title: The Neuroanatomy of Speech Processing: A Large-Scale Lesion Study

abstract: The neural basis of language has been studied for centuries, yet the networks critically involved in simply identifying or understanding a spoken word remain elusive. Several functional-anatomical models of critical neural substrates of receptive speech have been proposed, including (1) auditory-related regions in the left mid-posterior superior temporal lobe, (2) motor-related regions in the left frontal lobe (in normal and/or noisy conditions), the left anterior superior temporal lobe, or (4) bilateral mid-posterior superior temporal areas. One difficulty in comparing these models is that they often focus on different aspects of the sound-to-meaning pathway and are supported by different types of stimuli and tasks. Two auditory tasks that are typically used in separate studies--syllable discrimination and word comprehension--often yield different conclusions. We assessed syllable discrimination (words and nonwords) and word comprehension (clear speech and with a noise masker) in 158 individuals with focal brain damage: left (n=113) or right (n=19) hemisphere stroke, left (n=18) or right (n=8) anterior temporal lobectomy, and 26 neurologically-intact controls. Discrimination and comprehension tasks are doubly dissociable both behaviorally and neurologically. In support of a bilateral model, clear speech comprehension was near ceiling in 95% of left stroke cases and right temporal damage impaired syllable discrimination. Lesion-symptom mapping analyses for the syllable discrimination and noisy word comprehension tasks each implicated most of the left superior temporal gyrus (STG). Comprehension but not discrimination tasks also implicated the left pMTG, while discrimination but not comprehension tasks also implicated more dorsal sensorimotor regions in posterior perisylvian cortex.


title: Evaluating features of scientific conferences: A call for improvements

abstract:
Scientific conferences provide valuable opportunities for researchers across career stages and disciplines to present their latest work, and to network with their peers. These meetings have largely been held in-person with rapid proliferation in the number of meetings and attendees. Yet the format and quality of their organization lag behind what is possible and as a result, the current experience of attending conferences in many disciplines remains unchanged in many respects. We created a database of 270 national and international academic conferences held in-person during 2018-2019 in various disciplines and examined them for their features, costs and impact on the community. We found that many meetings could still be improved significantly in terms of diversity, inclusivity, promoting early career researcher (ECR) networking and career development, venue accessibility, and importantly, reducing the meetings carbon footprint. It is important to accelerate and mandate efforts to improve conferences so that researchers in all disciplines, in particular ECRs, consistently benefit from scientific gatherings, for years to come. We discuss a combination of approaches and recommendations to make conferences more modern, effective, equitable and intellectually productive for the research community and environmentally sustainable for our planet.

"They always say time changes things, but you actually have to change them yourself."

-- Andy Warhol

category: scientific communication and education


title: Live-cell 3D single-molecule tracking reveals how NuRD modulates enhancer dynamics

abstract: Enhancer-promoter dynamics are crucial for the spatiotemporal control of gene expression, but it remains unclear whether these dynamics are controlled by chromatin regulators, such as the nucleosome remodelling and deacetylase (NuRD) complex. The NuRD complex binds to all active enhancers to modulate transcription and here we use Hi-C experiments to show that it blurs TAD boundaries and increases the proximity of intermediate-range (~1 Mb) genomic sequences and enhancer-promoter interactions. To understand whether NuRD alters the dynamics of 3D genome structure, we developed an approach to segment and extract key biophysical parameters from 3D single-molecule trajectories of the NuRD complex determined using live-cell imaging. Unexpectedly, this revealed that the intact NuRD complex decompacts chromatin structure and makes NuRD-bound enhancers move faster, increasing the overall volume of the nucleus that these key regulatory regions explore. Interestingly, we also uncovered a rare fast-diffusing state of NuRD bound enhancers that exhibits directed motion. The NuRD complex reduces the amount of time that enhancers remain in this fast-diffusing state, which we propose might otherwise re-organise enhancer-promoter proximity. Thus, we uncover an intimate connection between a chromatin remodeller and the spatial dynamics of the local regions of the genome to which it binds.

category: cell biology


title: Live-cell imaging reveals the spatiotemporal organization of endogenous RNA polymerase II phosphorylation at a single gene

abstract: The carboxyl-terminal domain of RNA polymerase II is dynamically phosphorylated during transcription in eukaryotic cells. While residue-specific phosphorylation has been mapped with exquisite spatial resolution along the 1D genome in a population of fixed cells using immunoprecipitation-based assays, the timing, kinetics, and spatial organization of phosphorylation along a single-copy gene have not yet been measured in living cells. Here, we achieve this by combining multi-color, single-molecule microscopy with fluorescent antibody-based probes that specifically bind to unphosphorylated and phosphorylated forms of endogenous RNAP2 in living cells. Applying this methodology to a single-copy HIV-1 reporter gene provides live-cell evidence for heterogeneity in the distribution of RNAP2 along the length of the gene as well as clusters of Serine 5 phosphorylated RNAP2 that form around active genes and are separated in both space and time from nascent mRNA synthesis. Computational models fit to our data determine that 5 to 40 RNAP2 cluster around the promoter of a gene during typical transcriptional bursts. Rapid imaging demonstrates nearly all RNAP2 in the cluster acquire Serine 5 phosphorylation within 3-6 seconds of arrival. Transcription from the cluster appears to be highly efficient, with nearly half of the clustered RNAP2 ultimately escaping the promoter in 1.5 minutes on average to elongate a full-length mRNA in approximately five minutes. The highly dynamic and spatially organized concentrations of RNAP2 we observe support the notion of highly efficient transcription clusters that form around promoters and contain high concentrations of RNAP2 phosphorylated at Serine 5.

category: molecular biology


title: The role of KMT2D  and KDM6A in cardiac development: A cross-species analysis in humans, mice, and zebrafish

abstract: KMT2D and KDM6A are epigenetic regulators that have been implicated in Kabuki Syndrome, a rare congenital birth defect with multiple tissue and organ abnormalities, including craniofacial and heart defects. Our previous study identified human families with mutations in the epigenetic modifiers KMT2D and KDM6A, which is implicated in 32% and 10% of Kabuki Syndrome patients respectively. To understand the connection to Kabuki syndrome patients, and the transcriptional targets of KMT2D and KDM6A in humans, we performed RNA sequencing (seq) of lymphoblastoid cells from Kabuki Syndrome patients carrying mutations in KMT2D and KDM6A. We identified 1995 significant changes in transcriptional targets for KMT2D and 1917 for KDM6A, as compared to control. When compared with RNA-seq datasets obtained from other mouse and zebrafish studies, our analysis revealed KMT2D mutations affect the expression of 76 orthologous genes across all three datasets. Similarliy, KDM6A afftects the expprssion of 7 orthologous genes across three datasets. Despite the differences in cell types, stages, and species in the comparison between the transcriptomic datasets, there are common gene expression changes associated with KMT2D and KDM6A mutations. qPCR on novel zebrafish mutants confirmed the differentially expression in KMT2D or KDM6A mutant backgrounds. Taken together, our results show that KMT2D and KDM6A regulate common and unique genes across humans, mice, and zebrafish for early craniofacial and cardiac development and this information contributes to the understanding of epigenetic dysregulation during development of Kabuki syndrome.

category: developmental biology


title: The role of Kabuki Syndrome genes KMT2D and KDM6A in development: Analysis in Human sequencing data and compared to mice and zebrafish


title: A single-cell gene regulatory network inference method for identifying complex regulatory dynamics across cell phenotypes.

abstract: Single-cell RNA-Sequencing has made it possible to infer high-resolution gene regulatory networks (GRNs), providing deep biological insights by revealing regulatory interactions at single-cell resolution. However, current single-cell GRN analysis methods produce only a single GRN per input dataset, potentially missing relationships between cells from different phenotypes. To address this issue, we present SimiC, a single-cell GRN inference method that produces a GRN per phenotype while imposing a similarity constraint that forces a smooth transition between GRNs, allowing for a direct comparison between different states, treatments, or conditions. We show that jointly inferring GRNs can uncover variation in regulatory relationships across phenotypes that would have otherwise been missed. Moreover, SimiC can recapitulate complex regulatory dynamics across a range of systems, both model and non-model alike. Taken together, we establish a new approach to quantitating regulatory architectures between the GRNs of distinct cellular phenotypes, with far-reaching implications for systems biology.

category: bioinformatics


title: Sleep spindles preferentially consolidate weakly encoded memories

abstract:
Sleep has been shown to be critical for memory consolidation, with some research suggesting that certain memories are prioritized for consolidation. Initial strength of a memory appears to be an important boundary condition in determining which memories are consolidated during sleep. However, the role of consolidation-mediating oscillations, such as sleep spindles and slow oscillations, in this preferential consolidation has not been explored. Here, 54 human participants (76% female) studied pairs of words to three distinct encoding strengths, with recall being tested immediately following learning and again six hours later. Thirty-six had a two-hour nap opportunity following learning, whilst the remaining 18 remained awake throughout. Results showed that across six hours awake, weakly encoded memories deteriorated the fastest. In the nap group however, this effect was attenuated, with forgetting rates equivalent across encoding strengths. Within the nap group, consolidation of weakly encoded items was associated with fast sleep spindle density during non-rapid eye movement sleep. Moreover, sleep spindles that were coupled to slow oscillations predicted the consolidation of weak memories independently of uncoupled sleep spindles. These relationships were unique to weakly encoded items, with spindles not correlating with memory for intermediate or strong items. This suggests that sleep spindles facilitate memory consolidation, guided in part by memory strength.

