linked to Alzheimers disease.

category: biochemistry


title: Where Honey Bee Vitellogenin may Bind Zn2+-Ions

abstract: The protein Vitellogenin (Vg) plays a central role in lipid transportation in most egg-laying animals. High Vg levels correlate with stress resistance and lifespan potential in honey bees (Apis mellifera). Vg is the primary circulating zinc-carrying protein in honey bees. Zinc is an essential metal ion in numerous biological processes, including the function and structure of many proteins. Measurements of Zn2+ suggest a variable number of ions per Vg molecule in different animal species, but the molecular implications of zinc-binding by this protein are not well understood. We used inductively coupled plasma mass spectrometry (ICP-MS) to determine that, on average, each honey bee Vg molecule binds 3 Zn2+-ions. Our full-length protein structure and sequence analysis revealed seven potential zinc-binding sites. These are located in the {beta}-barrel and -helical subdomains of the N-terminal domain, the lipid binding site, and the cysteine-rich C-terminal region of unknown function. Interestingly, two potential zinc-binding sites in the {beta}-barrel can support a proposed role for this structure in DNA-binding. Overall, our findings illustrate the capacity of honey bee Vg to bind zinc at several functional regions, indicating that Zn2+-ions are important for many of the activities of this protein. In addition to being potentially relevant for other egg-laying species, these insights provide a platform for studies of metal ions in bee health, which is of global interest due to recent declines in pollinator numbers.


title: Evaluation of P. aeruginosa attachment on mineralized collagen scaffolds and addition of manuka honey to increase mesenchymal stem cell osteogenesis

abstract: The design of biomaterials to regenerate bone is likely to increasingly require modifications that reduce bacterial attachment and biofilm formation as infection during wound regeneration can significantly impede tissue repair and typically requires surgical intervention to restart the healing process. Here, we investigate the ability of a mineralized collagen biomaterial to natively resist infection as well as how the addition of manuka honey affects bacterial colonization and mesenchymal stem cell osteogenesis. We incorporate manuka honey into these scaffolds via either direct fabrication into the scaffold microarchitecture or via soaking the scaffold in a solution of Manuka honey after fabrication. Direct incorporation results in a change in the surface characteristics and porosity of mineralized collagen scaffolds. Soaking scaffolds in honey concentrations greater than 10% had significant negative effects on mesenchymal stem cell metabolic activity but soaking or incorporating 5% honey had no impact on endothelial cell tube formation. Soaking and incorporating 5% honey into scaffolds reduced metabolic activity of mesenchymal stem cells, however, soaking 5% honey into scaffolds increased calcium and phosphorous mineral formation, osteoprotegerin release, and alkaline phosphatase activity. The addition of manuka honey did not prevent P. aeruginosa attachment but may be able to limit attachment of other common wound-colonizing bacteria. Overall, our results demonstrate the potential for soaking mineralized collagen scaffolds in 5% manuka honey to increase osteogenesis of mesenchymal stem cells.

category: bioengineering


title: In vivo correction of cystic fibrosis mediated by PNA nanoparticles

abstract: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We sought to correct the multiple organ dysfunction of the F508del CF-causing mutation using systemic delivery of peptide nucleic acid gene editing technology mediated by biocompatible polymeric nanoparticles. We confirmed phenotypic and genotypic modification in vitro in primary nasal epithelial cells from F508del mice grown at air-liquid interface and in vivo in F508del mice following intravenous delivery. In vivo treatment resulted in a partial gain of CFTR function in epithelia as measured by in situ potential differences and Ussing chamber assays and correction of CFTR in both airway and GI tissues with no off-target effects above background. This is the first report of systemic gene editing for CF. Our data suggest that systemic delivery of PNA NPs designed to correct CF-causing mutations is a viable option to ameliorate the disease in multiple affected organs.


title: A methodology for co-simulation-based optimization of biofabrication protocols

abstract: Biofabrication processes are complex and often unsatisfactory. Trial-and-error methods are costly and yield only incremental innovation, starting from sub-optimal and poorly represented existing processes. Although computational techniques might support efficient process design to find optimal process configurations, intelligent computational approaches must comprise biological complexity to provide meaningful insights. This paper proposes a novel co-simulation-based optimization methodology for the systematic design of protocols for cell culture and biofabrication. The proposed strategy integrates evolutionary computation and simulation for efficient design space exploration and assessment of candidate protocols. A generic library supports the modular and flexible composition of multiscale and multidomain co-simulation scenarios. The feasibility of the presented approach was demonstrated in the automatic generation of protocols for the biofabrication of an epithelial cell monolayer. The results are twofold. First, the prototype co-simulation library helps build flexible, loosely coupled simulation scenarios. Second, the in-silico experimentation on the use case shows that the proposed approach is a viable first step towards standard and automated design in biofabrication.


