title: Electrophysiological Indicators of Sleep-associated Memory Consolidation in 5- to 6-Year-Old Children

abstract: In adults, the synchronised interplay of sleep spindles (SP) and slow oscillations (SO) supports memory consolidation. Given tremendous developmental changes in SP and SO morphology, it remains elusive whether across childhood the same mechanisms as identified in adults are functional. Based on topography and frequency, we characterise slow and fast SPs and their temporal coupling to SOs in 24 pre-school children. Further, we ask whether slow and fast SPs and their modulation during SOs are associated with behavioural indicators of declarative memory consolidation as suggested by the literature on adults. Employing an individually tailored approach, we reliably identify an inherent, development-specific fast centro-parietal SP type, nested in the adult-like slow SP frequency range, along with a dominant slow frontal SP type. Further, we provide evidence that the modulation of fast centro-parietal SPs during SOs is already present in pre-school children. However, the temporal coordination between fast centro-parietal SPs and SOs is weaker and less precise than expected from research on adults. While we do not find evidence for a critical contribution of SP-SO coupling for memory consolidation, crucially, slow frontal and fast centro-parietal SPs are each differentially related to sleep-associated consolidation of items of varying quality. While a higher number of slow frontal SPs is associated with stronger maintenance of medium-quality memories, a higher number of fast centro-parietal SPs is linked to a greater gain of low-quality items. Our results demonstrate two functionally relevant inherent SP types in pre-school children although SP-SO coupling is not yet fully mature.


title: Detection of infiltrating fibroblasts by single-cell transcriptomics in human kidney allografts

abstract: We tested the hypothesis that single-cell RNA-sequencing (scRNA-seq) analysis of human kidney allograft biopsies will reveal distinct cell types and states and yield insights to decipher the complex heterogeneity of alloimmune injury. We selected 3 biopsies of kidney cortex from 3 individuals for scRNA-seq and processed them fresh using an identical protocol on the 10x Chromium platform; (i) HK: native kidney biopsy from a living donor, (ii) AK1: allograft kidney with transplant glomerulopathy, tubulointerstitial fibrosis, and worsening graft function, and (iii) AK2: allograft kidney after successful treatment of active antibody-mediated rejection. We did not study T-cell-mediated rejections. We generated 7217 high-quality single cell transcriptomes. Taking advantage of the recipient-donor sex mismatches revealed by X and Y chromosome autosomal gene expression, we determined that in AK1 with fibrosis, 42 months after transplantation, more than half of the kidney allograft fibroblasts were recipient-derived and therefore likely migratory and graft infiltrative, whereas in AK2 without fibrosis, 84 months after transplantation, most fibroblasts were donor-organ-derived. Furthermore, AK1 was enriched for tubular progenitor cells overexpressing profibrotic extracellular matrix genes. AK2, eight months after successful treatment of rejection, contained endothelial cells that expressed T-cell chemoattractant cytokines. In addition to these key findings, our analysis revealed unique cell types and states in the kidney. Altogether, single-cell transcriptomics yielded novel mechanistic insights, which could pave the way for individualizing the care of transplant recipients.

category: molecular biology


title: BacAnt: A Combination Annotation Server for Bacterial DNA Sequences to Identify Antibiotic Resistance Genes, Integrons, and Transposable Elements.

abstract:
Whole genome sequencing (WGS) of bacteria has become a routine method in diagnostic laboratories. One of the clinically most useful advantages of WGS is the ability to predict antimicrobial resistance genes (ARGs) and mobile genetic elements (MGEs) in bacterial sequences. This allows comprehensive investigations of such genetic features but can also be used for epidemiological studies. A plethora of software programs have been developed for the detailed annotation of bacterial DNA sequences, such as RAST (Rapid Annotation using Subsystem Technology), Resfinder, ISfinder, INTEGRALL and The Transposon Registry. Unfortunately, to this day, a reliable annotation tool of the combination of ARGs and MGEs is not available, and the generation of genbank files requires much manual input. Here, we present a new webserver which allows the annotation of ARGs, integrons, and transposable elements at the same time. The pipeline generates genbank files automatically, which are compatible with easyfig for comparative genomic analysis. Our BacAnt code and standalone software package are available at https://github.com/xthua/bacant with an accompanying web application at http://bacant.net.

Graphical Abstract

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category: microbiology


title: A mathematical framework for dissecting normative foundations of objective-driven conservation decisions

abstract: Perspectives in conservation are based on a variety of value systems. Such differences in how people value nature and its components lead to different evaluations of the morality of conservation goals and approaches, and often underlie disagreements in the formulation and implementation of environmental management policies. Specifically, whether a conservation action (e.g. killing feral cats to reduce predation on bird species threatened with extinction) is viewed as appropriate or not can vary among people with different value systems. Here, we present a conceptual, mathematical framework intended as a tool to systematically explore and clarify core value statements in conservation approaches. Its purpose is to highlight how fundamental differences between these value systems can lead to different prioritizations of available management options and offer a common ground for discourse. The proposed equations decompose the question underlying many controversies around management decisions in conservation: what or who is valued, how, and to what extent? We compare how management decisions would likely be viewed under three different idealised value systems: ecocentric conservation, which aims to preserve biodiversity; new conservation, which considers that biodiversity can only be preserved if it benefits humans; and sentientist conservation, which aims at minimising suffering for sentient beings. We illustrate the utility of the framework by applying it to case studies involving invasive alien species, rewilding, and trophy hunting. By making value systems and their consequences in practice explicit, the framework facilitates debates on contested conservation issues, and complements philosophical discursive approaches about moral reasoning. We believe dissecting the core value statements on which conservation decisions are based will provide an additional tool to understand and address conservation conflicts.

category: ecology


title: What is valued in conservation? A framework to compare ethical perspectives


title: A minimal yet flexible likelihood framework to assess correlated evolution

abstract: An evolutionary process is reflected in the sequence of changes of any trait (e.g. morphological, molecular) through time. Yet, a better understanding of evolution would be procured by characterizing correlated evolution, or when two or more evolutionary processes interact. Many previously developed parametric methods often require significant computing time as they rely on the estimation of many parameters. Here we propose a minimal likelihood framework modelling the joint evolution of two traits on a known phylogenetic tree. The type and strength of correlated evolution is characterized by few parameters tuning mutation rates of each trait and interdependencies between these rates. The framework can be applied to study any discrete trait or character ranging from nucleotide substitution to gain or loss of a biological function. More specifically, it can be used to 1) test for independence between two evolutionary processes, 2) identify the type of interaction between them and 3) estimate parameter values of the most likely model of interaction. In its current implementation, the method takes as input a phylogenetic tree together with mapped discrete evolutionary events on it and then maximizes the likelihood for one or several chosen scenarios. The strengths and limits of the method, as well as its relative power when compared to a few other methods, are assessed using both simulations and data from 16S rRNA sequences in a sample of 54 {gamma}-enterobacteria. We show that even with datasets of fewer than 100 species, the method performs well in parameter estimation and in the selection of evolutionary scenario.

category: evolutionary biology


title: Relationship between Regional White Matter Hyperintensities and Alpha Oscillations in Older Adults

abstract: Aging is associated with increased white matter hyperintensities (WMHs) and with the alterations of alpha oscillations (7-13 Hz). However, a crucial question remains, whether changes in alpha oscillations relate to aging per se or whether this relationship is mediated by age-related neuropathology like WMHs. Using a large cohort of cognitively healthy older adults (N=907, 60-80 years), we assessed relative alpha power, alpha peak frequency, and long-range temporal correlations (LRTC) from resting-state EEG. We further associated these parameters with voxel-wise WMHs from 3T MRI. We found that a higher prevalence of WMHs in the superior and posterior corona radiata as well as in the thalamic radiation was related to elevated alpha power, with the strongest association in the bilateral occipital cortex. In contrast, we observed no significant relation of the WMHs probability with alpha peak frequency and LRTC. Finally, higher age was associated with elevated alpha power via total WMH volume. Although an increase in alpha oscillations due to WMH can have a compensatory nature, we rather suggest that an elevated alpha power is a consequence of WMH affecting a spatial organization of alpha sources.

category: neuroscience


title: Transcription initiation mapping in 31 bovine tissues reveals complex promoter activity, pervasive transcription, and tissue-specific promoter usage

abstract: Characterizing transcription start sites is essential for understanding the regulatory mechanisms that control gene expression. Recently, a new bovine genome assembly (ARS-UCD1.2) with high continuity, accuracy, and completeness was released; however, the functional annotation of the bovine genome lacks precise transcription start sites and contains a low number of transcripts in comparison to human and mouse. Using the RAMPAGE approach, this study identified transcription start sites at high resolution in a large collection of bovine tissues. We found several known and novel transcription start sites attributed to promoters of protein coding and lncRNA genes that were validated through experimental and in silico evidence. With these findings, the annotation of transcription start sites in cattle reached a level comparable to the mouse and human genome annotations. In addition, we identified and characterized transcription start sites for antisense transcripts derived from bidirectional promoters, potential lncRNAs, mRNAs, and pre-miRNAs. We also analyzed the quantitative aspects of RAMPAGE to produce a promoter activity atlas, reaching highly reproducible results comparable to traditional RNA-seq. Co-expression networks revealed considerable use of tissue specific promoters, especially between brain and testicle, which expressed several genes in common from alternate loci. Furthermore, regions surrounding co-expressed modules were enriched in binding factor motifs representative of each tissue. The comprehensive annotation of promoters in such a large collection of tissues will substantially contribute to our understanding of gene expression in cattle and other mammalian species, shortening the gap between genotypes and phenotypes.

