title: Varicella-Zoster Virus ORF9 Is an Antagonist of the DNA Sensor cGAS

abstract: Varicella-Zoster virus (VZV) causes chickenpox and shingles. Although infection is associated with severe morbidity in some individuals, molecular mechanisms that determine innate immune responses remain poorly defined. We found that the cGAS/STING DNA sensing pathway was required for type I interferon (IFN) induction during VZV infection and that recognition of VZV by cGAS restricted its replication. Viral gene overexpression screening identified the essential VZV tegument protein ORF9 as a cGAS antagonist. Ectopically and virally expressed ORF9 bound to endogenous cGAS. Confocal microscopy revealed co-localisation of cGAS and ORF9, which reduced the type I IFN response to transfected DNA. ORF9 and cGAS also interacted directly in a cell-free system and phase-separated together with DNA. Furthermore, ORF9 inhibited cGAMP production by cGAS. Taken together, we uncovered the importance of the cGAS/STING DNA sensing pathway for VZV recognition and identified a VZV immune antagonist that directly interferes with DNA sensing via cGAS.


title: Measuring protected-area outcomes with leech iDNA: large-scale quantification of vertebrate biodiversity in Ailaoshan reserve

abstract: 1Protected areas are central to meeting biodiversity conservation goals, but measuring their effectiveness is challenging. We address this challenge by using DNA from leech-ingested bloodmeals to estimate vertebrate occupancies across the 677 km2 Ailaoshan reserve in Yunnan, China. 163 park rangers collected 30,468 leeches from 172 patrol areas. We identified 86 vertebrate species, including amphibians, mammals, birds, and squamates. Multi-species occupancy modelling showed that species richness increased with elevation and distance to reserve edge, including the distributions of most of the large mammals (e.g. sambar, black bear, serow, tufted deer). The exceptions were the three domestic mammal species (cows, sheep, goats) and muntjak deer, which were more common at lower elevations. eDNA-estimated vertebrate occupancies are Granular, Repeatable, Auditable, Direct, Efficient, and Simple-to-understand measures that can be used to assess conservation effectiveness and thus to improve the contributions that protected areas make to achieving global biodiversity goals.

category: ecology


title: Profile-likelihood Bayesian model averaging for two-sample summary data Mendelian randomization in the presence of horizontal pleiotropy

abstract: Two-sample summary data Mendelian randomisation is a popular method for assessing causality in epidemiology, by using genetic variants as instrumental variables. If genes exert pleiotropic effects on the outcome not entirely through the exposure of interest, this can lead to heterogeneous and (potentially) biased estimates of causal effect. We investigate the use of Bayesian model averaging to preferentially search the space of models with the highest posterior likelihood. We develop a Metropolis-Hasting algorithm to perform the search using the recently developed Robust Adjusted Profile Likelihood of Zhao et al as the basis for defining a posterior distribution that efficiently accounts for pleiotropic and weak instrument bias. We demonstrate how our general modelling approach can be extended from a standard one-parameter causal model to a two-parameter model, which allows a large proportion of SNPs to violate the Instrument Strength Independent of Direct Effect assumption. We use Monte Carlo simulations to illustrate our methods and compare it to several related approaches. We finish by applying our approach in practice to investigate the causal role of cholesterol on the development age-related macular degeneration.

category: genetics


title: Biogeochemical variability in the California Current System

abstract: The biological productivity and diversity of the California Current System (CCS) is at the leading edge of major emerging climate trends, including hypoxia and acidification. We present results from a hindcast simulation (reanalysis) of an eddy-resolving oceanic physical-biogeochemical model of the CCS, to characterize its mean state and its patterns and drivers of variability in marine biogeochemical and ecosystem processes from 1995-2010. This is a companion paper to a physical analysis in Renault et al. (2021). The model reproduces long-term mean distributions of key ecosystem metrics, including surface nutrients and productivity and subsurface O2 and carbonate undersaturation. The spatial patterns of Net Primary Productivity (NPP) are broadly consistent with measured and remotely sensed rates, and they reflect a predominant limitation by nitrogen, with seasonal and episodic limitation by Fe nearshore in the central CCS, and in the open ocean northern CCS. The vertical distribution of NPP is governed by the trade-off between nutrient and light limitation, a balance that reproduces and explains the observed spatial variations in the depth of the deep Chl maximum. The seasonal to interannual variability of biogeochemical properties and rates is also well captured by model simulations. Because of the prevailing nutrient limitation, fluctuations in the depth of the pycnocline and associated nutricline are the leading single factor explaining interannual variability in the interior biogeochemical state, and the relationships between density and biogeochemical rates and tracers are consistent between model and observations. The magnitude and relationship between density structure and biogeochemical processes is illustrated by the 1997-98 El Nino event, which faithfully reproduces the single largest deviation from the mean state in the simulated period. A slower decadal shoaling of the pycnocline also accounts for the concomitant trends in hypoxic and corrosive conditions on the shelf. The resulting variability is key to understanding the vulnerability of marine species to oceanic change, and to the detection of such changes, soon projected to exceed the range of conditions in the past century.