title: The adapted Activity-By-Contact-model for enhancer-gene assignment and its combination with transcription factor affinities in single cell data

abstract: Identifying regulatory regions in the genome is of great interest for understanding the epigenomic landscape in cells. One fundamental challenge in this context is to find the target genes whose expression the regulatory regions affect. A recent successful method is the Activity-By-Contact (ABC) model [10] which scores enhancer-gene interactions based on enhancer activity and the contact frequency of an enhancer to its target gene. It requires two types of assays to measure enhancer activity, which limits the applicability. The ABC score describes regulatory interactions entirely from a genes perspective, and does not account for all the candidate target genes of an enhancer. Moreover, there is no implementation available which would allow for an integration with transcription factor (TF) binding information or an efficient analysis of single-cell data. We show that the ABC-model is comparably accurate with only one assay to measure enhancer activity. Further, we demonstrate that it can yield a higher accuracy by adapting the enhancer activity according to the number of contacts the enhancer has to its candidate target genes. We combined our adapted ABC-model with TF binding information and illustrate an analysis of a single-cell ATAC-seq data set of the human heart. We were able to characterise cell type-specific regulatory interactions as well as to prioritise candidate TFs that drive cell type-specific expression. All executed processing steps are incorporated into our new computational pipeline STARE. The software is available at https://github.com/schulzlab/STARE.


title: The adapted Activity-By-Contact model for enhancer-gene assignment and its application to single-cell data


title: Comparative analysis of machine learning algorithms on the microbial strain-specific AMP prediction

abstract: The evolution of drug-resistant pathogenic microbial species is a major global health concern. Naturally occurring, antimicrobial peptides (AMPs) are considered promising candidates to address antibiotic resistance problems. A variety of computational methods have been developed to accurately predict AMPs. The majority of such methods are not microbial strain-specific (MSS): they can predict whether a given peptide is active against some microbe, but cannot accurately calculate whether such peptide would be active against a particular microbial strain. Due to insufficient data on most microbial strains, only a few MSS predictive models have been developed so far. To overcome this problem, we developed a novel approach that allows to improve MSS predictive models (MSSPM), based on properties, computed for AMP sequences and characteristics of genomes, computed for target microbial strains. New models can perform predictions of AMPs for microbial strains that do not have data on peptides tested on them. We tested various types of feature engineering as well as different machine learning (ML) algorithms to compare the predictive abilities of resulting models. Among the ML algorithms, Random Forest and AdaBoost performed best. By using genome characteristics as additional features, the performance for all models increased significantly--on average by 7%--relative to models relying on AMP sequence-based properties only. Our novel MSS AMP predictor is freely accessible as part of DBAASP database resource at https://dbaasp.org/tools?page=genome-prediction


title: Neurogenesis and angiogenesis are associated features of aggressive breast cancer

abstract: The tumor microenvironment (TME) is important for cancer growth and progress. Whereas angiogenesis is an established hallmark of cancer, the field of cancer neuroscience is now emerging. Here, we asked whether neurogenesis and angiogenesis are associated features in breast cancer and related to aggressive behavior. Single cell-based spatial analysis by imaging mass cytometry (IMC) indicated significant colocalization of neural and vascular structures, suggesting the presence of neuro-vascular niches within the tumor tissue. By protein and gene expression data from human breast cancer cohorts, we found that neurogenesis and angiogenesis, together with a consolidated neuro-angiogenic signature score, were linked to high-grade breast cancer characteristics and reduced survival, also within the luminal tumor subgroup. Cases with high neuro-angiogenic score were split in two subgroups, one hormone receptor negative and one receptor positive. Our findings might be relevant for improved patient stratification and further exploration of novel treatment strategies.

category: cancer biology


title: Mechanodetection of neighbor plants elicits adaptive leaf movements through calcium dynamics

abstract: Plants detect their neighbors via various cues, including reflected light and touching of leaf tips, which elicit in upward leaf movement (hyponasty). It is currently unknown how touch is sensed and how the signal is transferred from the leaf tip to the petiole base that drives hyponasty. Here, we show that touch-induced hyponasty involves a signal transduction pathway that is distinct from light-mediated hyponasty. We found that mechanostimulation of the leaf tip upon touching causes cytosolic calcium ([Ca2+]cyt induction in leaf tip trichomes that spreads towards the petiole. Both perturbation of the calcium response and the absence of trichomes inhibit touch-induced hyponasty. Finally, using plant competition assays, we show that touch-induced hyponasty is adaptive in dense stands of Arabidopsis. We thus establish a novel, adaptive mechanism regulating hyponastic leaf movement in response to mechanostimulation by neighbors in dense vegetation.

category: plant biology


title: Face processing in the infant brain after pandemic lockdown

abstract: The role of visual experience in the development of face processing has long been debated. We present a new angle on this question through a serendipitous study that cannot easily be repeated. Infants viewed short blocks of faces during fMRI in a repetition suppression task. The same identity was presented multiple times in half of the blocks (Repeat condition) and different identities were presented once each in the other half (Novel condition). In adults, the fusiform face area (FFA) tends to show greater neural activity for Novel vs. Repeat blocks in such designs, suggesting that it can distinguish same vs. different face identities. As part of an ongoing study, we collected data before the COVID-19 pandemic and after an initial State lockdown was lifted. The resulting sample of 12 infants (9-24 months) divided equally into pre- and post-lockdown groups with matching ages and data quantity/quality. The groups had strikingly different FFA responses: pre-lockdown infants showed repetition suppression (Novel>Repeat), whereas post-lockdown infants showed the opposite (Repeat>Novel), often referred to as repetition enhancement. These findings provide speculative evidence that altered visual experience during the lockdown, or other correlated environmental changes, may have affected face processing in the infant brain.