category: genomics


title: The interplay of wind and uplift facilitates over-water flight in facultative soaring birds

abstract: Flying over the open sea is energetically costly for terrestrial birds. Despite this, over-water journeys of many birds, sometimes hundreds of kilometers long, are uncovered by bio-logging technology. To understand how these birds afford their flights over the open sea, we investigated the role of atmospheric conditions, specifically wind and uplift, in subsidizing over-water flight at the global scale. We first established that {Delta}T, the temperature difference between sea surface and air, is a meaningful proxy for uplift over water. Using this proxy, we showed that the spatio-temporal patterns of sea-crossing in terrestrial migratory birds is associated with favorable uplift conditions. We then analyzed route selection over the open sea for five facultative soaring species, representing all major migratory flyways. The birds maximized wind support when selecting their sea-crossing routes and selected higher uplift when suitable wind support was available. They also preferred routes with low long-term uncertainty in wind conditions. Our findings suggest that, in addition to wind, uplift may play a key role in the energy seascape for bird migration that in turn determines strategies and associated costs for birds crossing ecological barriers such as the open sea.

category: animal behavior and cognition


title: MiREDiBase: a manually curated database of validated and putative editing events in microRNAs

abstract: MicroRNAs (miRNAs) are regulatory small non-coding RNAs that function as translational repressors. MiRNAs are involved in most cellular processes, and their expression and function are presided by several factors. Amongst, miRNA editing is an epitranscriptional modification that alters the original nucleotide sequence of selected miRNAs, possibly influencing their biogenesis and target-binding ability. A-to-I and C-to-U RNA editing are recognized as the canonical types, with the A-to-I type being the predominant one. Albeit some bioinformatics resources have been implemented to collect RNA editing data, it still lacks a comprehensive resource explicitly dedicated to miRNA editing. Here, we present MiREDiBase, a manually curated catalog of editing events in miRNAs. The current version includes 3,059 unique validated and putative editing sites from 626 pre-miRNAs in humans and three primates. Editing events in mature human miRNAs are supplied with miRNA-target predictions and enrichment analysis, while minimum free energy structures are inferred for edited pre-miRNAs. MiREDiBase represents a valuable tool for cell biology and biomedical research and will be continuously updated and expanded at https://ncrnaome.osumc.edu/miredibase.

category: bioinformatics


title: Speech auditory-motor adaptation lacks an explicit component: reduced adaptation in adults who stutter reflects limitations in implicit sensorimotor learning.

abstract: The neural mechanisms underlying stuttering remain poorly understood. A large body of work has focused on sensorimotor integration difficulties in individuals who stutter, including recently the capacity for sensorimotor learning. Typically, sensorimotor learning is assessed with adaptation paradigms in which one or more sensory feedback modalities are experimentally perturbed in real-time. Our own previous work on speech with perturbed auditory feedback revealed substantial auditory-motor learning limitations in both children and adults who stutter (AWS). It remains unknown, however, which sub-processes of sensorimotor learning are impaired. Indeed, new insights from research on upper-limb motor control indicate that sensorimotor learning involves at least two distinct components: (a) an explicit component that includes intentional strategy use and presumably is driven by target error, and (b) an implicit component that updates an internal model without awareness of the learner and presumably is driven by sensory prediction error. Here, we attempted to dissociate these components for speech auditory-motor learning in AWS vs. adults who do not stutter (AWNS). Our formant-shift auditory-motor adaptation results replicated previous findings that such sensorimotor learning is limited in AWS. Novel findings are that neither control nor stuttering participants reported any awareness of changing their productions in response to the auditory perturbation, and that neither group showed systematic drift in auditory target judgments made throughout the adaptation task. These results indicate that speech auditory-motor adaptation relies exclusively on implicit learning processes. Thus, limited adaptation in AWS reflects poor implicit sensorimotor learning.


title: Experimental evolution confirms signatures of sexual selection in genomic divergence.

abstract:
Comparative genomics has contributed to the growing evidence that sexual selection is an important component of evolutionary divergence and speciation. Divergence by sexual selection is implicated in faster rates of divergence of the X chromosome and of genes thought to underlie sexually selected traits, including genes that are sex-biased in expression. However, accurately inferring the relative importance of complex and interacting forms of natural selection, demography and neutral processes which occurred in the evolutionary past is challenging. Experimental evolution provides an opportunity to apply controlled treatments for multiple generations and examine the consequent genomic divergence. Here we altered sexual selection intensity, elevating sexual selection in polyandrous lines and eliminating it in monogamous lines, and examined patterns of divergence in the genome of Drosophila pseudoobscura after more than 160 generations of experimental evolution. Divergence is not uniform across the genome but concentrated in "islands", many of which contain candidate genes implicated in mating behaviours and other sexually selected phenotypes. These are more often seen on the X chromosome, which shows divergence greater than neutral expectations. There are characteristic signatures of selection seen in these regions, with lower diversity and greater FST on the X chromosome than the autosomes, and differences in diversity on the autosomes between selection regimes. Reduced Tajimas D implies that selective sweeps have occurred within some of the divergent regions, despite considerable recombination. These changes are associated with both differential gene expression between the lines and sex-biased gene expression within the lines. Our results are very similar to those thought to implicate sexual selection in divergence in natural populations, and hence provide experimental support for the likely role of sexual selection in driving such types of genetic divergence, but also illustrate how variable outcomes can be for different genomic regions.

Impact SummaryHow does sexual selection contribute to the divergence of genomes? It is often thought that sexual selection is a potent force in evolutionary divergence, but finding  signatures of sexual selection in the genome is not straight-forward, and has been quite controversial recently. Here we used experimental evolution to allow replicate populations of fruit fly to evolve under relaxed or strengthened sexual selection for over 160 generations, then sequenced their genomes to see how they had diverged. The features we find are very similar to those reported in populations of natural species thought to be under strong sexual selection. We found that genomic divergence was concentrated in small patches of the genome rather than widespread. These are more often seen on the X chromosome, which overall shows especially elevated divergence. There are also characteristic signatures of selection seen in these regions, with lower genetic diversity suggesting that selection was strong in these regions. The changes are associated with both differential gene expression between the lines and sex-biased gene expression within the lines. Many of the patches of divergence also contain candidate genes implicated in mating behaviours and other sexually selected phenotypes. Our results provide experimental support for the likely role of sexual selection in driving such types of genetic divergence.


title: Discrimination of melanoma cell lines with Fourier Transform Infrared (FTIR) spectroscopy

abstract:
Among skin cancers, melanoma is the lethal form and the leading cause of death in humans. Melanoma begins in melanocytes and is curable at early stages. Thus, early detection and evaluation of its metastatic potential are crucial for effective clinical intervention. Fourier transform infrared (FTIR) spectroscopy has gained considerable attention due to its versatility in detecting biochemical and biological features present in the samples. Changes in these features are used to differentiate between samples at different stages of the disease. Previously, FTIR spectroscopy has been mostly used to distinguish between healthy and diseased conditions. With this study, we aim to discriminate between different melanoma cell lines based on their FTIR spectra. Formalin-fixed paraffin embedded samples from three melanoma cell lines (IPC-298, SK-MEL-30 and COLO-800) were used. Statistically significant differences were observed in the prominent spectral bands of three cell lines along with shifts in peak positions. A partial least square discriminant analysis (PLS-DA) model built for the classification of three cell lines showed an overall accuracy of 92.6% with a sensitivity of 85%, 95.75%, 96.54%, and specificity of 97.80%, 92.14%, 98.64% for the differentiation of IPC-298, SK-MEL-30, and COLO-800, respectively. The results suggest that FTIR spectroscopy can differentiate between different melanoma cell lines and thus potentially characterize the metastatic potential of melanoma.

Sources of FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.


title: Visual speech differentially modulates beta, theta, and high gamma bands in auditory cortex

abstract: Speech perception is a central component of social communication. While principally an auditory process, accurate speech perception in everyday settings is supported by meaningful information extracted from visual cues (e.g., speech content, timing, and speaker identity). Previous research has shown that visual speech modulates activity in cortical areas subserving auditory speech perception, including the superior temporal gyrus (STG), potentially through feedback connections from the multisensory posterior superior temporal sulcus (pSTS). However, it is unknown whether visual modulation of auditory processing in the STG is a unitary phenomenon or, rather, consists of multiple temporally, spatially, or functionally distinct processes. To explore these questions, we examined neural responses to audiovisual speech measured from intracranially implanted electrodes within the temporal cortex of 21 patients undergoing clinical monitoring for epilepsy. We found that visual speech modulates auditory processes in the STG in multiple ways, eliciting temporally and spatially distinct patterns of activity that differ across theta, beta, and high-gamma frequency bands. Before speech onset, visual information increased high-gamma power in the posterior STG and suppressed beta power in mid-STG regions, suggesting crossmodal prediction of speech signals in these areas. After sound onset, visual speech decreased theta power in the middle and posterior STG, potentially reflecting a decrease in sustained feedforward auditory activity. These results are consistent with models that posit multiple distinct mechanisms supporting audiovisual speech perception and provide a crucial map for subsequent studies to identify the types of visual features that are encoded by these separate mechanisms.


title: Characterization of ethylene-inducible pedicel-fruit abscission zone formation in non-climacteric sweet cherry (Prunus avium L.)