title: Modeling How Community Assembly Alters the Functioning of Ecosystems

abstract: Although the effects of species richness on ecosystem functioning have been extensively studied, there is increased interest in understanding how community assembly in general might alter the functioning of ecosystems. We focus on two complementary approaches for evaluating how community assembly influences ecosystem function (here, productivity). The first quantifies the relative importance of complementarity and selection by contrasting monocultures with polycultures. The second identifies the effects of species losses and/or gains relative to the baseline polyculture, as well as the indirect effects on other species productivity. We evaluate and contrast these two approaches, using simulated communities structured by different, known competition mechanisms, where species compete for different resources and experience varying levels of environmental heterogeneity. We find that the metrics provided by these approaches can jointly discriminate the mechanisms of competition driving productivity. We then apply our methods to data from a long-term biodiversity-ecosystem experiment (the Jena Experiment) and find that the data do not correspond to any of the competition scenarios we modeled. We address two additional possible complications: facilitation by nitrogen fixing plants, and non-equilibrium behavior during community assembly, and find that a combination of resource competition and facilitation by nitrogen fixing plants is the more likely explanation for the results obtained at Jena.


title: Evaluation of high-resolution atmospheric and oceanic simulations of the California Current System

abstract: This paper is the first of two that present a 16-year hindcast solution from a coupled physical and biogeochemical model of the California Current System (CCS) along the U. S. West Coast and validate the physical solution with respect to mean, seasonal, interannual, and sub-seasonal fields and, to a lesser degree, eddy variability. Its companion paper is Deutsch et al. (2021a). The intent is to construct and demonstrate a modeling tool that will be used for mechanistic explanations, attributive causal assessments, and forecasts of future evolution for circulation and biogeochemistry, with particular attention to the increasing oceanic stratification, deoxygenation, and acidification. A well-resolved mesoscale (dx = 4 km) simulation of the CCS circulation is made with the Regional Oceanic Modeling System over a hindcast period of 16 years from 1995 to 2010. The oceanic solution is forced by a high-resolution (dx = 6 km) regional configuration of the Weather and Research Forecast (WRF) atmospheric model. Both of these high-resolution regional oceanic and atmospheric simulations are forced by lateral open boundary conditions taken from larger-domain, coarser-resolution parent simulations that themselves have boundary conditions from the Mercator and Climate Forecast System reanalyses, respectively. We show good agreement between the simulated atmospheric forcing of the oceanic and satellite measurements for the spatial patterns and temporal variability for the surface fluxes of momentum, heat, and freshwater. The simulated oceanic physical fields are then evaluated with satellite and in situ measurements. The simulation reproduces the main structure of the climatological upwelling front and cross-shore isopycnal slopes, the mean current patterns (including the California Undercurrent), and the seasonal, interannual, and subseasonal variability. It also shows agreement between the mesoscale eddy activity and the windwork energy exchange between the ocean and atmosphere modulated by influences of surface current on surface stress. Finally, the impact of using a high frequency wind forcing is assessed for the importance of synoptic wind variability to realistically represent oceanic mesoscale activity and ageostrophic inertial currents.