Significance statementGiven the countless pieces of information we encode each day, how does the brain select which memories to commit to long-term storage? Sleep is known to aid in memory consolidation, and it appears that certain memories are prioritized to receive this benefit. Here, we found that compared to staying awake, sleep was associated with better memory for weakly encoded information. This suggests that sleep helps attenuate the forgetting of weak memory traces. Fast sleep spindles, a hallmark oscillation of non-rapid eye movement sleep, mediate consolidation processes. We extend this to show that fast spindles were uniquely associated with the consolidation of weakly encoded memories. This provides new evidence for preferential sleep-based consolidation and elucidate a physiological correlate of this benefit.

category: neuroscience


title: FlexDotPlot: a universal and modular dot plot visualization tool for complex multifaceted data

abstract:
MotivationDot plots are heatmap-like charts that provide a compact way to simultaneously display two quantitative information by means of dots of different sizes and colours. Despite the popularity of this visualization method, particularly in single-cell RNA-seq studies, existing tools used to make dot plots are limited in terms of functionality and usability.

ResultsWe developed FlexDotPlot, an R package for generating dot plots from multifaceted data, including single-cell RNA-seq data. It provides a universal and easy-to-use solution with a high versatility. An interactive R Shiny application is also available allowing non-R users to easily generate dot plots with several tunable parameters.

Availability and implementationSource code, detailed manual, and code to reproduce figures are available at https://github.com/Simon-Leonard/FlexDotPlot. A Shiny app is available as a stand-alone application within the package.


title: A Whole-Brain Map and Assay Parameter Analysis of Mouse VTA Dopaminergic Activation

abstract: Ascending dopaminergic projections from neurons located in the Ventral Tegmental Area (VTA) are key to the etiology, dysfunction, and control of motivation, learning, and addiction. Due to evolutionary conservation of this nucleus and the extensive use of mice as disease models, establishing an assay for VTA dopaminergic signalling in the mouse brain is crucial for the translational investigation of motivational control as well as of neuronal function phenotypes for diseases and interventions. In this article we use optogenetic stimulation directed at VTA dopaminergic neurons in combination with functional Magnetic Resonance Imaging (fMRI), a method widely used in human deep brain imaging. We present a comprehensive assay producing the first whole-brain opto-fMRI map of dopaminergic activation in the mouse, and show that VTA dopaminergic system function is consistent with its structural VTA projections, diverging only in a few key aspects. While the activation map predominantly highlights target areas according to their relative projection densities (e.g. strong activation of the nucleus accumbens and low activation of the hippocampus), it also includes areas for which a structural connection is not well established (such as the dorsomedial striatum). We further detail the variability of the assay with regard to multiple experimental parameters, including stimulation protocol and implant position, and provide evidence-based recommendations for assay reuse, publishing both reference results and a reference analysis workflow implementation.


title: Whole-Brain opto-fMRI Map of Mouse VTA Dopaminergic Activation Reflects Structural Projections with Small but Significant Deviations


title: Genomic Epidemiology with Mixed Samples

abstract: Genomic epidemiology is a tool for tracing transmission of pathogens based on whole-genome sequencing. We introduce the mGEMS pipeline for genomic epidemiology with plate sweeps representing mixed samples of a target pathogen, skipping the colony pick step. The pipeline includes the novel mGEMS read binner for probabilistic assignments of sequencing reads, and the scalable pseudoaligner Themisto. We demonstrate the effectiveness of our approach using closely related samples in a nosocomial setting, obtaining results that are comparable to those based on colony picks. Our results lend firm support to more widespread consideration of genomic epidemiology with mixed infection samples.


title: Mice carrying paternal knockout of imprinted Grb10 do not show compulsive behaviours

abstract: Mice lacking paternal expression of imprinted Grb10 show a number of social behaviour deficits, including an enhanced allogrooming phenotype. However, this could also index compulsive behaviour, and the increased whisker barbering seen in Grb10+/p mice has been suggested to be indicative of a trichotillomania-type behaviour. Here we test whether compulsive behaviour is a more general phenotype in Grb10+/p mice by examining marble burying. We also examined the mice for potentially confounding anxiety phenotypes using the elevated plus maze (EPM). Grb10+/p mice showed no difference from wild-type littermate controls on any measure in the marble burying test at any age. However, Grb10+/p mice were more willing to enter, spend time on, and head-dip on the open arm of the EPM than wild-type mice. These data suggest that Grb10+/p mice are not generally more compulsive, and that the enhanced allogrooming is probably indicative of altered social behaviour. Furthermore, the altered behaviours seen on the EPM adds to other published findings suggesting that Grb10 has a role in mediating risk-taking.

category: animal behavior and cognition


title: The lateral entorhinal cortex is a hub for local and global dysfunction in pre-tauopathy states

abstract: Functional network activity alterations are one of the earliest hallmarks of Alzheimers disease (AD), detected prior to amyloidosis and tauopathy. Better understanding the neuronal underpinnings of such network alterations could offer mechanistic insight into AD progression. Here, we examined a mouse model (early-tauopathy 3xTgAD mice) recapitulating this early AD stage. We found resting functional connectivity loss within ventral networks, including the entorhinal cortex, aligning with the spatial distribution of tauopathy reported in humans. Unexpectedly, in contrast to decreased connectivity at rest, 3xTgAD mice show enhanced fMRI signal within several projection areas following optogenetic activation of the entorhinal cortex. We corroborate this finding by demonstrating neuronal facilitation within ventral networks and synaptic hyperexcitability in projection targets. 3xTgAD mice thus reveal a dichotomic hypo-connected resting/hyper-responsive active phenotype. The strong homotopy between the areas affected supports the translatability of this pathophysiological model to tau-related deficits in humans.


title: Genetic architecture of a mutation's expressivity

abstract: Genetic background often influences the phenotypic consequences of mutations, resulting in variable expressivity. How standing genetic variants collectively cause this phenomenon is not fully understood. Here, we comprehensively identify loci in a budding yeast cross that impact the growth of individuals carrying a spontaneous missense mutation in the nuclear-encoded mitochondrial ribosomal gene MRP20. Initial results suggested that a single large effect locus influences the mutations expressivity, with one allele causing inviability in mutants. However, further experiments revealed this simplicity was an illusion. In fact, many additional loci shape the mutations expressivity, collectively leading to a wide spectrum of mutational responses. These results exemplify how complex combinations of alleles can produce a diversity of qualitative and quantitative responses to the same mutation.

category: genetics


title: Genetic basis of a spontaneous mutation's expressivity


title: Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression

abstract:
The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A1 receptors (A1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A1R-selective agonist, BnOCPA, is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A1Rs arises from BnOCPAs unique and exquisitely selective activation of Gob among the six Gi/o subtypes, and in the absence of {beta}-arrestin recruitment. BnOCPA thus demonstrates a highly-specific G-selective activation of the native A1R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective G agonism.

Short summaryWe describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective G agonism.

category: physiology


title: Multi-fluorescence high-resolution episcopic microscopy (MF-HREM) for three dimensional imaging of adult murine organs

abstract:
Three-dimensional microscopy of large biological samples (>0.5 cm3) is transforming biological research. Many existing techniques require trade-offs between image resolution, sample size and method complexity. A simple robust instrument with the potential to perform large volume 3D imaging currently exists in the form of the Optical HREM, however the development of the instrument to date is limited to single fluorescent wavelength imaging with non-specific eosin staining. This work presents developments to realize the potential of the HREM to become Multi-fluorescent High Resolution Episcopic Microscopy (MF-HREM).

MF-HREM is a serial-sectioning and block-facing wide-field fluorescence imaging technique, which does not require tissue clearing or optical sectioning. Multiple developments are detailed in sample preparation and image post-processing to enable multiple specific stains in large samples, and show how these enable segmentation and quantification of the data. The application of MF-HREM is demonstrated in a variety of biological contexts: 3D imaging of whole tumor vascular networks and tumor cell invasion in xenograft tumors up to 7.5 mm3 at resolutions of 2.75 m, quantification of glomeruli volume in the adult mouse kidney, and quantification of vascular networks and white matter track orientation in adult mouse brain.

category: biophysics


title: Achieving high-quality ddRAD-like reference catalogs for non-model species: the power of overlapping paired-end reads.

abstract: Reduced representation libraries (RRS) allow large scale studies on non-model species to be performed without the need for a reference genome, by building a pseudo-reference locus catalog directly from the data. However, using closely-related high-quality genomes can help maximize nucleotide variation identified from RRS libraries. While chromosome-level genomes remain unavailable for most species, researchers can still invest in building high-quality and project-specific de novo locus catalogs. Among methods that use restriction enzymes (RADSeq), those including fragment size selection to help obtain the desired number of loci - such as double-digest RAD (ddRAD) - are highly flexible but can present important technical issues. Inconsistent size selection reproducibility across libraries and variable coverage across fragment lengths can affect genotyping confidence, number of identified single nucleotide polymorphisms (SNPs), and quality and completeness of the de novo reference catalog. We have developed a strategy to optimize locus catalog building from ddRAD-like data by sequencing overlapping reads that recreate original fragments and add information about coverage per fragment size. Further in silico size selection and digestion steps limit the filtered dataset to well-covered sets of loci and identity thresholds are estimated based on sequence pairwise comparisons. We have developed a full workflow that identifies a set of reduced-representation single-copy orthologs (R2SCOs) for any given species and that includes estimating and evaluating allelic variation in comparison with SNP calling results. We also show how to use our concept in an established RADSeq pipeline - Stacks - and confirm that our approach increases average coverage and number of SNPs called per locus in the final catalog. We have demonstrated our full workflow using newly generated data from five sea turtle species and provided further proof-of-principle using published hybrid sea turtle and primate datasets. Finally, we showed that a project-specific set of R2SCOs perform better than a draft genome as a reference.