abstract: Harvesting of sweet cherry (Prunus avium L.) fruit is a labor-intensive process. Mechanical harvesting of sweet cherry fruit is feasible; however, it is dependent on the formation of an abscission zone at the fruit-pedicel junction. The natural propensity for pedicel-fruit abscission zone (PFAZ) formation varies by cultivar, and the general molecular basis for PFAZ formation is not well characterized. In this study, ethylene-inducible change in pedicel fruit retention force (PFRF) was recorded in a developmental time course with a concomitant analysis of the PFAZ transcriptome from three sweet cherry cultivars. In  Skeena, mean PFRF for both control and treatment fruit dropped below the 0.40kg-force (3.92N) threshold for mechanical harvesting and indicating the formation of a discrete PFAZ. In  Bing, mean PFRF for both control and treatment groups decreased over time. However, a mean PFRF conducive to mechanical harvesting was achieved only in the ethylene-treated fruit. While in  Chelan the mean PFRF of the control and treatment groups did not meet the threshold required for efficient mechanical harvesting. Transcriptome analysis of the PFAZ followed by the functional annotation, differential expression analysis, and gene ontology (GO) enrichment analyses of the data facilitated the identification of phytohormone-responsive and abscission-related transcripts as well as processes that exhibited differential expression and enrichment in a cultivar-dependent manner over the developmental time-course. Additionally, read alignment-based variant calling revealed several short variants in differentially expressed genes, associated with enriched gene ontologies and associated metabolic processes, lending potential insight into the genetic basis for different abscission responses between the cultivars. These results provide genetic targets for induction or inhibition of PFAZ formation, depending on the desire to harvest the fruit with or without the stem attached. Understanding the genetic mechanisms underlying the development of the PFAZ will inform future cultivar development while laying a foundation for mechanized sweet cherry harvest.

category: plant biology


title: The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

abstract: Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieves a durable remission. SIRT5 is a member of the sirtuin family of protein deacylases that regulate metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we show that SIRT5 is required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye and is incurable once metastatic. Likewise, SIRT5 is required for efficient tumor formation by melanoma xenografts and in an autochthonous mouse Braf;Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we find that SIRT5 is required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably include MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a novel, druggable genotype-independent addiction in melanoma.

category: cancer biology


title: EPH tyrosine kinase receptors regulate epithelial morphogenesis and phosphorylate the PAR-3 scaffold protein to modulate downstream signaling networks

abstract: The EPH family is the largest among receptor tyrosine kinases (RTKs) in humans. In contrast to other RTKs, EPH receptors (EPHRs) cognate ligands, ephrins, are tethered to the cell surface. This results in EPHR-ephrin signaling being mainly involved in short-range cell-cell communication events that regulate cell adhesion, migration and tissue boundary formation. Although EPHRs functions have been broadly studied, the molecular mechanisms by which they control these processes are far from being understood. To address this, we sought to identify new effector proteins acting downstream of EPHRs and determine their role in EPHR-regulated functions. To unravel EPHR-associated signaling complexes under native conditions, we applied a mass spectrometry-based approach, namely BioID proximity labeling. We obtained a composite proximity network from EPHA4, -B2, -B3 and -B4 receptors that comprises 395 proteins, most of which were not previously linked to EPH signaling. A gene ontology and pathway term analysis of the most common candidates highlighted cell polarity as a novel function associated with EPHR activity. We found that EPHA1 and EPHB4 expression is restricted to the basal and lateral membrane domains in polarized Caco-2 3D spheroidal cell cultures. We further discovered that their depletion impairs the compartmentalized distribution of polarity proteins as well as overall spheroid morphogenesis. Moreover, we examined the contribution of a number of candidates, selected from EPHR proximity networks, via loss-of-function in an EPHR-dependent cell segregation assay. We found that depletion of the signaling scaffold PAR-3 blocks cell sorting. We also delineated a signalling complex involving the C-terminal SRC kinase (CSK), whose recruitment to PAR-3 complexes is dependent on EPHR signals. Our work sheds a new light on EPHR signaling networks and describes conceptually novel the mechanisms by which EPHRs signal at the membrane to contribute to the regulation of cellular phenotypes.


title: Shifts in mutation spectra enhance access to beneficial mutations

abstract:
Biased mutation spectra are pervasive, with widely varying direction and magnitude of mutational biases that influence genome evolution and adaptation. Why are unbiased spectra rare, and how do such diverse biases evolve? Our experiments show that changing the mutation spectrum allows populations to sample previously under-sampled mutational space, including beneficial mutations. The resulting shift in the distribution of fitness effects is advantageous: beneficial mutation supply and beneficial pleiotropy both increase, and deleterious load reduces. More broadly, simulations indicate that the evolution of a mutational bias in an unbiased ancestor is selectively neutral; but reversing the direction of a long-term bias is always selectively favoured. Indeed, we predict frequent spectrum changes in the bacterial phylogeny, typically involving reversals of ancestral bias. Thus, shifts in mutation spectra may evolve under selection, and can directly alter the outcome of adaptive evolution by facilitating access to beneficial mutations.

SIGNIFICANCE STATEMENTMutations are important because they provide raw material for evolution. Some types of mutations occur more often than others, but the direction and degree of such mutational biases varies. How do mutational biases evolve, and do they influence evolution? We experimentally measured the immediate effects of changing the mutation bias of E. coli, and used simulations to test the long-term effects. Altering mutational bias is beneficial whenever the new bias increases sampling of mutational classes that were previously under-sampled. We also show that historically, bacteria have often experienced such beneficial bias switches. Our work demonstrates the importance of mutational biases in evolution. By allowing exploration of new mutational space, altered mutation biases could drive rapid adaptation even in constant environments.


title: A comparison of population receptive fields from fMRI and large-scale neurophysiological recordings in non-human primates.

abstract: Population receptive field (pRF) modeling is a popular fMRI method to map the retinotopic organization of the human brain. While fMRI-based pRF-maps are qualitatively similar to invasively recorded single-cell receptive fields in animals, it remains unclear what neuronal signal they represent. We addressed this question in awake non-human primates comparing whole-brain fMRI and large-scale neurophysiological recordings in areas V1 and V4 of the visual cortex. We examined the fits of several pRF-models based on the fMRI BOLD-signal, multi-unit spiking activity (MUA) and local field potential (LFP) power in different frequency bands. We found that pRFs derived from BOLD-fMRI were most similar to MUA-pRFs in V1 and V4, while pRFs based on LFP gamma power also gave a good approximation. FMRI-based pRFs thus reliably reflect neuronal receptive field properties in the primate brain. In addition to our results in V1 and V4, the whole-brain fMRI measurements revealed retinotopic tuning in many other cortical and subcortical areas with a consistent increase in pRF-size with increasing eccentricity, as well as a retinotopically specific deactivation of default-mode network nodes similar to previous observations in humans.


title: Population receptive fields in non-human primates from whole-brain fMRI and large-scale neurophysiology in visual cortex


title: Self-Supervised Natural Image Reconstruction and Large-Scale Semantic Classification from Brain Activity

abstract: Reconstructing natural images and decoding their semantic category from fMRI brain recordings is challenging. Acquiring sufficient pairs of images and their corresponding fMRI responses, which span the huge space of natural images, is prohibitive. We present a novel self-supervised approach that goes well beyond the scarce paired data, for achieving both: (i) state-of-the art fMRI-to-image reconstruction, and (ii) first-ever large-scale semantic classification from fMRI responses. By imposing cycle consistency between a pair of deep neural networks (from image-to-fMRI & from fMRI-to-image), we train our image reconstruction network on a large number of "unpaired" natural images (images without fMRI recordings) from many novel semantic categories. This enables to adapt our reconstruction network to a very rich semantic coverage without requiring any explicit semantic supervision. Specifically, we find that combining our self-supervised training with high-level perceptual losses, gives rise to new reconstruction & classification capabilities. In particular, this perceptual training enables to classify well fMRIs of never-before-seen semantic classes, without requiring any class labels during training. This gives rise to: (i) Unprecedented image-reconstruction from fMRI of never-before-seen images (evaluated by image metrics and human testing), and (ii) Large-scale semantic classification of categories that were never-before-seen during network training. Such large-scale (1000-way) semantic classification from fMRI recordings has never been demonstrated before. Finally, we provide evidence for the biological consistency of our learned model.


title: Forward genetics in Wolbachia: Regulation of Wolbachia proliferation by the amplification and deletion of an addictive genomic island

abstract: Wolbachia is one of the most prevalent bacterial endosymbionts, infecting approximately 40% of terrestrial arthropod species. Wolbachia is often a reproductive parasite but can also provide fitness benefits to its host, as, for example, protection against viral pathogens. This protective effect is currently being applied to fight arboviruses transmission by releasing Wolbachia-transinfected mosquitoes. Titre regulation is a crucial aspect of Wolbachia biology. Higher titres can lead to stronger phenotypes and fidelity of transmission but can have a higher cost to the host. Since Wolbachia is maternally transmitted, its fitness depends on host fitness, and, therefore, its cost to the host may be under selection. Understanding how Wolbachia titres are regulated and other aspects of Wolbachia biology has been hampered by the lack of genetic tools. Here we developed a forward genetic screen to identify new Wolbachia over-proliferative mutant variants. We characterized in detail two new mutants, wMelPop2 and wMelOctoless, and show that the amplification or loss of the Octomom genomic region lead to over-proliferation. These results confirm previous data and expand on the complex role of this genomic region in the control of Wolbachia proliferation. Both new mutants shorten the host lifespan and increase antiviral protection. Moreover, we show that Wolbachia proliferation rate in Drosophila melanogaster depends on the interaction between Octomom copy number, the host developmental stage, and temperature. Our analysis also suggests that the life shortening and antiviral protection phenotypes of Wolbachia are dependent on different, but related, properties of the endosymbiont; the rate of proliferation and the titres near the time of infection, respectively. Altogether, we demonstrate the feasibility of a novel and unbiased experimental approach to study Wolbachia biology, which can be further adapted to characterize other genetically intractable bacterial endosymbionts.


title: Contributions of h- and Na+/K+ pump currents to the generation of episodic and continuous rhythmic activities

abstract:
Developing spinal motor networks produce a diverse array of outputs, including episodic and continuous patterns of rhythmic activity. Variation in excitability state and neuromodulatory tone can facilitate transitions between episodic and continuous rhythms; however, the intrinsic mechanisms that govern these rhythms and their transitions are poorly understood. Here, we tested the capacity of a single central pattern generator (CPG) circuit with tunable properties to generate multiple outputs. To address this, we deployed a computational model composed of an inhibitory half-centre oscillator (HCO). Following predictions of our computational model, we tested the contributions of key properties to the generation of an episodic rhythm produced by isolated spinal cords of the newborn mouse. The model recapitulates the diverse state-dependent rhythms evoked by dopamine. In the model, episodic bursting depended predominantly on the endogenous oscillatory properties of neurons, with Na+/K+ ATPase pump (IPump) and hyperpolarization-activated currents (Ih) playing key roles. Modulation of either IPumpMax or Ih produced transitions between episodic and continuous rhythms and silence. As IPump increased, the episode duration and period increased along with a reduction in interepisode interval. Increasing Ih increased the episode period along with an increase in episode duration. Pharmacological manipulations of Ih with ZD7288 and IPump with ouabain or monensin in isolated spinal cords produced findings consistent with the model. Our modelling and experimental results highlight key roles of Ih and IPump in producing episodic rhythms and provide insight into mechanisms that permit a single CPG to produce multiple patterns of rhythmicity.