title: A population-level invasion by transposable elements triggers genome expansion in a fungal pathogen

abstract: AO_SCPLOWBSTRACTC_SCPLOWGenome evolution is driven by the activity of transposable elements (TEs). The spread of TEs can have deleterious effects including the destabilization of genome integrity and expansions. However, the precise triggers of genome expansions remain poorly understood because genome size evolution is typically investigated only among deeply divergent lineages. Here, we use a large population genomics dataset of 284 individuals from populations across the globe of Zymoseptoria tritici, a major fungal wheat pathogen. We built a robust map of genome-wide TE insertions and deletions to track a total of 2,456 polymorphic loci within the species. We show that purifying selection substantially depressed TE frequencies in most populations but some rare TEs have recently risen in frequency and likely confer benefits. We found that specific TE families have undergone a substantial genome-wide expansion from the pathogens center of origin to more recently founded populations. The most dramatic increase in TE insertions occurred between a pair of North American populations collected in the same field at an interval of 25 years. We find that both genome-wide counts of TE insertions and genome size have increased with colonization bottlenecks. Hence, the demographic history likely played a major role in shaping genome evolution within the species. We show that both the activation of specific TEs and relaxed purifying selection underpin this incipient expansion of the genome. Our study establishes a model to recapitulate TE-driven genome evolution over deeper evolutionary timescales.

category: genomics


title: The Pebble/Rho1/Anillin pathway controls polyploidization and axonal wrapping activity in the glial cells of the Drosophila eye

abstract: During development glial cell are crucially important for the establishment of neuronal networks. Proliferation and migration of glial cells can be modulated by neurons, and in turn glial cells can differentiate to assume key roles such as axonal wrapping and targeting. To explore the roles of actin cytoskeletal rearrangements in glial cells, we studied the function of Rho1 in Drosophila developing visual system. We show that the Pebble (RhoGEF)/Rho1/Anillin pathway is required for glia proliferation and to prevent the formation of large polyploid perineurial glial cells, which can still migrate into the eye disc if generated. Surprisingly, this Rho1 pathway is not necessary to establish the total glial membrane area or for the differentiation of the polyploid perineurial cells. The resulting polyploid wrapping glial cells are able to initiate wrapping of axons in the basal eye disc, however the arrangement and density of glia nuclei and membrane processes in the optic stalk are altered and the ensheathing of the photoreceptor axonal fascicles is reduced.

category: developmental biology


title: Predicting the retinotopic organization of human visual cortex from anatomy using geometric deep learning

abstract: Whether it be in a single neuron or a more complex biological system like the human brain, form and function are often directly related. The functional organization of human visual cortex, for instance, is tightly coupled with the underlying anatomy with cortical shape having been shown to be a useful predictor of the retinotopic organization in early visual cortex. Although the current state-of-the-art in predicting retinotopic maps is able to account for gross individual differences, such models are unable to account for any idiosyncratic differences in the structure-function relationship from anatomical information alone due to their initial assumption of a template. Here we developed a geometric deep learning model capable of exploiting the actual structure of the cortex to learn the complex relationship between brain function and anatomy in human visual cortex such that more realistic and idiosyncratic maps could be predicted. We show that our neural network was not only able to predict the functional organization throughout the visual cortical hierarchy, but that it was also able to predict nuanced variations across individuals. Although we demonstrate its utility for modeling the relationship between structure and function in human visual cortex, our approach is flexible and well-suited for a range of other applications involving data structured in non-Euclidean spaces.

category: neuroscience


title: Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers

abstract: Chromosomal translocations are important drivers of haematological malignancies whereby proto-oncogenes are activated by juxtaposition with enhancers, often called enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the super-enhancers of the immunoglobulin heavy locus (IGH) and proto-oncogene CCND1 that are common in B-cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterised the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of its gene body. We observed similar cancer-specific H3K4me3-BDs associated with hijacking of super-enhancers of other common oncogenes in B-cell (MAF, MYC and FGFR3/NSD2) and T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs can be created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs from cell identity genes to oncogenes accompanies the translocation of super-enhancers.