category: evolutionary biology


title: Structural and functional networks involved in empathy for positive and negative emotions in late adulthood

abstract: Empathy, among other social-cognitive processes, changes across adulthood. More specifically, cognitive components of empathy (understanding anothers perspective) appear to decline with age, while findings for affective empathy (sharing anothers emotional state) are rather mixed. Structural and functional correlates underlying cognitive and affective empathy in aging and the extent to which valence affects empathic response in brain and behavior are not well understood yet. To fill these research gaps, younger and older adults completed a modified version of the Multifaceted Empathy Test, which measures both cognitive and affective empathy as well as empathic responding to both positive and negative stimuli (i.e., positive vs. negative empathy). Adopting a multimodal imaging approach and applying multivariate analysis, the study found that for cognitive empathy to negative emotions, regions of the salience network including the anterior insula and anterior cingulate were more involved in older than younger adults. For affective empathy to positive emotions, in contrast, younger and older adults recruited a similar brain network including main nodes of the default mode network. Additionally, increased structural integrity (fractional anisotropy values) of the posterior, but not the anterior, cingulum bundle was related to activation of default mode regions during affective empathy for positive emotions in both age groups. These findings provide novel insights into the functional networks subserving cognitive and affective empathy in younger and older adults and highlight the importance of considering valence in empathic response in aging research. Further this study, for the first time, underscores the role of the posterior cingulum bundle in higher-order social-cognitive processes such as empathy, specifically for positive emotions, in aging.


title: Age-related differences in negative cognitive empathy but similarities in positive affective empathy


title: Topological Analysis of Differential Effects of Ketamine and Propofol Anesthesia on Brain Dynamics

abstract: Research has found that the vividness of conscious experience is related to brain dynamics. Despite both being anesthetics, propofol and ketamine produce different subjective states: we explore the different effects of these two anaesthetics on the structure of dynamic attractors reconstructed from electrophysiological activity recorded from cerebral cortex of two macaques. We used two methods: the first embeds the recordings in a continuous high-dimensional manifold on which we use topological data analysis to infer the presence of higher-order dynamics. The second reconstruction, an ordinal partition network embedding, allows us to create a discrete state-transition network, which is amenable to information-theoretic analysis and contains rich information about state-transition dynamics. We find that the awake condition generally had the "richest" structure, visiting the most states, the presence of pronounced higher-order structures, and the least deterministic dynamics. In contrast, the propofol condition had the most dissimilar dynamics, transitioning to a more impoverished, constrained, low-structure regime. The ketamine condition, interestingly, seemed to combine aspects of both: while it was generally less complex than the awake condition, it remained well above propofol in almost all measures. These results provide provides deeper and more comprehensive insights than what is typically gained by using point-measures of complexity.


title: Neural dynamics of phoneme sequences: Position-invariant code for content and order

abstract:
Speech consists of a continuously-varying acoustic signal. Yet human listeners experience it as a sequence of discrete units (phonemes and words). To identify how the brain continuously represents and updates speech units, we recorded two-hour magnetoencephalograms from 21 subjects listening to short narratives. Our encoding and decoding analyses show that the human brain uses a dynamic coding scheme to represent approximately three successive phonetic features at each time sample. These dynamic phonetic representations, not directly accessible from the acoustic signal, are active earlier when phonemes are more predictable, and are sustained when lexical identity is uncertain. The results reveal how phoneme sequences in natural speech are neurally represented and shed new light on how the human brain combines them to probe the mental lexicon.

One sentence summaryThe human brain keeps track of the relative order of speech sound sequences by jointly encoding content and elapsed processing time


title: Neural mechanisms underlying distractor inhibition on the basis of feature and/or spatial expectations.

abstract: A rapidly growing body of research indicates that inhibition of distracting information may not be under flexible, top-down control, but instead heavily relies on expectations derived from past experience about the likelihood of events. Yet, how expectations about distracting information influence distractor inhibition at the neural level remains unclear. To determine how expectations induced by distractor features and/or location regularities modulate distractor processing, we measured EEG while participants performed two variants of the additional singleton paradigm. Critically, in these different variants, target and distractor features either randomly swapped across trials, or were fixed, allowing for the development of distractor feature-based expectations. Moreover, the task was initially performed without any spatial regularities, after which a high probability distractor location was introduced. Our results show that both distractor feature- and location regularities contributed to distractor inhibition, as indicated by corresponding reductions in distractor costs during visual search and an earlier distractor-evoked Pd component. Yet, control analyses showed that while observers were sensitive to regularities across longer time scales, the observed effects to a large extent reflected intertrial repetition. Large individual differences further suggest a functional dissociation between early and late Pd components, with the former reflecting early sensory suppression related to intertrial priming and the latter reflecting suppression sensitive to expectations derived over a longer time scale. Also, counter to some previous findings, no increase in anticipatory alpha-band activity was observed over visual regions representing the expected distractor location, although this effect should be interpreted with caution as the effect of spatial statistical learning was also less pronounced than in other studies. Together, these findings suggest that intertrial priming and statistical learning may both contribute to distractor suppression and reveal the underlying neural mechanisms.


title: Iterative community-driven development of a SARS-CoV-2 tissue simulator

abstract: The 2019 novel coronavirus, SARS-CoV-2, is a pathogen of critical significance to international public health. Knowledge of the interplay between molecular-scale virus-receptor interactions, single-cell viral replication, intracellular-scale viral transport, and emergent tissue-scale viral propagation is limited. Moreover, little is known about immune system-virus-tissue interactions and how these can result in low-level (asymptomatic) infections in some cases and acute respiratory distress syndrome (ARDS) in others, particularly with respect to presentation in different age groups or pre-existing inflammatory risk factors. Given the nonlinear interactions within and among each of these processes, multiscale simulation models can shed light on the emergent dynamics that lead to divergent outcomes, identify actionable "choke points" for pharmacologic interventions, screen potential therapies, and identify potential biomarkers that differentiate patient outcomes. Given the complexity of the problem and the acute need for an actionable model to guide therapy discovery and optimization, we introduce and iteratively refine a prototype of a multiscale model of SARS-CoV-2 dynamics in lung tissue. The first prototype model was built and shared internationally as open source code and an online interactive model in under 12 hours, and community domain expertise is driving regular refinements. In a sustained community effort, this consortium is integrating data and expertise across virology, immunology, mathematical biology, quantitative systems physiology, cloud and high performance computing, and other domains to accelerate our response to this critical threat to international health. More broadly, this effort is creating a reusable, modular framework for studying viral replication and immune response in tissues, which can also potentially be adapted to related problems in immunology and immunotherapy.

category: systems biology


title: Adaptive actin organization buffers endocytosis against changes in membrane tension

abstract: Clathrin-mediated endocytosis (CME) robustness under elevated membrane tension is maintained by actin assembly-mediated force generation. However, whether more actin assembles at endocytic sites in response to increased load, as has been observed in lamellipodia, has not previously been investigated. Here actin network ultrastructure at CME sites was examined under low and high membrane tension. Actin and N-WASP spatial organization indicate that actin polymerization initiates at the base of clathrin-coated pits and that the network then grows away from the plasma membrane. Actin network height at individual CME sites was not coupled to coat shape, raising the possibility that local differences in mechanical load feedback on assembly. By manipulating membrane tension and Arp2/3 complex activity we tested the hypothesis that actin assembly at CME sites increases in response to elevated load. Indeed, in response to elevated membrane tension, actin grew higher, resulting in greater coverage of the clathrin coat, and CME slowed. When membrane tension was elevated and the Arp2/3 complex was inhibited, shallow clathrin-coated pits accumulated, indicating that this adaptive mechanism is especially crucial for coat curvature generation. We propose that actin assembly increases in response to increased load to ensure CME robustness over a range of plasma membrane tensions.


title: Load adaptation of endocytic actin networks


title: SARS-COV-2 RBD Oral Vaccine Boosted by Mucosal Immune Adjuvant LTB26 via DCs and B Cells Activation in Mice

abstract: Although several SARS-COV-2 vaccines have been approved, no one oral live vaccine is available. Here, an oral SARS-COV-2 RBD live vaccine containing LTB26 adjuvant has been developed. BALB/c mice are oral vaccinated with attenuated Salmonella typhimurium SL7207 containing pcDNA3.1-LTB26RBD or pcDNA3.1-RBD plasmids. The result shows that the high level of RBD specific antibody is produced in pcDNA3.1- LTB26RBD treatment. The mechanism indicates that LTB26 enhances RBD antibody production by significantly upregulating the activity of MHC II+ DCs and CD19+CD45+ B cells. LTB26 mutant is derived from heat-labile enterotoxin B subunit (LTB) wild type of Escherichia coli with enhanced immune adjuvanticity. Based on the pre-experiment result that SL7207 interferes the function of LTB26, the purified LTB26 was mixed with purified human rotavirus VP8 antigen to explore the mechanism of adjuvant. The results suggests that LTB26 enhances mucosal immune responses via increased of BCR and MHC II+ expression. Furthermore, LTB26 promotes both Th1 and Th2 cell mediated immunity. Therefore, LTB26 maybe a potent adjuvant for mucosal vaccine development in view of the safety of LTB26 than LT toxin.

category: immunology


title: Trading accuracy for speed over the course of a decision

abstract:
Humans and other animals often need to balance the desire to gather sensory information (to make the best choice) with the urgency to act, facing a speed-accuracy tradeoff (SAT). Given the ubiquity of SAT across species, extensive research has been devoted to understanding the computational mechanisms allowing its regulation at different timescales, including from one context to another, and from one decision to another. However, animals must frequently change their SAT on even shorter timescales - i.e., over the course of an ongoing decision - and little is known about the mechanisms that allow such rapid adaptations. The present study aimed at addressing this issue. Human subjects performed a decision task with changing evidence. In this task, subjects received rewards for correct answers but incurred penalties for mistakes. An increase or a decrease in penalty occurring halfway through the trial promoted rapid SAT shifts, favoring speeded decisions either in the early or in the late stage of the trial. Importantly, these shifts were associated with stage-specific adjustments in the accuracy criterion exploited for committing to a choice. Those subjects who decreased the most their accuracy criterion at a given decision stage exhibited the highest gain in speed, but also the highest cost in terms of performance accuracy at that time. Altogether, the current findings offer a unique extension of previous work, by suggesting that dynamic changes in accuracy criterion allow the regulation of the SAT within the timescale of a single decision.