Significance statementThe ability of a single CPG to produce and transition between multiple rhythmic patterns of activity is poorly understood. We deployed a complementary computational half-centre oscillator model and an isolated spinal cord experimental preparation to identify key currents whose interaction produced episodic and continuous rhythmic activity. Together, our experimental and modelling approaches suggest mechanisms in spinal networks that govern diverse rhythms and transitions between them. This work sheds light on the ability of a single CPG to produce episodic bouts observed in behavioural and pathological contexts.


title: Mental Chronometry of Speaking in Dialogue: Semantic Interference Turns into Facilitation

abstract:
Numerous studies demonstrate that the production of words is delayed when speakers process in temporal proximity semantically related words. Yet the experimental settings underlying this effect are different from those under which we typically speak. This study demonstrates that semantic interference disappears, and can even turn into facilitation, when semantically related words are embedded in a meaningful communicative exchange. Experiment 1 and 3 (each N=32 university students) implemented a picture- word interference task in a game played between two participants: one named the distractor word and, after a stimulus-onset-asynchrony of -150ms or -650ms, the other named a semantically related or unrelated target picture. Semantic interference reappeared with identical experimental parameters in a single-person picture-word interference setting (Experiment 2, N=32). We conclude that the inhibitory context effects leading to semantic interference in single-subject settings are attenuated whereas facilitatory effects are enhanced in communicative settings.

HighlightsO_LIIn isolated speakers processing semantically related words interferes with speaking
C_LIO_LIYet we typically speak to communicate with others
C_LIO_LIThis study transfers picture-word interference to a communicative setting
C_LIO_LISemantically related words produced by a partner do not interfere with speaking
C_LI


title: The N-terminus of varicella-zoster virus glycoprotein B has a functional role in fusion.

abstract:
Abstract.Varicella-zoster virus (VZV) is a medically important alphaherpesvirus that induces fusion of the virion envelope and the cell membrane during entry, and between cells to form polykaryocytes within infected tissues during pathogenesis. All members of the Herpesviridae, including VZV, have a conserved core fusion complex composed of glycoproteins, gB, gH and gL. The ectodomain of the primary fusogen, gB, has five domains, DI-V, of which DI contains the fusion loops needed for fusion function. We recently demonstrated that DIV is critical for fusion initiation, which was revealed by a 2.8[A] structure of a VZV neutralizing mAb, 93k, bound to gB and mutagenesis of the gB-93k interface. To further assess the mechanism of mAb 93k neutralization, the binding site of a non-neutralizing mAb to gB, SG2, was compared to mAb 93k using single particle cryogenic electron microscopy (cryo-EM). The gB-SG2 interface partially overlapped with that of gB-93k but, unlike mAb 93k, mAb SG2 did not interact with the gB N-terminus, suggesting a potential role for the gB N-terminus in membrane fusion. The gB ectodomain structure in the absence of antibody was defined at near atomic resolution by single particle cryo-EM (3.9[A]) of native full-length gB purified from infected cells and by X-ray crystallography (2.4[A]) of the transiently expressed ectodomain. Both structures revealed that the VZV gB N-terminus (aa72-114) was flexible based on the absence of visible structures in the cryo-EM or X-ray crystallography data but the presence of gB N-terminal peptides were confirmed by mass spectrometry. Notably, N-terminal residues 109KSQD112 were predicted to form a small -helix and alanine substitution of these residues abolished cell-cell fusion in a virus-free assay. Importantly, transferring the 109AAAA112 mutation into the VZV genome significantly impaired viral propagation. These data establish a functional role for the gB N-terminus in membrane fusion broadly relevant to the Herpesviridae.

Author SummaryHerpesviruses are ubiquitous infectious agents of medical and economic importance, including varicella-zoster virus (VZV), which causes chicken pox and shingles. A unifying theme of herpesviruses is their mechanism of entry into host cells, membrane fusion, via a core complex of virally expressed envelope glycoproteins gB, gH and gL. Of these, the primary fusogen, gB, is activated by the heterodimer gH-gL through an unknown mechanism and enables the virus envelope to merge with cell membranes to release the DNA containing capsid into the cytoplasm to initiate infection. By using a human antibody that neutralizes VZV we have recently demonstrated that the initiation of membrane fusion is associated with the crown region of gB. Here, we use cryogenic electron microscopy to compare the structure of this human neutralizing antibody, 93k, to a non-neutralizing antibody SG2. Surprisingly, both antibodies bind to the crown of gB with considerable overlap of their footprints on gB with one important exception, SG2 does not bind to a flexible region in the gB N-terminus. Mutations incorporated into this flexible region disrupts gB mediated membrane fusion and significantly impairs VZV propagation, identifying an Achilles heel in viral replication.


title: Seasonal and long-term consequences of esca on grapevine stem xylem integrity

abstract:
Hydraulic failure has been extensively studied during drought-induced plant dieback, but its role in plant-pathogen interactions is under debate. During esca, a grapevine (Vitis vinifera) disease, symptomatic leaves are prone to irreversible hydraulic dysfunctions but little is known about the hydraulic integrity of perennial organs over the short- and long-term. We investigated the effects of esca on stem hydraulic integrity in naturally infected plants within a single season and across season(s). We coupled direct (ks) and indirect (kth) hydraulic conductivity measurements, and tylose and vascular pathogen detection with in vivo X-ray microtomography visualizations. We found xylem occlusions (tyloses), and subsequent loss of stem ks, in all of the shoots with severe symptoms (apoplexy) and in more than 60% of the shoots with moderate symptoms (tiger-stripe), and no tyloses in shoots that were currently asymptomatic. In vivo stem observations demonstrated that tyloses were observed only when leaf symptoms appeared, and resulted in more than 50% PLC in 40% of symptomatic stems, unrelated to symptom age. The impact of esca on xylem integrity was only seasonal and no long-term impact of disease history was recorded. Our study demonstrated how and to what extent a vascular disease such as esca, affecting xylem integrity, could amplify plant mortality by hydraulic failure.

HighlightOur study reveals that esca can critically affect xylem water movement in grapevine perennial organs, by the presence of plant-derived tyloses.


title: The Temporal Dynamics of Opportunity Costs: A Normative Account of Cognitive Fatigue and Boredom

abstract: Cognitive fatigue and boredom are two phenomenological states that reflect overt task disengagement. In this paper, we present a rational analysis of the temporal structure of controlled behavior, which provides a formal account of these phenomena. We suggest that in controlling behavior, the brain faces competing behavioral and computational imperatives, and must balance them by tracking their opportunity costs over time. We use this analysis to flesh out previous suggestions that feelings associated with subjective effort, like cognitive fatigue and boredom, are the phenomenological counterparts of these opportunity cost measures, instead of reflecting the depletion of resources as has often been assumed. Specifically, we propose that both fatigue and boredom reflect the competing value of particular options that require foregoing immediate reward but can improve future performance: Fatigue reflects the value of offline computation (internal to the organism) to improve future decisions, while boredom signals the value of exploration (external in the world). We demonstrate that these accounts provide a mechanistically explicit and parsimonious account for a wide array of findings related to cognitive control, integrating and reimagining them under a single, formally rigorous framework.


title: Enhanced endogenous activity predicts elimination of adult-born neurons in the mouse olfactory bulb

abstract: Adult-born cells, arriving daily into the rodent olfactory bulb, either integrate into the neural circuitry or get eliminated. Whether these two populations differ in their morphological or functional properties remains, however, unclear. Using longitudinal in vivo two-photon imaging, we monitored dendritic morphogenesis, odor-evoked responsiveness, endogenous Ca2+ signaling, and survival/death of adult-born juxtaglomerular neurons (abJGNs). We found that maturation of abJGNs is accompanied by a significant reduction in dendritic complexity, with surviving and subsequently eliminated cells showing similar degrees of dendritic remodeling. Surprisingly, 63% of eliminated abJGNs acquired odor-responsiveness before death, with amplitudes and time courses of odor-evoked responses similar to those recorded in surviving cells. We observed, however, a significant long-lasting enhancement of endogenous Ca2+ signaling in subsequently eliminated abJGNs, visible already 6 days before death. These findings identify ongoing endogenous Ca2+ signaling as a key predictor of abJGNs fate.


title: Simplicial and Topological Descriptions of Human Brain Dynamics

abstract:
Whereas brain imaging tools like functional Magnetic Resonance Imaging (fMRI) afford measurements of whole-brain activity, it remains unclear how best to interpret patterns found amid the datas apparent self-organization. To clarify how patterns of brain activity support brain function, one might identify metric spaces that optimally distinguish brain states across experimentally defined conditions. Therefore, the present study considers the relative capacities of several metric spaces to disambiguate experimentally defined brain states. One fundamental metric space interprets fMRI data topographically, i.e, as the vector of amplitudes of a multivariate signal, changing with time. Another perspective considers the condition-dependency of the brains Functional Connectivity (FC), i.e., the similarity matrix computed across the variables of a multivariate signal. More recently, metric spaces that think of the data topologically, e.g., as an abstract geometric object, have become available. In the abstract, uncertainty prevails regarding the distortions imposed by the mode of measurement upon the object under study. Features that are invariant under continuous deformations, such as rotation and inflation, constitute the features of topological data analysis. While there are strengths and weaknesses of each metric space, we find that metric spaces that track topological features are optimal descriptors of the brains experimentally defined states.