title: Viral integration transforms chromatin to drive oncogenesis

abstract: Human papillomavirus (HPV) drives almost all cervical cancers and up to [~]70% of head and neck cancers. Frequent integration into the host genome occurs only for tumourigenic strains of HPV. We hypothesized that changes in the epigenome and transcriptome contribute to the tumourigenicity of HPV. We found that viral integration events often occurred along with changes in chromatin state and expression of genes near the integration site. We investigated whether introduction of new transcription factor binding sites due to HPV integration could invoke these changes. Some regions within the HPV genome, particularly the position of a conserved CTCF binding site, showed enriched chromatin accessibility signal. ChIP-seq revealed that the conserved CTCF binding site within the HPV genome bound CTCF in 4 HPV+ cancer cell lines. Significant changes in CTCF binding pattern and increases in chromatin accessibility occurred exclusively within 100 kbp of HPV integration sites. The chromatin changes co-occurred with out-sized changes in transcription and alternative splicing of local genes. We analyzed the essentiality of genes upregulated around HPV integration sites of The Cancer Genome Atlas (TCGA) HPV+ tumours. HPV integration upregulated genes which had significantly higher essentiality scores compared to randomly selected upregulated genes from the same tumours. Our results suggest that introduction of a new CTCF binding site due to HPV integration reorganizes chromatin and upregulates genes essential for tumour viability in some HPV+ tumours. These findings emphasize a newly recognized role of HPV integration in oncogenesis.

category: cancer biology


title: Human papillomavirus integration transforms chromatin to drive oncogenesis


title: Host-induced gene silencing involves Arabidopsis ESCRT-III pathway for the transfer of dsRNA-derived siRNA

abstract: Small (s)RNAs and their double-stranded (ds)RNA precursors have been adopted to control diseases in crop plants through expression in transgenic plants and targeted gene silencing (host-induced gene silencing, HIGS). While HIGS strategies proved to be effective, the mechanism of RNA transfer at the plant - pathogen interface is widely unknown. Here we show that extracellular vesicles (EVs) purified from Arabidopsis thaliana plants expressing CYP3RNA, a dsRNA originally designed to target the three CYP51 genes of the fungal pathogen Fusarium graminearum, contain CYP3RNA-derived small interfering (si)RNAs as shown by RNA sequencing (RNA-seq) analysis. These transgene specific siRNAs had a length of 21 and 22 nucleotides with a bias towards 5-uracil (U) and 5-adenine (A). Notably, stringent protease and RNase treated EV fractions contained >70% less CYP3RNA-derived siRNAs, suggesting the presence of co-purified extravesicular nucleoprotein complexes stabilizing siRNAs outside of EVs. In addition, mutants of the ESCRT-III complex showed a loss of HIGS-mediated disease resistance and EVs isolated from these mutants were free of CYP3RNA-derived siRNAs. Together, these findings support the view that endosomal vesicle trafficking is required for HIGS mediating the transfer of transgene-derived siRNAs between donor host cells and recipient fungal cells probably in an EV-independent manner.

category: plant biology


title: Glycopeptide antibiotic teicoplanin inhibits cell entry of SARS-CoV-2 by suppressing the proteolytic activity of cathepsin L

abstract:
Since the outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the public health worldwide has been greatly threatened. The development of an effective treatment for this infection is crucial and urgent but is hampered by the incomplete understanding of the viral infection mechanism and the lack of specific antiviral agents. We previously reported that teicoplanin, a glycopeptide antibiotic that has been commonly used in the clinic to treat bacterial infection, significantly restrained the cell entry of Ebola virus, SARS-CoV and MERS-CoV by specifically inhibiting the activity of cathepsin L (CTSL). Here, we found that the cleavage sites of CTSL on the Spike of SARS-CoV-2 were highly conserved among all the variants. The treatment with teicoplanin suppressed the proteolytic activity of CTSL on Spike and prevented the cellular infection of different pseudotyped SARS-CoV-2 viruses. Teicoplanin potently prevented the entry of authentic SARS-CoV-2 into the cellular cytoplasm with an IC50 of 2.038 M for the Wuhan-Hu-1 reference strain and an IC50 of 2.116 M for the SARS-CoV-2 (D614G) variant. The pre-treatment of teicoplanin also prevented SARS-CoV-2 infection in hACE2 mice. In summary, our data reveal that CTSL is required for both SARS-CoV-2 and SARS-CoV infection and demonstrate the therapeutic potential of teicoplanin for universal anti-CoVs intervention.