New and noteworthyExtensive research has been devoted to understanding the mechanisms allowing the regulation of the speed-accuracy tradeoff (SAT) from one context to another and from one decision to another. Here, we show that humans can voluntarily change their SAT on even shorter timescales - i.e., over the course of a decision. These rapid SAT shifts are associated with dynamic adjustments in the accuracy criterion exploited for committing to a choice.


title: An integrative eco-evo-devo framework identifies complex drivers of oral morphology in tailed frog (Ascaphus spp.) tadpoles

abstract:
O_LIMorphological variation is often maintained by complex and interrelated factors, complicating the identification of underlying drivers. Comprehensive understanding of the evolution of morphological traits thus requires the use of integrative methods that can simultaneously investigate potentially interacting drivers.
C_LIO_LITadpole oral morphology is one such trait that may be driven by the direct and indirect effects of the environment and variation in developmental processes. Although many studies have investigated tadpole oral morphological diversity among species, few have sought to understand the drivers that underlie intraspecific variation.
C_LIO_LIIn this study, we investigated potential drivers of labial tooth number variation among populations of two species of tailed frogs, the Rocky Mountain tailed frog (Ascaphus montanus) and the Coastal tailed frog (A. truei). We used an integrative eco-evo-devo framework to test the direct and indirect effects of developmental processes (population variation in size by developmental stage) and environmental selection (temperature) on labial tooth number across three tooth rows in 240 tadpoles.
C_LIO_LIUsing this framework, we explained 64-81% of the variation in labial tooth number variation in three labial tooth rows for A. montanus and 37-54% of the variation in labial tooth number in the same tooth rows for A. truei. Apart from the consistent effects of tadpole length on labial tooth number, we found strong support for temperature as a direct driver for increased labial tooth number, supporting our eco-evo hypothesis in both species. In A. montanus, we also found strong support for variation in our proxy for developmental processes influencing labial tooth number variation (devo-evo), as well as the interacting effects of temperature and this developmental process proxy (i.e., developmental plasticity; eco-devo). In A. truei, we found mixed support for these latter two drivers among labial tooth rows.
C_LIO_LIWe conclude that labial tooth number variation in tailed frogs is driven by complex and interacting environmental and developmental factors. Without the use of an interdisciplinary framework, these relationships may not have been uncovered and our ability to explain the variation in this morphological trait would have been limited.
C_LI

category: ecology


title: Mitochondrial Aurora kinase A induces mitophagy by interacting with MAP1LC3 and Prohibitin 2

abstract: Epithelial and haematologic tumours often show the overexpression of the serine/threonine kinase AURKA. Recently, AURKA was shown to localise at mitochondria, where it regulates mitochondrial dynamics and ATP production. Here we define the molecular mechanisms of AURKA in regulating mitochondrial turnover by mitophagy. When overexpressed, AURKA induces the disappearance of Outer Mitochondrial Membrane proteins by the proteasome. Then, AURKA triggers the degradation of Inner Mitochondrial Membrane (IMM)/matrix proteins by interacting with core components of the autophagy pathway. On the IMM, the kinase forms a tripartite complex with MAP1LC3 and the mitophagy receptor PHB2. This complex is necessary to trigger mitophagy in a PARK2/Parkin-independent manner. The formation of the tripartite complex is induced by the phosphorylation of PHB2 on Ser39, which is required for MAP1LC3 to interact with PHB2. Last, treatment with the PHB2 ligand Xanthohumol blocks AURKA-induced mitophagy by destabilising the tripartite complex. This treatment also restores normal ATP production levels. Altogether, these data provide evidence for a previously undetected role of AURKA in promoting mitophagy through the interaction with PHB2 and MAP1LC3. This work paves the way to the use of function-specific pharmacological inhibitors to counteract the effects of the overexpression of AURKA in cancer.


title: pre-mRNA spatial distributions suggest that splicing can occur post-transcriptionally

abstract: Splicing is the molecular process by which introns are removed from pre-mRNA and exons are joined together to form the sequence of the mature mRNA. While the biochemical steps of splicing have been largely worked out, the ordering and spatial distribution of these steps, especially in relation to the transcriptional process itself, remain controversial. Here, we use single molecule RNA FISH together with expansion microscopy to measure the spatial distribution of nascent and partially spliced transcripts in mammalian cells, allowing us to infer the order in which an intron is transcribed and spliced out of the pre-mRNA. We show that 4 out of 4 genes we interrogated exhibit clear post-transcriptional splicing of at least one intron, and that introns can be spliced in any order. Expansion microscopy further revealed the presence of a transcription site proximal zone in which the motion of RNA is slower than in the nucleoplasm. Full length pre-mRNA undergo continuous splicing as they move through this zone after transcription. Upon leaving this zone, some genes transcripts localize to speckles during the process of splicing while others appear to traffic freely through the nucleus without localizing to any other nuclear compartment. Our results suggest a model in which transcription and splicing are largely independent, and the existence of a slow moving zone around the transcription site allows for the unification of co-transcriptional and post-transcriptional models of splicing.


title: Invasion and maintenance of meiotic drivers in populations of ascomycete fungi

abstract: Meiotic drivers are selfish genetic elements that are able to become over-represented among the products of meiosis. This transmission advantage makes it possible for them to spread in a population even when they impose fitness costs on their host organisms. Whether a meiotic driver can invade a population, and subsequently reach fixation or coexist in a stable polymorphism, depends on the one hand on the biology of the host organism, including its life-cycle, mating system, and population structure, and on the other hand on the specific fitness effects of the driving allele on the host. Here, we present a population genetic model for spore killing, a type of drive specific to fungi. We show how ploidy level, rate of selfing, and efficiency of spore killing affect the invasion probability of a driving allele and the conditions for its stable coexistence with the non-driving allele. Our model can be adapted to different fungal life-cycles, and is applied here to two well-studied genera of filamentous ascomycetes known to harbor spore killing elements, Neurospora and Podospora. We discuss our results in the light of recent empirical findings for these two systems.


title: Rapid Assessment of T-Cell Receptor Specificity of the Immune Repertoire

abstract: Accurate assessment of TCR-antigen specificity at the whole immune repertoire level lies at the heart of improved cancer immunotherapy, but predictive models capable of high-throughput assessment of TCR-peptide pairs are lacking. Recent advances in deep sequencing and crystallography have enriched the data available for studying TCR-p-MHC systems. Here, we introduce a pairwise energy model, RACER, for rapid assessment of TCR-peptide affinity at the immune repertoire level. RACER applies supervised machine learning to efficiently and accurately resolve strong TCR-peptide binding pairs from weak ones. The trained parameters further enable a physical interpretation of interacting patterns encoded in each specific TCR-p-MHC system. When applied to simulate thymic selection of an MHC-restricted T-cell repertoire, RACER accurately estimates recognition rates for tumor-associated neoantigens and foreign peptides, thus demonstrating its utility in helping address the large computational challenge of reliably identifying the properties of tumor antigen-specific T-cells at the level of an individual patients immune repertoire.


title: Signatures of mito-nuclear coevolution in a warbler species complex

abstract: Mitochondrial (mtDNA) and nuclear (nDNA) genes interact to govern metabolic pathways of mitochondria. When differentiated populations interbreed at secondary contact, incompatibilities between mtDNA of one population and nDNA of the other could result in low fitness of hybrids. In northwestern North America, two hybridizing species of warblers, Setophaga occidentalis (abbreviated as SOCC) and S. townsendi (STOW), provide an excellent system to investigate the potential co-adaptation of mitochondrial and nuclear DNA. The inland population of STOW (inland STOW) harbors mtDNA haplotype that is half a million years divergent from the SOCC mtDNA, and these populations also differ strongly in a few nDNA regions. Coastal populations of STOW (coastal STOW) have mixed ancestry, consistent with ancient hybridization of SOCC and inland STOW-like population. Of the few highly-differentiated nDNA regions between inland STOW and SOCC, one of these regions (on chromosome 5) is also differentiated between coastal STOW and inland STOW, and covaries with mtDNA among coastal STOW populations. Genes in this 1.2Mb region of chromosome 5 are associated with fatty acid oxidation and energy-related signaling transduction, both of which are closely associated with mitochondrial function. This chromosome 5 region is correlated with mtDNA haplotypes both within and across sampling sites, a pattern consistent with mitonuclear co-adaptation. We show that such mitonuclear coevolution might be maintained by climate-related selection, because mitonuclear ancestry is correlated with climatic conditions among sampling sites. Together, our observation suggests climatic-associated adaptation shaping mitonuclear differentiation and introgression in this species complex.