AUTHOR SUMMARYTime-Varying Functional Connectivity (TVFC) leverages brain imaging data to interpret brain function as time-varying patterns of coordinating activity among brain regions. While many questions remain regarding the organizing principles through which brain function emerges from multi-regional interactions, advances in the mathematics of Topological Data Analysis (TDA) may provide new insights into the brains functional self-organization. One tool from TDA, "persistent homology", observes the occurrence and persistence of n-dimensional holes in a sequence of simplicial complexes extracted from a weighted graph. The occurrence of such holes within the TVFC graph may indicate preferred routes of information flow among brain regions. In the present study, we compare the use of persistence homology versus more traditional metrics at the task of segmenting brain states that differ across experimental conditions. We find that the structures identified by persistence homology more accurately segment the stimuli, more accurately segment high versus low performance levels under common stimuli, and generalize better across volunteers. These findings support the topological interpretation of brain dynamics.


title: Synaptic plasticity in the orbitofrontal cortex explains how risk attitude adapts to the range of risk prospects

abstract: Many deleterious societal trends, such as skepticism towards climate change or ideological refusal of vaccination, are irrational. But is irrational behavior the incidental outcome of biological constraints imposed on neural information processing? Recent studies indicate that orbitofrontal neurons encode decision value in relative terms, i.e. value signals in OFC neurons are normalized with respect to the context. A seducing explanation is "efficient coding": OFC neurons may mitigate information loss by adapting their (bounded) output firing properties to the recent value range. However, whether the behavioral implications of this scenario are met, how it generalizes to realistic situations in which OFC neurons construct value from multiple decision-relevant attributes, and what its neurophysiological bases are is unclear. Here, we address these issues by re-analyzing two open fMRI datasets from the OpenNeuro.org initiative, where people have to integrate prospective gains and losses to decide whether to gamble or not. First, we show that peoples' risk attitudes critically depend on the range of gain prospects they are exposed to. Importantly, counter to simple efficient coding scenarios, differences in gain ranges induced progressive changes in peoples' sensitivity to both gains and losses. Second, we use artificial neural network models to show that synaptic rewiring processes between attribute-specific and integration neurons predict both irrational changes in loss aversion and multivariate patterns of fMRI activity in the OFC. Our results demonstrate how synaptic plasticity within brain networks may result in range adaptation, eventually yielding complex though predictable irrational behavior.


title: Visual QC Protocol for FreeSurfer Cortical Parcellations from Anatomical MRI

abstract: Quality control of morphometric neuroimaging data is essential to improve reproducibility. Owing to the complexity of neuroimaging data and subsequently the interpretation of their results, visual inspection by trained raters is the most reliable way to perform quality control. Here, we present a protocol for visual quality control of the anatomical accuracy of FreeSurfer parcellations, based on an easy-to-use open source tool called VisualQC. We comprehensively evaluate its utility in terms of error detection rate and inter-rater reliability on two large multi-site datasets, and discuss site differences in error patterns. This evaluation shows that VisualQC is a practically viable protocol for community adoption.


title: The effects of multi-day rTMS and cardiorespiratory fitness on working memory and local GABA concentration

abstract: Working memory (WM) refers to the capacity to temporarily retain and manipulate finite amounts of information; a critical process in complex behaviours such as reasoning, comprehension, and learning. This cognitive function is supported by a parietal-prefrontal network and linked to the activity of key neurotransmitters, such as gamma-aminobutyric acid (GABA). Impairments in WM are seen in a range of psychiatric and neurological disorders, and there are currently no effective treatments. In this study, we analysed secondary outcome measures from a trial investigating the effects of multi-day rTMS on cognition. Participants received four days of 20 Hz rTMS to an individualised region of left parietal cortex in one week, and an individualised region of pre-supplementary motor area (pre-SMA) in a separate week. We assessed changes to WM function before and after each week of stimulation (N = 39), and changes to GABA concentration before and after stimulation in week one using MR spectroscopy (N = 18 per stimulation condition). We hypothesised that parietal rTMS would enhance WM and alter GABA concentration at the site of stimulation, but this was not observed. Instead, we report some evidence of improved WM function following the first week of pre-SMA rTMS stimulation, and a generalised increase in GABA concentration across both parietal and pre-SMA voxels following pre-SMA rTMS. Additionally, we found that higher cardiorespiratory fitness was associated with greater WM improvement following pre-SMA stimulation. This study does not support the use of parietal multi-day rTMS for the enhancement of working memory. In contrast, the results suggest that increasing cardiorespiratory fitness may provide a novel approach to enhance the effects of pre-SMA rTMS on cognition.


title: Human cells contain myriad excised linear intron RNAs with potential functions in gene regulation and as disease biomarkers

abstract: By using TGIRT-seq, we identified >8,500 short full-length excised linear intron (FLEXI) RNAs in human cells. Subsets of FLEXIs accumulated in a cell-type specific manner, and [~]200 corresponded to agotrons or mirtrons or encoded snoRNAs. Analysis of CLIP-seq datasets identified potential interactions between FLEXIs and >100 different RNA-binding proteins (RBPs), 53 of which had binding sites in [≥]30 different FLEXIs. In addition to proteins that function in RNA splicing, these 53 RBPs included transcription factors, chromatin remodeling proteins, and cellular growth regulators that impacted FLEXI host gene alternative splicing and/or mRNA levels in knockdown datasets. We computationally identified six groups of RBPs whose binding sites were enriched in different subsets of FLEXIs: AGO1-4 and DICER associated with agotrons and mirtrons; AATF, DKC1, NOLCI, and SMNDC1 associated with snoRNA-encoding FLEXIs; two different combinations of alternative splicing factors found in stress granules; and two novel RBP-intron combinations, one including LARP4 and PABC4, which function together in the cytoplasm to regulate ribosomal protein translation. Our results suggest a model in which proteins involved in transcriptional regulation, alternative splicing, or post-splicing secondary functions bind and stabilize cell-type specific subsets of FLEXIs that perform different biological functions and have potential utility as biomarkers.


title: Human cells contain myriad excised linear introns with potential functions in gene regulation and as RNA biomarkers


title: Human cells contain myriad excised linear intron RNAs with links to gene regulation and potential utility as biomarkers


title: Comparing synthetic refocusing to deconvolution for the extraction of neuronal calcium transients from light-fields

abstract:
SignificanceLight-field microscopy (LFM) enables fast, light-efficient, volumetric imaging of neuronal activity with calcium indicators. Calcium transients differ in temporal signal-to-noise ratio (tSNR) and spatial confinement when extracted from volumes reconstructed by different algorithms.

AimWe evaluated the capabilities and limitations of two light-field reconstruction algorithms for calcium fluorescence imaging.

ApproachWe acquired light-field image series from neurons either bulk-labeled or filled intracellularly with the red-emitting calcium dye CaSiR-1 in acute mouse brain slices. We compared the tSNR and spatial confinement of calcium signals extracted from volumes reconstructed with synthetic refocusing and Richardson-Lucy 3D deconvolution with and without total variation regularization.

ResultsBoth synthetic refocusing and Richardson-Lucy deconvolution resolved calcium signals from single cells and neuronal dendrites in three dimensions. Increasing deconvolution iteration number improved spatial confinement but reduced tSNR compared to synthetic refocusing. Volumetric light-field imaging did not decrease calcium signal tSNR compared to interleaved, widefield image series acquired in matched planes.

ConclusionsLFM enables high-volume rate, volumetric imaging of calcium transients in single cells (bulk-labeled), somata and dendrites (intracellular loaded). The trade-offs identified for tSNR, spatial confinement, and computational cost indicate which of synthetic refocusing or deconvolution can better realize the scientific requirements of future LFM calcium imaging applications.

category: bioengineering


title: A machine-learning approach to human footprint index estimation with applications to sustainable development

abstract: The human footprint index is an extensively used tool for interpreting the accelerating pressure of humanity on Earth. Up to now, the process of creating the human footprint index has required significant data and modeling, and updated versions of the index often lag the present day by many years. Here we introduce a near-present, global-scale machine learning-based human footprint index (ml-HFI) which is capable of routine update using satellite imagery alone. We present the most up-to-date map of the human footprint index, and document changes in human pressure during the past 20 years (2000 to 2019). Moreover, we demonstrate its utility as a monitoring tool for the United Nations Sustainable Development Goal 15 (SDG15), "Life on Land", which aims to foster sustainable development while conserving biodiversity. We identify 43 countries that are making progress toward SDG15 while also experiencing increases in their ml-HFI. We examine a subset of these in the context of conservation policies that may or may not enable continued progress toward SDG15. This has immediate policy relevance, since the majority of countries globally are not on track to achieve Goal 15 by the declared deadline of 2030. Moving forward, the ml-HFI may be used for ongoing monitoring and evaluation support toward the twin goals of fostering a thriving society and global Earth system.