title: Curiosity and mesolimbic functional connectivity drive information seeking in real life

abstract:
Curiosity reflects the intrinsic motivation of an individual to seek information in order to close information gaps. Laboratory-based experiments have shown that both curiosity and information seeking are associated with enhanced neural dynamics in the mesolimbic dopaminergic circuit. However, it is unclear whether curiosity and its associated neural dynamics in the dopaminergic circuit drive information seeking in real life. The present study investigated (i) whether curiosity traits predict different characteristics of real-life information seeking and (ii) whether functional connectivity within the mesolimbic dopaminergic circuit is associated with information seeking outside of the laboratory. Up to 15 month before the COVID-19 pandemic, we conducted curiosity and anxiety questionnaires as well as a 10-minute resting-state fMRI session. In a follow-up survey early during the COVID-19 pandemic, participants repeated the questionnaires and filled out an additional questionnaire about their COVID-19-related information seeking. Curiosity but not anxiety remained stable over time. Individual differences in curiosity were positively associated with the frequency of information-seeking behaviour. Anxiety during the pandemic was not linked to any characteristics of real-life information seeking. Interestingly, the frequency of information seeking was also independently predicted by individual differences in resting-state functional connectivity between the ventral tegmental area and the nucleus accumbens. The present translational study paves the way for future studies on the role of curiosity in real-life information seeking by showing that curiosity drives information seeking in real-life situations and that the curiosity-promoting mesolimbic dopaminergic functional network supports the frequency of real-life information-seeking behaviour.

SIGNIFICANCE STATEMENTCuriosity is a key driver of learning and information seeking in everyday life. However, the temporal stability of curiosity traits, their relationship to real-life information seeking, and the associated dopaminergic brain activity are poorly understood. The present study provides evidence that curiosity traits are stable over time - even through a major event, such as the COVID-19 pandemic - and that both curiosity and intrinsic functional connectivity within the mesolimbic dopaminergic circuit are associated with the frequency of real-life information seeking. These findings contribute to a better understanding of cognitive and neural differences that shape how individuals seek out information and may offer the opportunity to help individuals with suboptimal information-seeking behaviour that negatively affects their well-being or mental health.


title: Vagus nerve stimulation recruits the central cholinergic system to enhance perceptual learning

abstract: Perception can be refined by experience up to certain limits. It is unclear if limitations are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies highlight the utility of peripheral nerve stimulation - specifically vagus nerve stimulation (VNS) - for altering neural activity and augmenting experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS occurring during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Using two-photon imaging, we identified changes to auditory cortical responses and activation of cortically-projecting cholinergic axons with VNS. Anatomical and optogenetic experiments revealed that VNS seemed to enhance task performance via activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS, perhaps enabling further refinement of VNS methodology for clinical conditions.


title: On the clinical benefit of on-scalp MEG: A modeling study of on-scalp MEG epileptic activity source estimation ability

abstract:
ObjectiveWhole-head on scalp magnetoencephalography (osMEG) is a novel, cutting-edge functional neuroimaging technique that positions MEG sensors closer to the cortical sources. OsMEG allows both for free head movements and improved spatial resolution compared to conventional MEG. OsMEG thus might improve clinical epilepsy evaluations. However, it remains largely unknown how osMEG characterizes epileptic activity. Here, we aimed to compare epileptic activity source estimation accuracy of osMEG, high-density EEG (hd-EEG), conventional MEG (convMEG) and subdural EEG (sbdEEG).

MethodIED and seizure onset zone source estimations of osMEG, hdEEG, convMEG and sbdEEG were evaluated using equivalent current dipoles. Cancellation index of all non-invasive modalities were calculated and compared statistically. To further investigate any similarity between osMEG and sbdEEG, representational similarity analysis was used to compare IED source estimations of these two modalities.

ResultsWe found that osMEG IED source estimations were significantly (p<0.05) better than both convMEG and hdEEG. Furthermore, osMEG mesial temporal lobe SOZ source estimations were superior to those of convMEG and hdEEG. OsMEG cancellation index did not differ significantly from convMEG. Interestingly, comparing osMEG and sbdEEG IED source estimation demonstrated that osMEG might be less sensitive to source directions than convMEG.

ConclusionWe demonstrated that whole-head osMEG exhibited very accurate non-invasive IED and SOZ source estimations, better than both hd-EEG and convMEG.

SignificanceOsMEG has a promising potential to become a safe, highly sensitive neuroimaging modality for whole head epilepsy evaluations.

HighlightsO_LIAnalysis of novel on-scalp MEG (osMEG) sensors in epilepsy evaluations
C_LIO_LICompares osMEG, EEG, conventional MEG & intracranial EEG epilepsy source estimations
C_LIO_LIOur study demonstrates potential great clinical value of osMEG whole-head sensors
C_LI