title: Unsupervised Learning Predicts Human Perception and Misperception of Gloss

abstract: Reflectance, lighting, and geometry combine in complex ways to create images. How do we disentangle these to perceive individual properties, like surface glossiness? We suggest that brains disentangle properties by learning to model statistical structure in proximal images. To test this, we trained unsupervised generative neural networks on renderings of glossy surfaces and compared their representations with human gloss judgments. The networks spontaneously cluster images according to distal properties such as reflectance and illumination, despite receiving no explicit information about them. Intriguingly, the resulting representations also predict the specific patterns of  successes and  errors in human perception. Linearly decoding specular reflectance from the models internal code predicts human gloss perception better than ground truth, supervised networks, or control models, and predicts, on an image-by-image basis, illusions of gloss perception caused by interactions between material, shape, and lighting. Unsupervised learning may underlie many perceptual dimensions in vision, and beyond.


title: Adhatoda Vasica ameliorates cellular hypoxia dependent mitochondrial dysfunction in acute and severe asthmatic mice.

abstract:
Severe asthma is a chronic airway disease that exhibits poor response to conventional asthma therapies. Growing evidence suggests that elevated hypoxia increases the severity of asthmatic inflammation among patients and in model systems. In this study, we elucidate the therapeutic effects and mechanistic basis of Adhatoda Vasica (AV) aqueous extract on mouse models of acute allergic as well as severe asthma subtypes at physiological, histopathological, and molecular levels. Oral administration of AV extract attenuates the increased airway resistance and inflammation in acute allergic asthmatic mice and alleviates the molecular signatures of steroid (dexamethasone) resistance like IL-17A, KC, and HIF-1 (hypoxia inducible factor-1alpha) in severe asthmatic mice. AV inhibits HIF-1 levels through restoration of expression of its negative regulator-PHD2 (prolyl hydroxylase domain-2). Alleviation of hypoxic response mediated by AV is further confirmed in the acute and severe asthma model. AV reverses cellular hypoxia-induced mitochondrial dysfunction in human bronchial epithelial cells - evident from bioenergetic profiles and morphological analysis of mitochondria. In silico docking of AV constituents reveal higher negative binding affinity for C and O-glycosides for HIF-1, IL-6, Janus kinase 1/3, TNF- and TGF-{beta}-key players of hypoxia-inflammation. This study for the first time provides a molecular basis of action and effect of AV whole extract that is widely used in Ayurveda practice for diverse respiratory ailments. Further, through its effect on hypoxia-induced mitochondrial dysfunction, the study highlights its potential to treat severe steroid-resistant asthma.

Significance StatementSevere asthma is a global health concern with a large fraction unresponsive to current treatment modalities involving corticosteroids. Recent findings suggest that elevated hypoxia has a critical role in severity of asthma. Here, we report therapeutic treatment with aqueous extract of Adhatoda Vasica (AV), an ayurvedic medicine, attenuates sever steroid insensitive asthmatic features in mice. The observed effects of AV are through inhibition of hypoxic response, both in vivo and in vitro. AV also reverses mitochondrial dysfunction, a key consequence associated with hypoxia, and asthma. This study highlights the translational potential of AV for the treatment of severe asthma and provides opportunities for its usage in other disease conditions where hypoxia is pertinent.


title: Sensory coding and contrast invariance emergefrom the control of plastic inhibition overemergent selectivity

abstract: Visual stimuli are represented by a highly efficient code in the primary visual cortex, but the development of this code is still unclear. Two distinct factors control coding efficiency: Representational efficiency, which is determined by neuronal tuning diversity, and metabolic efficiency, which is influenced by neuronal gain. How these determinants of coding efficiency are shaped during development, supported by excitatory and inhibitory plasticity, is only partially understood. We investigate a fully plastic spiking network of the primary visual cortex, building on phenomenological plasticity rules. Our results suggest that inhibitory plasticity is key to the emergence of tuning diversity and accurate input encoding. We show that inhibitory feedback (random and specific) increases the metabolic efficiency by implementing a gain control mechanism. Interestingly, this led to the spontaneous emergence of contrast-invariant tuning curves. Our findings highlight that (1) interneuron plasticity is key to the development of tuning diversity and (2) that efficient sensory representations are an emergent property of the resulting network.


title: Separating measurement and expression models clarifies confusion in single cell RNA-seq analysis

abstract: AO_SCPLOWBSTRACTC_SCPLOWThe high proportion of zeros in typical scRNA-seq datasets has led to widespread but inconsistent use of terminology such as "dropout" and "missing data". Here, we argue that much of this terminology is unhelpful and confusing, and outline simple ideas to help reduce confusion. These include: (1) observed scRNA-seq counts reflect both true gene expression levels and measurement error, and carefully distinguishing these contributions helps clarify thinking; and (2) method development should start with a Poisson measurement model, rather than more complex models, because it is simple and generally consistent with existing data. We outline how several existing methods can be viewed within this framework and highlight how these methods differ in their assumptions about expression variation. We also illustrate how our perspective helps address questions of biological interest, such as whether mRNA expression levels are multimodal among cells.

category: genomics


title: Capsid Proteins are Necessary for Replication of a Parvovirus

abstract:
AO_SCPLOWBSTRACTC_SCPLOWDespite tight genetic compression, viral genomes are often organized in functional gene clusters, a modular structure that might favor their evolvability. This has greatly facilitated biotechnological developments, such as the recombinant Adeno-Associated Virus (AAV) systems for gene therapy. Following this lead, we endeavored to engineer the related insect parvovirus Junonia coenia densovirus (JcDV) to create addressable vectors for insect pest biocontrol. To enable safer manipulation of capsid mutants, we translocated the non-structural (ns) gene cluster outside the viral genome. To our dismay, this yielded a virtually non-replicable clone. We linked the replication defect to an unexpected modularity breach, as ns translocation truncated the overlapping 3 UTR of the capsid transcript (vp). We found that native vp 3UTR is necessary to high VP production, but that decreased expression do not adversely impact the expression of NS proteins, which are known replication effectors. As nonsense vp mutations recapitulate the replication defect, VP proteins appear directly implicated in the replication process. Our findings suggest intricate replication-encapsidation couplings that favor maintenance of genetic integrity. We discuss possible connections with an intriguing cis-packaging phenomenon previously observed in parvoviruses, whereby capsids preferentially package the genome from which they were expressed.

IO_SCPLOWMPORTANCEC_SCPLOWDensoviruses could be used as biological control agents to manage insect pests. Such applications require in depth biological understanding and associated molecular tools. However, the genomes of these viruses remain hard to manipulate due too poorly tractable secondary structures at their extremities. We devised a construction strategy that enable precise and efficient molecular modifications. Using this approach, we endeavored to create a split clone of the Junonia coenia densovirus (JcDV) that can be used to safely study the impact of capsid mutations on host specificity. Our original construct proved to be non-functional. Fixing this defect led us to uncover that capsid proteins and their correct expression are essential for continued rolling-hairpin replication. This points to an intriguing link between replication and packaging, which might be shared with related viruses. This serendipitous discovery illustrates the power of synthetic biology approaches to advance our knowledge of biological systems.

category: microbiology


title: Effects of the selective dopamine D3 receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice

abstract: Recent preclinical studies have reported that pretreatment with the novel and highly-selective dopamine D3 receptor (D3R) antagonists R-VK4-40 or VK4-116 attenuates the abuse-related behavioral effects of oxycodone while enhancing its analgesic properties. However, whether these observed effects are generalizable to the broad class of D3R antagonists and/or extend to opioids other than oxycodone has not been extensively explored. The present study sought to assess the impact of pretreatment with another selective D3R antagonist, PG01037, on several behavioral effects of morphine in mice. C57Bl/6J mice were pretreated with PG01037 (0 - 10 mg/kg) and tested for 1) hyperlocomotion induced by acute morphine (5.6 - 56 mg/kg), 2) locomotor sensitization following repeated morphine (56 mg/kg), 3) antinociception following acute morphine (18 mg/kg), and 4) catalepsy following administration of PG01037 alone or in combination with morphine (56 mg/kg). PG01037 dose-dependently attenuated morphine-induced hyperlocomotion and morphine-induced antinociception at doses that did not alter basal locomotion or nociception alone, but did not prevent the induction of locomotor sensitization following repeated morphine administration. Moreover, PG01037 did not induce catalepsy either alone or in combination with morphine. These results suggest that attenuation of acute opioid-induced hyperlocomotion may be a behavioral effect shared among D3R-selective antagonists, thus supporting continued investigations into their use as potential treatments for opioid use disorder. However, PG01037 is unlike newer, highly-selective D3R antagonists in its capacity to reduce opioid-induced antinociception, indicating that modulation of opioid analgesia may vary across different D3R antagonists.


title: Neural harmonics of syntactic structure

abstract: Can neural rhythms reflect purely internal syntactic processes in multi-word constructions? To test this controversial conjecture - relevant to language in particular and cognition more broadly - we recorded electroencephalographic and behavioural data as participants listened to isochronously presented sentences of varying in syntactic complexity. Each trial comprised ten concatenated sentences and was either fully grammatical (regular) or rendered ungrammatical via randomly distributed word order violations. We found that attending the regular repetition of abstract syntactic categories (phrases and sentences) generates neural rhythms whose harmonics are mathematically independent of word rate. This permits to clearly separate endogenous syntactic rhythms from exogenous speech rhythms. We demonstrate that endogenous but not exogenous rhythms predict participants grammaticality judgements, and allow for the neural decoding of regular vs. irregular trials. Neural harmonic series constitute a new form of behaviourally relevant evidence for syntactic competence.


title: Graph convolutional networks for drug response prediction

abstract:
BackgroundDrug response prediction is an important problem in computational personalized medicine. Many machine-learning-based methods, especially deep learning-based ones, have been proposed for this task. However, these methods often represent the drugs as strings, which are not a natural way to depict molecules. Also, interpretation (e.g., what are the mutation or copy number aberration contributing to the drug response) has not been considered thoroughly.