title: AA_stat: intelligent profiling of in vivo and in vitro modifications from open search results

abstract: Characterization of post-translational modifications is among the most challenging tasks in tandem mass spectrometry-based proteomics which has yet to find an efficient solution. The ultra-tolerant (open) database search attempts to meet this challenge. However, interpretation of the mass shifts observed in open search still requires an effective and automated solution. We have previously introduced the AA_stat tool for analysis of amino acid frequencies at different mass shifts and generation of hypotheses on unaccounted in vitro modifications. Here, we report on the new version of AA_stat, which now complements amino acid frequency statistics with a number of new features: (1) MS/MS-based localization of mass shifts and localization scoring, including shifts which are the sum of modifications; (2) inferring fixed modifications to increase method sensitivity; (3) inferring monoisotopic peak assignment errors and variable modifications based on abundant mass shift localizations to increase the yield of closed search; (4) new mass calibration algorithm to account for partial systematic shifts; (5) interactive integration of all results and a rated list of possible mass shift interpretations. With these options, we improve interpretation of open search results and demonstrate the utility of AA_stat for profiling of abundant and rare amino acid modifications. AA_stat is implemented in Python as an open-source command-line tool available at https://github.com/SimpleNumber/aa_stat.


title: CancerSiamese: one-shot learning for predicting primary and metastatic tumor types unseen during model training

abstract: We consider cancer classification based on one single gene expression profile. We proposed CancerSiamese, a new one-shot learning model, to predict the cancer type of a query primary or metastatic tumor sample based on a support set that contains only one known sample for each cancer type. CancerSiamese receives pairs of gene expression profiles and learns a representation of similar or dissimilar cancer types through two parallel Convolutional Neural Networks joined by a similarity function. We trained CancerSiamese for both primary and metastatic cancer type predictions using samples from TCGA and MET500. Test results for different N-way predictions yielded an average accuracy improvement of 8% and 4% over the benchmark 1-Nearest Neighbor (1-NN) classifier for primary and metastatic tumors, respectively. Moreover, we applied the guided gradient saliency map and feature selection to CancerSiamese to identify and analyze the marker-gene candidates for primary and metastatic cancers. Our work demonstrated, for the first time, the feasibility of applying one-shot learning for expression-based cancer type prediction when gene expression data of cancer types are limited and could inspire new and ingenious applications of one-shot and few-shot learning solutions for improving cancer diagnosis, treatment planning, and our understanding of cancer.


title: A shift to shorter cuticular hydrocarbons accompanies sexual isolation among Drosophila americana group populations

abstract: Because sensory signals often evolve rapidly, they could be instrumental in the emergence of reproductive isolation between species. However, pinpointing their specific contribution to isolating barriers, and the mechanisms underlying their divergence, remains challenging. Here we demonstrate sexual isolation due to divergence in chemical signals between two populations of Drosophila americana (SC and NE) and one population of D. novamexicana, and dissect its underlying phenotypic and genetic mechanisms. Mating trials revealed strong sexual isolation between Drosophila novamexicana males and SC Drosophila americana females, as well as more moderate bi-directional isolation between D. americana populations. Mating behavior data indicates SC D. americana males have the highest courtship efficiency and, unlike males of the other populations, are accepted by females of all species. Quantification of cuticular hydrocarbon (CHC) profiles--chemosensory signals that are used for species recognition and mate finding in Drosophila--shows that the SC D. americana population differs from the other populations primarily on the basis of compound carbon chain-length. Moreover, manipulation of male CHC composition via heterospecific perfuming--specifically perfuming D. novamexicana males with SC D. americana males--abolishes their sexual isolation from these D. americana females. Of a set of candidates, a single gene--elongase CG17821--had patterns of gene expression consistent with a role in CHC differences between species. Sequence comparisons indicate D. novamexicana and our Nebraska (NE) D. americana population share a derived CG17821 truncation mutation that could also contribute to their shared "short" CHC phenotype. Together, these data suggest an evolutionary model for the origin and spread of this allele and its consequences for CHC divergence and sexual isolation in this group.


title: Screening of candidate host cell membrane proteins involved in SARS-CoV-2 entry

abstract: Coronavirus disease (COVID-19) represents a real threat to the global population, and understanding the biological features of the causative virus, i.e., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is imperative for mitigating this threat. Analyses of proteins such as primary receptors and co-receptors (co-factors), which are involved in the entry of SARS-CoV-2 into host cells, will provide important clues to help control the virus. Here, we identified host cell membrane protein candidates present in proximity to the attachment sites of SARS-CoV-2 spike proteins, using proximity labeling and proteomic analysis. The identified proteins represent key candidate factors that may be required for viral entry. DPP4, Cadherin-17, and CD133 were found to co-localize with cell membrane-bound SARS-CoV-2 spike proteins in Caco-2 cells and thus showed potential as candidate factors. The experimental infection with a SARS-CoV-2 pseudovirus indicated a 2-fold enhanced infectivity in the CD133-ACE2-coexpressing HEK293T cells compared to that in HEK293T cells expressing ACE-2 alone. The information and resources regarding these co-receptor labeling and analysis techniques could be utilized for the development of antiviral agents against SARS-CoV-2 and other emerging viruses.

category: biochemistry


title: Frontal cortical regions associated with attention connect more strongly to central than peripheral V1

abstract:
The functionality of central vision is different from peripheral vision. Central vision is used for fixation and has higher acuity that makes it useful for everyday activities such as reading and object identification. The central and peripheral representations in primary visual cortex (V1) also differ in how higher-order processing areas modulate their responses. For example, attention and expectation are top-down processes (i.e., high-order cognitive functions) that influence visual information processing during behavioral tasks. This top-down control is different for central vs. peripheral vision. Since functional networks can influence visual information processing in different ways, networks (such as the Fronto-Parietal (FPN), Default Mode (DMN), and Cingulo-Opercular (CON)) likely differ in how they connect to representations of the visual field across V1. Prior work indicated the central representing portion of V1 was more functionally connected to regions belonging to the FPN, and the far-peripheral representing portion of V1 was more functionally connected to regions belonging to the DMN.

Our goals were 1) Assess the reproducibility and generalizability of retinotopic effects on functional connections between V1 and functional networks. 2) Extend this work to understand structural connections of central vs. peripheral representations in V1. 3) Examine the overlapping eccentricity differences in functional and structural connections of V1.

We used resting-state BOLD fMRI and DWI to examine whether portions of V1 that represent different visual eccentricities differ in their functional and structural connectivity to functional networks. All data were acquired and minimally preprocessed by the Human Connectome Project. We identified central and far-peripheral representing regions from a retinotopic template. Functional connectivity was measured by correlated activity between V1 and functional networks, and structural connectivity was measured by probabilistic tractography and converted to track probability. In both modalities, differences between V1 eccentricity segment connections were compared by paired, two-tailed t-test. Dice Coefficients were used to determine spatial overlap between modalities.

We found 1) Centrally representing portions of V1 are more strongly functionally connected to frontal regions than are peripherally representing portions of V1, 2) Structural connections also show stronger connections between central V1 and frontal regions, 3) Patterns of structural and functional connections overlaps in the lateral frontal cortex.

In summary, the works main contribution is a greater understanding of higher-order functional networks connectivity to V1. There are stronger structural connections to central representations in V1, particularly for lateral frontal regions, implying that the functional relationship between central V1 and frontal regions is built upon direct, long-distance connections. Overlapping structural and functional connections reflect differences in V1 eccentricities, with central V1 preferentially connected to attention-associated regions. Understanding how V1 is functionally and structurally connected to higher-order brain areas contributes to our understanding of how the human brain processes visual information and forms a baseline for understanding any modifications in processing that might occur with training or experience.


title: Action-value processing underlies the role of the dorsal anterior cingulate cortex in performance monitoring during self-regulation of affect

abstract: In this study, we merged methods from engineering control theory, machine learning, and human neuroimaging to critically test the putative role of the dorsal anterior cingulate cortex (dACC) in goal-directed performance monitoring during an emotion regulation task. Healthy adult participants (n=94) underwent cued-recall and re-experiencing of their responses to affective image stimuli with concurrent functional magnetic resonance imaging and psychophysiological response recording. During cued-recall/re-experiencing trials, participants engaged in explicit self-regulation of their momentary affective state to match a pre-defined affective goal state. Within these trials, neural decoding methods measured affect processing from fMRI BOLD signals across the orthogonal affective dimensions of valence and arousal. Participants affective brain states were independently validated via facial electromyography (valence) and electrodermal activity (arousal) responses. The decoded affective states were then used to contrast four computational models of performance monitoring (i.e., error, predicted response outcome, action-value, and conflict) by their relative abilities to explain emotion regulation task-related dACC activation. We found that the dACC most plausibly encodes action-value for both valence and arousal processing. We also confirmed that dACC activation directly encodes affective arousal and also likely encodes recruitment of attention and regulation resources. Beyond its contribution to improving our understanding of the roles that the dACC plays in emotion regulation, this study introduced a novel analytical framework through which affect processing and regulation may be functionally dissociated, thereby permitting mechanistic analysis of real-world emotion regulation strategies, e.g., distraction and reappraisal, which are widely employed in cognitive behavioral therapy to address clinical deficits in emotion regulation.


title: Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats

abstract:
Antipsychotic treatment can produce a dopamine-supersensitive state, potentiating the response to dopamine receptor stimulation. In both schizophrenia patients and rats, this is linked to tolerance to ongoing antipsychotic treatment. In rodents, dopamine supersensitivity is often confirmed by an exaggerated psychomotor response to d-amphetamine after discontinuation of antipsychotic exposure. Here we examined in rats the dopaminergic mechanisms mediating this enhanced behavioural response, as this could uncover pathophysiological processes underlying the expression of antipsychotic-evoked dopamine supersensitivity. Rats received 0.5 mg/kg/day haloperidol via osmotic minipump for 2 weeks, before treatment was discontinued. After cessation of antipsychotic treatment, rats showed a supersensitive psychomotor response to the D2 agonist quinpirole, but not to the D1 partial agonist SKF38393 or the dopamine reuptake blocker GBR12783. Furthermore, acute D1 receptor blockade (using SCH39166) decreased the exaggerated psychomotor response to d-amphetamine in haloperidol-pretreated rats, whereas acute D2 receptor blockade (using sulpiride) enhanced it. Thus, after discontinuation of antipsychotic treatment, D1- and D2-mediated transmission differentially modulate the expression of a supersensitive response to d-amphetamine. This supersensitive behavioural response was accompanied by enhanced GSK3{beta} activity and suppressed ERK1/2 activity in the nucleus accumbens (but not caudate-putamen), suggesting increased mesolimbic D2 transmission. Finally, after discontinuing haloperidol treatment, neither increasing ventral midbrain dopamine impulse flow nor infusing d-amphetamine into the cerebral ventricles triggered the expression of already established antipsychotic-evoked dopamine supersensitivity, suggesting that peripheral effects are required. Thus, while dopamine receptor-mediated signalling regulates the expression of antipsychotic-evoked dopamine supersensitivity, a simple increase in central dopamine neurotransmission is insufficient to trigger this supersensitivity.

HIGHLIGHTSO_LIAntipsychotic exposure can lead to a state of dopamine (DA) supersensitivity
C_LIO_LIIn rats, this DA supersensitivity potentiates d-amphetamine-induced locomotion
C_LIO_LIWe report that D2 transmission promotes DA supersensitivity and D1 transmission tempers it
C_LIO_LID-amphetamines central effects are also insufficient to reveal DA supersensitivity
C_LI

category: pharmacology and toxicology


title: Integrative approaches to improve the informativeness of deep learning models for human complex diseases

abstract: Deep learning models have achieved great success in predicting genome-wide regulatory effects from DNA sequence, but recent work has reported that SNP annotations derived from these predictions contribute limited unique information for human complex disease. Here, we explore three integrative approaches to improve the disease informativeness of allelic-effect annotations (predicted difference between reference and variant alleles) constructed using several previously trained deep learning models: DeepSEA, Basenji and DeepBind (and a related machine learning model, deltaSVM). First, we employ gradient boosting to learn optimal combinations of deep learning annotations, using fine-mapped SNPs and matched control SNPs (on held-out chromosomes) for training. Second, we improve the specificity of these annotations by restricting them to SNPs implicated by (proximal and distal) SNP-to-gene (S2G) linking strategies, e.g. prioritizing SNPs involved in gene regulation. Third, we predict gene expression (and derive allelic-effect annotations) from deep learning annotations at SNPs implicated by S2G linking strategies -- generalizing the previously proposed ExPecto approach, which incorporates deep learning annotations based on distance to TSS. We evaluated these approaches using stratified LD score regression, using functional data in blood and focusing on 11 autoimmune diseases and blood-related traits (average N =306K). We determined that the three approaches produced SNP annotations that were uniquely informative for these diseases/traits, despite the fact that linear combinations of the underlying DeepSEA, Basenji, DeepBind and deltaSVM blood annotations were not uniquely informative for these diseases/traits. Our results highlight the benefits of integrating SNP annotations produced by deep learning models with other types of data, including data linking SNPs to genes.

category: genetics


title: Global Importance Analysis: An Interpretability Method to Quantify Importance of Genomic Features in Deep Neural Networks

abstract: Deep neural networks have demonstrated improved performance at predicting the sequence specificities of DNA- and RNA-binding proteins compared to previous methods that rely on k-mers and position weight matrices. To gain insights into why a DNN makes a given prediction, model interpretability methods, such as attribution methods, can be employed to identify motif-like representations along a given sequence. Because explanations are given on an individual sequence basis and can vary substantially across sequences, deducing generalizable trends across the dataset and quantifying their effect size remains a challenge. Here we introduce global importance analysis (GIA), a model interpretability method that quantifies the population-level effect size that putative patterns have on model predictions. GIA provides an avenue to quantitatively test hypotheses of putative patterns and their interactions with other patterns, as well as map out specific functions the network has learned. As a case study, we demonstrate the utility of GIA on the computational task of predicting RNA-protein interactions from sequence. We first introduce a convolutional network, we call ResidualBind, and benchmark its performance against previous methods on RNAcompete data. Using GIA, we then demonstrate that in addition to sequence motifs, ResidualBind learns a model that considers the number of motifs, their spacing, and sequence context, such as RNA secondary structure and GC-bias.


title: Long-read sequencing reveals rapid evolution of immunity- and cancer-related genes in bats

abstract: Bats are exceptional among mammals for their powered flight, extended lifespans, and robust immune systems. To investigate the genomic underpinnings of unique bat adaptations, we sequenced the genomes of the Jamaican fruit bat (Artibeus jamaicensis) and the Mesoamerican mustached bat (Pteronotus mesoamericanus) and compared them to a diverse collection of 13 additional bat species together with other mammals. We used the Oxford Nanopore Technologies long-read platform to generate highly complete assemblies (N50: 28-29Mb) and facilitate analysis of complex genomic regions containing duplicated genes. Using gene family size analysis, we found that the type I interferon locus was contracted by eight genes in the most recent common ancestor (MRCA) of bats, shifting the proportion of interferon-{omega} to interferon- and making interferon-{omega} the most common type I interferon in bats. Antiviral genes stimulated by type I interferons were also rapidly evolving, with interferon-induced transmembrane genes experiencing a lineage-specific duplication and strong positive selection in the gene IFIT2. Moreover, the lineage of phyllostomid bats showed an unprecedented expansion of PRDM9, a recombination-related gene also involved in infection responses, raising the possibility that this gene contributes to bat antiviral defenses. These modifications in the bat innate immune system may be important adaptations allowing them to harbor viruses asymptomatically. We additionally found evidence of positive selection on the branch leading to the MRCA of bats acting on 33 tumor suppressors and six DNA repair genes, which may contribute to the low cancer rates and longevity observed across bats. These new genomic resources enable insights into the extraordinary adaptations of bats, with implications for mammalian evolutionary studies and public health.


title: Universal Spectrum Explorer: A standalone (web-)application for cross-resource spectrum comparison

abstract: Here we present the Universal Spectrum Explorer (USE), a web-based tool based on IPSA for cross-resource (peptide) spectrum visualization and comparison (https://www.proteomicsdb.org/use/). Mass spectra under investigation can either be provided manually by the user (table format), or automatically retrieved from online repositories supporting access to spectral data via the universal spectrum identifier (USI), or requested from other resources and services implementing a newly designed REST interface. As a proof of principle, we implemented such an interface in ProteomicsDB thereby allowing the retrieval of spectra acquired within the ProteomeTools project or real-time prediction of tandem mass spectra from the deep learning framework Prosit. Annotated mirror spectrum plots can be exported from the USE as editable scalable high quality vector graphics. The USE was designed and implemented with minimal external dependencies allowing local usage and integration into other websites (https://github.com/kusterlab/universal_spectrum_explorer).


title: Pervasive selection pressure in wild and domestic pigs

abstract: Animal domestication typically affected numerous polygenic quantitative traits, such as behaviour, development and reproduction. However, uncovering the genetic basis of quantitative trait variation is challenging, since it is probably caused by small allele-frequency changes. To date, only a few causative mutations related to domestication processes have been reported, strengthening the hypothesis that small effect variants have a prominent role. So far, the studies on domestication have been limited to the detection of the global effect of domestication on deleterious mutations and on strong beneficial variants, ignoring the importance of variants with small selective effects. In addition, very often, the study of the effects of selection are conducted on genome sequences that contain a non-negligible fraction of missing data, especially in non-model organisms. Hence, appropriate methods to account for these positions are needed. To overcome these difficulties, here we propose to estimate the proportion of beneficial variants using the asymptotic MacDonald-Kreitman (MK) method based on estimates of variability that summarizes the site frequency spectrum (SFS) while accounting for missing data and use them to perform an Approximate Bayesian Computation (ABC) analysis to infer the Distribution of Fitness Effects (DFE) of each population. We applied this approach to 46 genome sequences of pigs from three different populations, one wild and two domestics, with very different demographic histories and selective pressures. The obtained results showed that domestic and wild pig populations do not differ in nonsynonymous fixed mutations. Therefore, differences in  estimation among breeds are determined by their polymorphisms. The comparison of  for total and exclusive mutations suggests that the different domestic populations have suffered recent divergent changes in their functional versus neutral polymorphisms ratio, while the wild population is compatible with =0. Besides, the DFE inferred with ABC indicates that both wild and domestic pigs display a large number of deleterious mutations at low frequency and a high number of neutral and/or nearly-neutral mutations that may have a significant effect on the evolution of domestic and wild populations. In addition, models not considering beneficial mutations have higher posterior probabilities, suggesting that beneficial mutations are difficult to detect or are scarce. Indeed, for all three populations, the median proportion of the strong favourable mutations are very low ([≤] 0.1%) in those models that includes positive selection, with the average values of weak beneficial mutations around 0.6% for wild boar and 0.8-1.0% for the domestic pigs. Lastly, the analysis based on exclusive mutations showed that recent demographic changes may have severely affected the fitness of populations, especially that of the local Iberian breed.


title: Structural Genetics of circulating variants affecting the SARS CoV-2 Spike / human ACE2 complex

abstract:
SARS-CoV-2 entry in human cells is mediated by the interaction between the viral Spike protein and the human ACE2 receptor. This mechanism evolved from the ancestor bat coronavirus and is currently one of the main targets for antiviral strategies. However, there currently exist several Spike protein variants in the SARS-CoV-2 population as the result of mutations, and it is unclear if these variants may exert a specific effect on the affinity with ACE2 which, in turn, is also characterized by multiple alleles in the human population. In the current study, the GBPM analysis, originally developed for highlighting host-guest interaction features, has been applied to define the key amino acids responsible for the Spike/ACE2 molecular recognition, using four different crystallographic structures. Then, we intersected these structural results with the current mutational status, based on more than 295,000 sequenced cases, in the SARS-CoV-2 population. We identified several Spike mutations interacting with ACE2 and mutated in at least 20 distinct patients: S477N, N439K, N501Y, Y453F, E484K, K417N, S477I and G476S. Among these, mutation N501Y in particular is one of the events characterizing SARS-CoV-2 lineage B.1.1.7, which has recently risen in frequency in Europe. We also identified five ACE2 rare variants that may affect interaction with Spike and susceptibility to infection: S19P, E37K, M82I, E329G and G352V.