MethodsIn this study, we propose a novel method, GraphDRP, based on graph convolutional network for the problem. In GraphDRP, drugs were represented in molecular graphs directly capturing the bonds among atoms, meanwhile cell lines were depicted as binary vectors of genomic aberrations. Representative features of drugs and cell lines were learned by convolution layers, then combined to represent for each drug-cell line pair. Finally, the response value of each drug-cell line pair was predicted by a fully-connected neural network. Four variants of graph convolutional networks were used for learning the features of drugs.

ResultsWe found that GraphDRP outperforms tCNNS in all performance measures for all experiments. Also, through saliency maps of the resulting GraphDRP models, we discovered the contribution of the genomic aberrations to the responses.

ConclusionRepresenting drugs as graphs can improve the performance of drug response prediction.

Availability of data and materialsData and source code can be downloaded at https://github.com/hauldhut/GraphDRP.


title: State-dependent regulation of cortical processing speed via gain modulation

abstract: AO_SCPLOWBSTRACTC_SCPLOWTo thrive in dynamic environments, animals must be capable of rapidly and flexibly adapting behavioral responses to a changing context and internal state. Examples of behavioral flexibility include faster stimulus responses when attentive and slower responses when distracted. Contextual or state-dependent modulations may occur early in the cortical hierarchy and may be implemented via top-down projections from cortico-cortical or neuromodulatory pathways. However, the computational mechanisms mediating the effects of such projections are not known. Here, we introduce a theoretical framework to classify the effects of cell-type specific top-down perturbations on the information processing speed of cortical circuits. Our theory demonstrates that perturbation effects on stimulus processing can be predicted by intrinsic gain modulation, which controls the timescale of the circuit dynamics. Our theory leads to counter-intuitive effects such as improved performance with increased input variance. We tested the model predictions using large-scale electrophysiological recordings from the visual hierarchy in freely running mice, where we found that a decrease in single-cell intrinsic gain during locomotion led to an acceleration of visual processing. Our results establish a novel theory of cell-type specific perturbations, applicable to top-down modulation as well as optogenetic and pharmacological manipulations. Our theory links connectivity, dynamics, and information processing via gain modulation.


title: Implicit motor learning within three trials

abstract: In motor learning, the slow development of implicit learning is traditionally taken for granted. While much is known about training performance during adaptation to a perturbation in reaches, saccades and locomotion, little is known about the time course of the underlying implicit processes during normal motor adaptation. Implicit learning is characterized by both changes in internal models and state estimates of limb position. Here, we measure both as reach aftereffects and shifts in hand localization in our participants, after every training trial. The observed implicit changes were near asymptote after only one to three perturbed training trials and were not predicted by a two-rate models slow process that is supposed to capture implicit learning. Hence, we show that implicit learning is much faster than conventionally believed, which has implications for rehabilitation and skills training.


title: Deciphering the scopolamine challenge rat model by preclinical functional MRI

abstract: During preclinical drug testing, the systemic administration of scopolamine (SCO), a cholinergic antagonist, is widely used. However, it suffers important limitations, like non-specific behavioural effects partly due to its peripheral side-effects. Therefore, neuroimaging measures would enhance its translational value. To this end, in Wistar rats, we measured whisker-stimulation induced functional MRI activation after SCO, peripherally acting butylscopolamine (BSCO), or saline administration in a cross-over design. Besides the commonly used gradient-echo echo-planar imaging (GE EPI), we also used an arterial spin labeling method in isoflurane anesthesia. With the GE EPI measurement, SCO decreased the evoked BOLD response in the barrel cortex (BC), while BSCO increased it in the anterior cingulate cortex. In a second experiment, we used GE EPI and spin-echo (SE) EPI sequences in a combined (isoflurane + i.p. dexmedetomidine) anesthesia to account for anesthesia-effects. Here, we also examined the effect of donepezil. In the combined anesthesia, with the GE EPI, SCO decreased the activation in the BC and the inferior colliculus (IC). BSCO reduced the response merely in the IC. Our results revealed that SCO attenuated the evoked BOLD activation in the BC as a probable central effect in both experiments. The likely peripheral vascular actions of SCO with the given fMRI sequences depended on the type of anesthesia or its dose.


title: CytoPy: an autonomous cytometry analysis framework

abstract: Cytometry analysis has seen a considerable expansion in recent years in the maximum number of parameters that can be acquired in a single experiment. In response to this technological advance there has been an increased effort to develop new computational methodologies for handling high-dimensional single cell data acquired by flow or mass cytometry. Despite the success of numerous algorithms and published packages to replicate and outperform traditional manual analysis, widespread adoption of these techniques has yet to be realised in the field of immunology. Here we present CytoPy, a Python framework for automated analysis of cytometry data that integrates a document-based database for a data-centric and iterative analytical environment. In addition, our algorithm agnostic design provides a platform for open-source cytometry bioinformatics in the Python ecosystem. We demonstrate the ability of CytoPy to phenotype T cell subsets in whole blood samples even in the presence of significant batch effects due to technical and user variation. The complete analytical pipeline was then used to immunophenotype the local inflammatory infiltrate in individuals with and without acute bacterial infection. CytoPy is open-source and licensed under the MIT license. CytoPy is open source and available at https://github.com/burtonrj/CytoPy, with notebooks accompanying this manuscript (https://github.com/burtonrj/CytoPyManuscript) and software documentation at https://cytopy.readthedocs.io/.


title: 3D Variability Analysis: Resolving continuous flexibility and discrete heterogeneity from single particle cryo-EM

abstract: Single particle cryo-EM excels in determining static structures of protein molecules, but existing 3D reconstruction methods have been ineffective in modelling flexible proteins. We introduce 3D variability analysis (3DVA), an algorithm that fits a linear subspace model of conformational change to cryo-EM data at high resolution. 3DVA enables the resolution and visualization of detailed molecular motions of both large and small proteins, revealing new biological insight from single particle cryo-EM data. Experimental results demonstrate the ability of 3DVA to resolve multiple flexible motions of -helices in the sub-50 kDa transmembrane domain of a GPCR complex, bending modes of a sodium ion channel, five types of symmetric and symmetry-breaking flexibility in a proteasome, large motions in a spliceosome complex, and discrete conformational states of a ribosome assembly. 3DVA is implemented in the cryoSPARC software package.


title: Continuous manipulation of mental representations is compromised in cerebellar degeneration

abstract: Here we test the hypothesis that the cerebellum aids in the dynamic transformation of mental representations. We report a series of neuropsychological experiments comparing the performance of individuals with cerebellar degeneration (CD) on cognitive tasks that either entail continuous, movement-like mental operations or more discrete mental operations. In visual cognition, individuals with CD exhibited an impaired rate of mental rotation, an operation hypothesized to require the continuous manipulation of a visual representation. In contrast, individuals with CD showed a normal processing rate when scanning items in visual working memory, an operation hypothesized to require the maintenance and retrieval of representations. In mathematical cognition, individuals with CD were impaired at single-digit addition, an operation hypothesized to require iterative manipulations along a mental number-line; this group was not impaired on arithmetic tasks requiring memory retrieval (e.g., single-digit multiplication). These results, obtained in tasks from two disparate domains, suggest one potential constraint on the contribution of the cerebellum to cognitive tasks. This constraint may parallel the cerebellums role in motor control, involving coordinated dynamic transformations in a mental workspace.


title: Interdependence between histone marks and steps in Pol II transcription

abstract: The role of histone modifications in transcription remains incompletely understood. Here we used experimental perturbations combined with sensitive machine learning tools that infer the distribution of histone marks using maps of nascent transcription. Transcription predicted the variation in active histone marks and complex chromatin states, like bivalent promoters, down to single-nucleosome resolution and at an accuracy that rivaled the correspondence between independent ChIP-seq experiments. Blocking transcription rapidly removed two punctate marks, H3K4me3 and H3K27ac, from chromatin indicating that transcription is required for active histone modifications. Transcription was also required for maintenance of H3K27me3 consistent with a role for RNA in recruiting PRC2. A subset of DNase-I hypersensitive sites were refractory to prediction, precluding models where transcription initiates pervasively at any open chromatin. Our results, in combination with past literature, support a model in which active histone modifications serve a supportive, rather than a regulatory, role in transcription.


title: Interaction capacity underpins community diversity

abstract: How patterns in community diversity emerge is a long-standing question in ecology. Theories and experimental studies suggested that community diversity and interspecific interactions are interdependent. However, evidence from multitaxonomic, high-diversity ecological communities is lacking because of practical challenges in characterizing speciose communities and their interactions. Here, I analyzed time-varying causal interaction networks that were reconstructed using 1197 species, DNA-based ecological time series taken from experimental rice plots and empirical dynamic modeling, and show that species interaction capacity, namely, the sum of interaction strength that a single species gives and receives, underpins community diversity. As community diversity increases, the number of interactions increases exponentially but the mean species interaction capacity of a community becomes saturated, weakening interaction among species. These patterns are explicitly modeled with simple mathematical equations, based on which I propose the "interaction capacity hypothesis," namely, that species interaction capacity and network connectance are proximate drivers of community diversity. Furthermore, I show that total DNA copy number and temperature influence species interaction capacity and connectance nonlinearly, explaining a large proportion of diversity patterns observed in various systems. The interaction capacity hypothesis enables mechanistic explanations of community diversity, and how species interaction capacity is determined is a key question in ecology.


title: Average semivariance yields accurate estimates of the fraction of marker-associated genetic variance and heritability in complex trait analyses

abstract:
The development of genome-informed methods for identifying quantitative trait loci (QTL) and studying the genetic basis of quantitative variation in natural and experimental populations has been driven by advances in high-throughput genotyping. For many complex traits, the underlying genetic variation is caused by the segregation of one or more  large-effect loci, in addition to an unknown number of loci with effects below the threshold of statistical detection. The large-effect loci segregating in populations are often necessary but not sufficient for predicting quantitative phenotypes. They are, nevertheless, important enough to warrant deeper study and direct modelling in genomic prediction problems. We explored the accuracy of statistical methods for estimating the fraction of marker-associated genetic variance (p) and heritability [Formula] for large-effect loci underlying complex phenotypes. We found that commonly used statistical methods overestimate p and [Formula]. The source of the upward bias was traced to inequalities between the expected values of variance components in the numerators and denominators of these parameters. Algebraic solutions for bias-correcting estimates of p and [Formula] were found that only depend on the degrees of freedom and are constant for a given study design. We discovered that average semivariance methods, which have heretofore not been used in complex trait analyses, yielded unbiased estimates of p and [Formula], in addition to best linear unbiased predictors of the additive and dominance effects of the underlying loci. The cryptic bias problem described here is unrelated to selection bias, although both cause the overestimation of p and [Formula]. The solutions we described are predicted to more accurately describe the contributions of large-effect loci to the genetic variation underlying complex traits of medical, biological, and agricultural importance.