Significance StatementWe developed a method to identify key amino acids responsible for the initial interaction between SARS-CoV-2 (the COVID-19 virus) and human cells, through the analysis of Spike/ACE2 complexes. We further identified which of these amino acids show variants in the viral and human populations. Our results will facilitate scientists and clinicians alike in identifying the possible role of present and future Spike and ACE2 sequence variants in cell entry and general susceptibility to infection.


title: Antagonism between killer yeast strains as an experimental model for biological nucleation dynamics

abstract: Antagonistic interactions are widespread in the microbial world and affect microbial evolutionary dynamics. Natural microbial communities often display spatial structure, which affects biological interactions, but much of what we know about microbial warfare comes from laboratory studies of well-mixed communities. To overcome this limitation, we manipulated two killer strains of the budding yeast Saccharomyces cerevisiae, expressing different toxins, to independently control the rate at which they released their toxins. We developed mathematical models that predict the experimental dynamics of competition between toxin-producing strains in both well-mixed and spatially structured populations. In both situations, we experimentally verified theorys prediction that a stronger antagonist can invade a weaker one only if the initial invading population exceeds a critical frequency or size. Finally, we found that toxin-resistant cells and weaker killers arose in spatially structured competitions between toxin-producing strains, suggesting that adaptive evolution can affect the outcome of microbial antagonism in spatial settings.


title: Global genome decompaction leads to stochastic activation of gene expression as a first step toward fate commitment in human hematopoietic stem cells.

abstract: When human cord blood derived CD34+ cells are induced to differentiate in vitro, they undergo rapid and dynamic morphological and molecular transformations that are critical for fate commitment. Using ATAC-seq and single-cell RNA sequencing, we detected two phases in this process. In the first phase, we observed a rapid and global chromatin opening that makes most of the gene promoters in the genome accessible, followed by widespread upregulation of gene transcription and a concomitant increase in the cell-to-cell variability of gene expression. The second phase is marked by a slow chromatin closure and a subsequent overall downregulation of gene transcription and emergence of coherent expression profiles corresponding to distinct cell subpopulations. These observations are consistent with a model based on the spontaneous probabilistic organization of the cellular process of fate commitment.

category: cell biology


title: Cytosolic sequestration of spatacsin by Protein Kinase A and 14-3-3 proteins

abstract: Mutations in SPG11, encoding spatacsin, constitute the major cause of autosomal recessive Hereditary Spastic Paraplegia (HSP) with thinning of the corpus callosum. Previous studies showed that spatacsin orchestrates cellular traffic events through the formation of a coat-like complex and its loss of function results in lysosomal and axonal transport impairments. However, the upstream mechanisms that regulate spatacsin trafficking are unknown. Here, using proteomics and CRISPR/Cas9-mediated tagging of endogenous spatacsin, we identified a subset of 14-3-3 proteins as physiological interactors of spatacsin. The interaction is modulated by Protein Kinase A (PKA)-dependent phosphorylation of spatacsin at Ser1955, which initiates spatacsin trafficking from the plasma membrane to the intracellular space. Our study provides novel insight in understanding spatacsin physio-pathological roles with mechanistic dissection of its associated pathways.


title: Phase separation of tunable biomolecular condensates predicted by an interacting particle model

abstract: Phase separation is emerging as key principle in the spatiotemporal organization of living cells. Given its relevance in the regulation of numerous biological functions, including gene transcription and chromatin architecture, modeling biomolecular condensation is gaining interest. Yet, most models developed so far rely on specific descriptions and/or experimentally inaccessible properties. Here we propose a theoretical model, where phase separation is explained by means of interaction probabilities between particles. With minimum model requirements, particle condensates emerge above a critical interaction probability. We tested the model predictions with single molecule experiments of tunable transcription factor condensates in the nucleus of living cells. Phase separation, condensate sizes, diffusion behavior, and mobility parameters, quantified by data analysis and machine learning, are fully recapitulated by our model. Our combined theoretical and experimental approach provides a general framework to investigate the biophysical parameters controlling phase separation in living cells and in other soft matter-based interacting systems.

category: biophysics


title: A new mechanism of fibronectin fibril assembly revealed by live imaging and super-resolution microscopy.

abstract: Fn1 fibrils have long been viewed as continuous fibers composed of extended, periodically aligned Fn1 molecules. However, our live imaging and single-molecule localization microscopy (SMLM) are inconsistent with this traditional view and show that Fn1 fibrils are composed of roughly spherical nanodomains containing 6-11 Fn1 dimers. As they move toward the cell center, Fn1 nanodomains become organized into linear arrays, wherein nanodomains are spaced at the average periodicity of 105{+/-}17 nm. Periodical Fn1 nanodomain arrays are bona fide fibrils: they are resistant to deoxycholate treatment and retain nanodomain periodicity in the absence of cells. The nanodomain periodicity in fibrils remained constant when probed with antibodies recognizing distinct Fn1 epitopes or combinations of antibodies recognizing epitopes spanning the length of Fn1. FUD, a bacterial peptide that binds Fn1 N-terminus and disrupts Fn1 fibrillogenesis does not disrupt the formation of Fn1 nanodomains, instead, it blocks the organization of Fn1 nanodomains into periodical arrays. These studies establish a new paradigm of Fn1 fibrillogenesis.


title: Ophthalmic Changes in a Spaceflight Analog Are Associated with Brain Functional Reorganization

abstract:
Following long-duration spaceflight, some astronauts exhibit ophthalmic structural changes referred to as Spaceflight Associated Neuro-ocular Syndrome (SANS). Optic disc edema is a common sign of SANS. The origin and effects of SANS are not understood as signs of SANS have not manifested in previous spaceflight analog studies. In the current spaceflight analog study, eleven subjects underwent 30 days of strict head down-tilt bed rest in elevated ambient carbon dioxide (HDBR+CO2). Using functional magnetic resonance imaging (fMRI), we acquired resting-state fMRI data at 6 time points: before (2), during (2), and after (2) the HDBR+CO2 intervention. Five participants developed optic disc edema during the intervention (SANS subgroup) and 6 did not (NoSANS group). This occurrence allowed us to explore whether development of signs of SANS during the spaceflight analog impacted resting-state functional connectivity during HDBR+CO2. In light of previous work identifying genetic and biochemical predictors of SANS, we further assessed whether the SANS and NoSANS subgroups exhibited differential patterns of resting-state functional connectivity prior to the HDBR+CO2 intervention. We found that the SANS and NoSANS subgroups exhibited distinct patterns of resting-state functional connectivity changes during HDBR+CO2 within visual and vestibular-related brain networks. The SANS and NoSANS subgroups also exhibited different resting-state functional connectivity prior to HDBR+CO2 within a visual cortical network and within a large-scale network of brain areas involved in multisensory integration. We further present associations between functional connectivity within the identified networks and previously identified genetic and biochemical predictors of SANS. Subgroup differences in resting-state functional connectivity changes may reflect differential patterns of visual and vestibular reweighting as optic disc edema develops during the spaceflight analog. This finding suggests that SANS impacts not only neuro-ocular structures, but also functional brain organization. Future prospective investigations incorporating sensory assessments are required to determine the functional significance of the observed connectivity differences.

HIGHLIGHTSWe investigated resting-state functional connectivity (FC) during a spaceflight analog with elevated CO2 (HDBR+CO2).

During the HDBR+CO2 intervention, a subset of participants developed optic disc edema, a sign of spaceflight-associated neuro-ocular syndrome (SANS).

Participants with signs of SANS exhibited a distinct pattern of resting-state functional connectivity changes within visual and vestibular-related networks during HDBR+CO2.

Participants who developed optic disc edema exhibited different FC prior to the spaceflight analog within a visual cortical network and within a large-scale network of brain areas involved in multisensory integration.


title: Genome-wide association and prediction study in grapevine deciphers the genetic architecture of multiple traits and identifies genes under many new QTLs

abstract: To cope with the challenges faced by agriculture, speeding-up breeding programs is a worthy endeavor, especially for perennials such as grapevine, but requires understanding the genetic architecture of target traits. To go beyond the mapping of quantitative trait locus (QTL) in bi-parental crosses, we exploited a diverse panel of 279 Vitis vinifera L. cultivars. This panel planted in five blocks in the vineyard was phenotyped over several years for 127 traits including yield components, organic acids, aroma precursors, polyphenols, and a water stress indicator. The panel was genotyped for 63k single nucleotide polymorphisms (SNPs) by combining an 18K microarray and genotyping-by-sequencing (GBS). The experimental design allowed to reliably assess the genotypic values for most traits. Marker densification via GBS markedly increased the proportion of genetic variance explained by SNPs, and two multi-SNP models identified QTLs not found by a SNP-by-SNP model. Overall, 489 reliable QTLs were detected for 41% more response variables than by a SNP-by-SNP model with microarray-only SNPs, many new ones compared to the results from bi-parental crosses. Prediction accuracy higher than 0.42 was obtained for 50% of the response variables. Our overall approach as well as QTL and prediction results provide insights into the genetic architecture of target traits. New candidate genes and the application in breeding are discussed.