Author summaryThe contributions of individual genes to the phenotypic variation observed for genetically complex traits has been an ongoing and important challenge in biology, medicine, and agriculture. While many genes have statistically undetectable effects, those with large effects often warrant in-depth study and can be important predictors of complex phenotypes such as disease risk in humans or disease resistance in domesticated plants and animals. The genes identified through associations with genetic markers in complex trait analyses typically account for a fraction of the heritable variation, a genetic parameter we called  marker heritability. We discovered that textbook statistical methods systematically overestimate marker heritability and thus overestimate the contributions of specific genes to the phenotypic variation observed for complex traits in natural and experimental populations. We describe the source of the upward bias, validate our findings through computer simulation, describe methods for bias-correcting estimates of marker heritability, and illustrate their application through empirical examples. The statistical methods we describe supply investigators with more accurate estimates of the contributions of specific genes or networks of interacting genes to the heritable variation observed in complex trait studies.


title: Activity dependent translation in astrocytes dynamically alters the proteome of the perisynaptic astrocyte process

abstract:
Gene expression requires two steps - transcription and translation - which can be regulated independently to allow nuanced, localized, and rapid responses to cellular stimuli. Neurons are known to respond transcriptionally and translationally to bursts of brain activity, and a transcriptional response to this activation has also been recently characterized in astrocytes. However, the extent to which astrocytes respond translationally is unknown. We tested the hypothesis that astrocytes also have a programmed translational response by characterizing the change in transcript ribosome occupancy in astrocytes using Translating Ribosome Affinity Purification(TRAP) subsequent to a robust induction of neuronal activity in vivo via acute seizure. We identified a change in transcripts on astrocyte ribosomes, highlighted by a rapid decrease in transcripts coding for ribosomal and mitochondrial components, and a rapid increase in transcripts related to cytoskeletal dynamics, motor activity, ion transport, and cell communication. This indicates a set of dynamic responses, some of which might be secondary to activation of Receptor Tyrosine Kinase(TRK) signaling. Using acute slices, we quantified the extent to which individual cues and sequela of neuronal activity can activate translation acutely in astrocytes. We identified both BDNF and ion concentration changes as contributors to translation induction, with potassium using both action-potential sensitive and insensitive components. We showed this translational response requires the presence of neurons, indicating the response is non-cell autonomous. We also show that this induction of new translation extends into peripheral astrocyte processes (PAPs). Accordingly, proteomics following fear conditioning in mice, showed that new translation influences peri-synaptic astrocyte protein composition in vivo under physiological conditions. Regulation of translation in astrocytes by neuronal activity suggests an additional mechanism by which astrocytes may dynamically modulate nervous system functioning.

Main PointsAstrocytes have a programmed, transcript-specific translational response to neuronal activity.

Both BDNF and K+, cues of neuronal activity, trigger this response.

This response requires the presence of neurons.

This response alters the astrocytic protein composition at the synapse.


title: The Series of a Four-node Motif and Coherent Type-1 Feed-forward Loop can Provide Sensitive Detection over Arbitrary Range of Input Signal, thereby Explain Weber's Law in Higher-Order Sensory Processes, and Compute Logarithm

abstract: Webers law states that the ratio of the smallest perceptual change in an input signal and the background signal is constant. The law is observed across the perception of weight, light intensity, and sound intensity and pitch. Conventionally, two models of perception have been proposed to explain Webers law, namely the logarithmic and the linear model. Later, another formulation of Webers law was proposed which links it with exact adaptation. This paper argues in favour of the linear model, which requires the sensory system to generate linear input-output relationship over several orders of magnitude. To this end, a four-node motif (FNM) is constructed from first principles whose series provides almost linear relationship between input signal and output over arbitrary range of input signal. Mathematical analysis into the origin of this quasi-linear relationship shows that the series of coherent type-1 feed-forward loop (C1-FFL) is able to provide perfectly linear input-output relationship over arbitrary range of input signal. FNM also reproduces the neuronal data of numerosity detection study on monkey. The series of FNM also provides a mechanism for sensitive detection over arbitrary range of input signal when the output has an upper limit. Further, the series of FNM provides a general basis for a class of bow-tie architecture where the number of receptors is much lower than the range of input signal and the "decoded output". Besides (quasi-)linear input-output relationship, another example of this class of bow-tie architecture that the series of FNM is able to produce is absorption spectra of cone opsins of humans. Further, the series of FNM and C1-FFL, respectively, can compute logarithm over arbitrary range of input signal.


title: ConvDip: A convolutional neural network for better M/EEG Source Imaging

abstract: 1The EEG is a well-established non-invasive method in neuroscientific research and clinical diagnostics. It provides a high temporal but low spatial resolution of brain activity. In order to gain insight about the spatial dynamics of the EEG one has to solve the inverse problem, i.e. finding the neural sources that give rise to the recorded EEG activity. The inverse problem is ill-posed, which means that more than one configuration of neural sources can evoke one and the same distribution of EEG activity on the scalp. Artificial neural networks have been previously used successfully to find either one or two dipoles sources. These approaches, however, have never solved the inverse problem in a distributed dipole model with more than two dipole sources. We present ConvDip, a novel convolutional neural network (CNN) architecture that solves the EEG inverse problem in a distributed dipole model based on simulated EEG data. We show that (1) ConvDip learned to produce inverse solutions from a single time point of EEG data and (2) outperforms state-of-the-art methods on all focused performance measures. It is more flexible when dealing with varying number of sources, produces less ghost sources and misses less real sources than the comparison methods. It produces plausible inverse solutions for real EEG recordings from human participants. (4) The trained network needs less than 40 ms for a single prediction. Our results qualify ConvDip as an efficient and easy-to-apply novel method for source localization in EEG data, with high relevance for clinical applications, e.g. in epileptology and real time applications.


title: Computational search of hybrid human/ SARS-CoV-2 dsRNA reveals unique viral sequences that diverge from those of other coronavirus strains

abstract: The role of the RNAi/Dicer/Ago system to degrade RNA viruses has been elusive in mammals, which prompted authors to think that interferon (IFN) synthesis is essential in this clade relegating the RNAi defense strategy against viral infection as accessory function. We explore the theoretical possibilities that RNAi triggered by SARS-CoV-2 might degrade some host transcripts in the opposite direction although this hypothesis seems counter intuitive. SARS-CoV-2 genome was therefore computational searched for exact intra pairing within the viral RNA and also hybrid exact pairing with human transcriptome over a minimum 20 bases length. Minimal segments of 20 bases length of SARS-CoV-2 RNA were found based on the theoretical matching with existing complementary strands in the human host transcriptome. Few human genes potentially annealing with SARS-CoV-2 RNA, among them mitochondrial deubiquitinase USP30, a subunit of ubiquitin protein ligase complex FBXO21 along with two long coding RNAs were retrieved. The hypothesis that viral originated RNAi might mediate degradation of messengers of the host transcriptome was corroborated by clinical observation and phylogenetic comparative analysis indicating a strong specificity of these hybrid pairing sequences for both SARS-CoV-2 and human genomes.


title: bHLH11 inhibits bHLH IVc proteins by recruiting the TOPLESS/TOPLESS-RELATED corepressors in Arabidopsis

abstract:
Iron (Fe) homeostasis is essential for plant growth and development. Many transcription factors play pivotal roles in the maintenance of Fe homeostasis. bHLH11 was identified as a negative transcription factor regulating Fe homeostasis, however, the underlying molecular mechanism remains elusive. We generated two loss-of-function bhlh11 mutants which display the enhanced sensitivity to Fe excess, the increased Fe accumulation and the elevated expression of Fe deficiency responsive genes. bHLH11 protein, localized in both the cytoplasm and nucleus, decreases in response to Fe deficiency. Coexpression assays indicate that bHLH IVc transcription factors (TFs) (bHLH34, bHLH104, bHLH105, and bHLH115) facilitate the nuclear accumulation of bHLH11 protein. Further analysis indicates that bHLH11 represses the transactivity of bHLH IVc TFs towards bHLH Ib genes (bHLH38, bHLH39, bHLH100, and bHLH101). bHLH11 contains two EAR motifs which are responsible for the repression function by recruiting the TOPLESS/TOPLESS-RELATED (TPL/TPRs) corepressors. Correspondingly, the expression of Fe uptake genes increases in the tpr1 tpr4 tpl mutant. Moreover, genetic analysis reveals that bHLH11 has functions independent of FIT. This study provides insights into the complicate Fe homeostasis signaling network.

One-sentence summarybHLH IVc proteins promote the bHLH11 protein accumulation in the nucleus where bHLH11 inhibits the transcriptional activation ability of bHLH IVc via its EAR motifs recruiting the TOPLESS/TOPLESS-RELATED corepressors.

category: plant biology


title: Estimating the Probability of Early Afterdepolarization and Predicting Arrhythmic Risk associated with Long QT Syndrome Type 1 Mutations

abstract:
Early after-depolarizations (EADs) are action potential (AP) repolarization abnormalities that can trigger lethal arrhythmias. Simulations using biophysically-detailed cardiac myocyte models can reveal how model parameters influence the probability of these cellular arrhythmias, however such analyses can pose a huge computational burden. We have previously developed a highly simplified approach in which logistic regression models (LRMs) map parameters of complex cell models to the probability of ectopic beats (EBs). Here, we extend this approach to predict the probability of early after-depolarizations (P(EAD)). We use the LRM to investigate how changes in parameters of the slow-activating delayed rectifier current (IKs) affect P(EAD) for 17 different Long QT syndrome type 1 (LQTS1) mutations. We compare P(EAD) for these 17 LQTS1 mutations with two other recently proposed model-based arrhythmia risk metrics. These three model-based risk metrics yield similar prediction performance; however, they all fail to predict relative clinical risk for a significant number of the 17 studied LQTS1 mutations. The consistent successes and failures of all three risk metrics suggest that important functional characteristics of LQTS1 mutations may not yet be fully known.

Author summaryAn early after-depolarization (EAD) is an abnormal cellular electrical event which can trigger dangerous arrhythmias in the heart. We use our previously developed method to build a simple logistic regression model (LRM) that estimates the probability of EAD (P(EAD)) as a function of myocyte model parameters. Using this LRM along with two other recently published model-based arrhythmia risk predictors, we estimate risk of arrhythmia for 17 Long QT syndrome type 1 (LQTS1) mutations. Results show that all approaches have similar prediction performance in that there are a set of mutations whose relative clinical risk for arrhythmia are well estimated using these metrics, but that relative risk is consistently over- or under-estimated across all approaches for a significant number of other mutations. We believe this indicates that the functional characterization of the LQTS1 phenotype is incomplete.


title: Cytoplasmic mRNA decay represses RNA polymerase II transcription during early apoptosis

abstract:
RNA abundance is generally sensitive to perturbations in decay and synthesis rates, but crosstalk between RNA polymerase II transcription and cytoplasmic mRNA degradation often leads to compensatory changes in gene expression. Here, we reveal that widespread mRNA decay during early apoptosis represses RNAPII transcription, indicative of positive (rather than compensatory) feedback. This repression requires active cytoplasmic mRNA degradation, which leads to impaired recruitment of components of the transcription preinitiation complex to promoter DNA. Importin /{beta}- mediated nuclear import is critical for this feedback signaling, suggesting that proteins translocating between the cytoplasm and nucleus connect mRNA decay to transcription. We also show that an analogous pathway activated by viral nucleases similarly depends on nuclear protein import. Collectively, these data demonstrate that accelerated mRNA decay leads to the repression of mRNA transcription, thereby amplifying the shutdown of gene expression. This highlights a conserved gene regulatory mechanism by which cells respond to threats.

IMPACT STATEMENTHuman cells respond to cytoplasmic mRNA depletion during early apoptosis by inhibiting RNA polymerase II transcription, thereby magnifying the gene expression shutdown during stress.


title: Putative condition-dependent viability selection in wild type stocks of Drosophila pseudoobscura

abstract: Meiotic recombination rates vary in response to intrinsic and extrinsic factors. Recently, heat stress has been shown to reveal plasticity in recombination rates in Drosophila pseudoobscura. Here, a combination of molecular genotyping and X-linked recessive phenotypic markers were used to investigate differences in recombination rates due to either heat stress or advanced maternal age. However, haplotype frequencies deviated from equal proportions for crosses using phenotypic markers, indicating viability selection. Interestingly, skews in haplotype frequency were condition-dependent, consistent with the fixation of alleles in the wild type stocks used that are unfit at high temperature. Evidence of viability selection due to heat stress in the wild type haplotypes was most apparent on days 7-9 when more mutant non-crossover haplotypes were recovered in comparison to wild type (p=2.2e-4). Despite the condition-dependent mutational load in both wild type and mutant stocks, an analysis of recombination rate plasticity revealed days 7-9 (p=0.0085) and day 9 (p=0.037) to be significantly higher due to heat stress and days 1-3 as significantly higher due to maternal age (p=0.025). Still, to confirm these findings, SNP genotyping markers were used to further investigate recombination rate. This analysis supported days 9-10 as significantly different due to heat stress in two pairs of consecutive SNP markers (p=0.018; p=0.015), suggesting this time period as when recombination rate is most sensitive to heat stress. This peak timing for recombination plasticity is consistent with D. melanogaster based on comparison of similarly timed key meiotic events, enabling future mechanistic work of temperature stress on recombination rate.


title: PKD promotes activity-dependent AMPA receptorendocytosis in hippocampal neurons

abstract: AMPA type glutamate receptors (AMPARs) mediate the majority of fast excitatory neurotransmission in the brain. The continuous trafficking of AMPARs into and out of synapses is a core feature of synaptic plasticity, which is considered as the cellular basis of learning and memory. The molecular mechanisms underlying the postsynaptic AMPAR trafficking, however, are still not fully understood. In this work, we demonstrate that the Protein Kinase D (PKD) family promotes basal and activity-induced AMPAR endocytosis in primary hippocampal neurons. Pharmacological inhibition of PKD increased synaptic levels of GluA1-containing AMPARs, slowed down their endocytic trafficking and increased neuronal network activity. By contrast, ectopic expression of constitutive active PKD decreased the synaptic level of AMPARs, while increasing their co-localization with early endosomes. Our results thus establish an important role for PKD in the regulation of postsynaptic AMPAR trafficking during synaptic plasticity.


title: Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity

abstract:
Monitoring the mutation dynamics of SARS-CoV-2 is critical for the development of effective approaches to contain the pathogen. By analyzing 106 SARS-CoV-2 and 39 SARS genome sequences, we provided direct genetic evidence that SARS-CoV-2 has a much lower mutation rate than SARS. Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history. The discrepant phylogenies for the spike protein and its receptor binding domain proved a previously reported structural rearrangement prior to the emergence of SARS-CoV-2. Despite that we found the spike glycoprotein of SARS-CoV-2 is particularly more conserved, we identified a receptor binding domain mutation that leads to weaker ACE2 binding capability based on in silico simulation, which concerns a SARS-CoV-2 sample collected on 27th January 2020 from India. This represents the first report of a significant SARS-CoV-2 mutant, and requires attention from researchers working on vaccine development around the world.

HighlightsO_LIBased on the currently available genome sequence data, we provided direct genetic evidence that the SARS-COV-2 genome has a much lower mutation rate and genetic diversity than SARS during the 2002-2003 outbreak.
C_LIO_LIThe spike (S) protein encoding gene of SARS-COV-2 is found relatively more conserved than other protein-encoding genes, which is a good indication for the ongoing antiviral drug and vaccine development.
C_LIO_LIMinimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history.
C_LIO_LIWe confirmed a previously reported rearrangement in the S protein arrangement of SARS-COV-2, and propose that this rearrangement should have occurred between human SARS-CoV and a bat SARS-CoV, at a time point much earlier before SARS-COV-2 transmission to human.
C_LIO_LIWe provided first evidence that a mutated SARS-COV-2 with reduced human ACE2 receptor binding affinity have emerged in India based on a sample collected on 27th January 2020.
C_LI


title: LADON, a natural antisense transcript of NODAL, promotes the acquisition of an invasive behaviour in melanoma cells.

abstract: The TGF{beta} family member NODAL, known for its role during embryonic development, has also been associated with tumor progression in several cancers. Some of the evidence supporting its involvement in melanoma appeared contradictory, suggesting that NODAL in this context might rely on a non-canonical signalling mode. We found that NODAL inactivation in a metastatic melanoma cell line prevents the cells from acquiring invasive behaviour. However, we show that this phenotype does not result from the absence of NODAL, but from a defect in the expression of a natural antisense transcript of NODAL, here called LADON. We found that LADON promotes the mesenchymal to amoeboid transition that is critical to melanoma cell invasiveness, and that a WNT/{beta}-CATENIN signalling-dependent increase in LADON expression is required to complete this transition. LADONs downstream effectors include, among others, the proto-oncogene MYCN. These results identify LADON as a player in the regulatory network that governs tumor progression in melanoma, and possibly in other types of cancer.

category: cancer biology


title: LADON, a natural antisense transcript of NODAL, promotes an invasive behaviour in melanoma cells.


title: Systems Biology under heat stress in Indian Cattle

abstract: Transcriptome profiling of Vrindavani and Tharparkar cattle revealed that more numbers of genes dysregulated in Vrindavani than in Tharparkar. A contrast in gene expression was observed with 18.5 % of upregulated genes in Vrindavani were downregulated in Tharparkar and 17.5% upregulated genes in Tharparkar were downregulated in Vrindavani. Functional annotation of genes differentially expressed in Tharparkar and Vrindavani revealed that the systems biology in Tharparkar is moving towards counteracting the effects due to heat stress. Unlike Vrindavani, Tharparkar is not only endowed with higher expression of the scavengers (UBE2G1, UBE2S, and UBE2H) of misfolded proteins but also with protectors (VCP, Serp1, and CALR) of naive unfolded proteins. Further, higher expression of the antioxidants in Tharparkar enables it to cope up with higher levels of free radicals generated as a result of heat stress. In this study we found relevant genes dysregulated in Tharparkar in the direction that can counter heat stress.