ImportanceDisease prevention and treatment are two important countermeasures to end the coronavirus disease 2019 (COVID-19). However, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, evolves all the time, resulting in the emerging of many epidemic SARS-CoV-2 mutants, which significantly impairs the effectiveness of early strain-based vaccines and antibodies. Developing universal vaccines and broad-spectrum antiviral drugs are essential to confront SARS-CoV-2 mutants including those may emerge in the future. Our study reported here showed that the cleavage sites of cellular cathepsin L (CTSL) are highly conserved among all the SARS-CoV-2 mutants and SARS-CoV. The CTSL inhibitor teicoplanin not only inhibited the cell entry of two live SARS-CoV-2 strains and various pseudotyped viruses but also prevented live virus infection in animal models. Based on our previous finding that teicoplanin also inhibited SARS-CoV and MERS-CoV infection, we believe that teicoplanin possesses the potential to become a universal anti-CoVs drug.

category: microbiology


title: Macrophages transfer mitochondria to neurons to resolve inflammatory pain

abstract:
The current paradigm is that inflammatory pain passively resolves following the cessation of inflammation. Yet, in a substantial proportion of patients with inflammatory diseases, resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain. Mechanistic insight how inflammatory pain is resolved is lacking. Here we show that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. The resolution of pain and the transfer of mitochondria requires expression of CD200 Receptor (CD200R) on macrophages and the non-canonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain.

Graphical Abstract

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title: Neu-p11 induces NLRP3 inflammasome-induced pyroptosis via provoking NOX4-mediated mitochondrial oxidative injury in chordoma cells

abstract: The authors have withdrawn their manuscript as they have discovered some potential inconsistencies in their results after further experimentation. Therefore, the authors do not wish this work to be cited as reference for the project.


title: Single exposure to social defeat or immobilization stress fails to induce lasting alterations in general anxiety and hippocampal neurogenesis in Wistar and wild-type Groningen rats

abstract: Suppression of hippocampal neurogenesis is a readout for stress-induced alterations in neuroplasticity. In this study, we hypothesized that a single episode of severe social or non-social stress would differentially suppress neurogenesis in the dentate gyrus (DG) 10 days later in two rat strains. We anticipated that the suppression following social stress would be less severe in wildtype Groningen (WTG) rats, a rat strain considered relatively resilient to social stressors. Male Wistar and WTG were subjected to either social defeat or to immobilization stress. Behavioral response to social defeat and acute corticosterone response to both stressors was measured as well as anxiety behavior 10 days later on the elevated plus maze. Subsequently, brains were collected following cardiac aldehyde perfusion. The behavioral freezing response to defeat was much stronger in Wistar rats as compared to WTG rats. Acute corticosteroid response was similar in both strains although Wistar rats more rapidly resumed baseline values. There was no significant effect of both stressors on hippocampal DG cell proliferation and differentiation as well as on anxiety behavior. However, a striking strain difference appeared in anxiety behavior and both markers of neurogenesis. The WTG strain exhibiting much lower anxiety as well as reduced rate of hippocampal neurogenesis under all treatments. The results in this study suggest that both short-lasting acute stressors failed to induce lasting anxiety or decreased neurogenesis in the DG. Future studies could explore if and how rate of hippocampal neurogenesis is related with behavioral coping with stress.


title: Parallel processing of sensory cue and spatial information in the Dentate Gyrus

abstract: During exploration, animals form an internal map of an environment by combining information about specific sensory cues or landmarks with the animals motion through space, a process which critically depends on the mammalian hippocampus. The dentate gyrus (DG) is the first stage of the hippocampal trisynaptic circuit where self-motion and sensory cue information are integrated, yet it remains unknown how neurons within the DG encode both cue related ("what") and spatial ("where") information during cognitive map formation. Using two photon calcium imaging in head fixed mice running on a treadmill, along with on-line sensory cue manipulation at specific track locations, we have identified robust sensory cue responses in DG granule cells largely independent of spatial location. Granule cell cue responses are stable for long periods of time, selective for the modality of the stimulus and accompanied by strong inhibition of the firing of other active neurons. At the same time, there is a smaller fraction of neurons whose firing is spatially tuned but insensitive to the presentation of nearby cues, similar to traditional place cells. These results demonstrate the existence of "cue cells" in addition to the better characterized "place cells" in the DG, an important heterogeneity that has been previously overlooked. We hypothesize that the granule cell population may support multiple channels of spatial and non-spatial information that contribute distinctly to local and down-stream computations and impact the role of the dentate gyrus in spatial navigation and episodic memory.


title: Live cell imaging reveals that RecA finds homologous DNA by reduced dimensionality search

abstract: Homologous recombination (HR) is essential for the accurate repair of double-stranded DNA breaks (DSBs); it begins when the RecBCD2 complex resects the ends of the DSB into 3' single-stranded DNA (ssDNA) on which a RecA filament assembles. HR depends on the ability of this RecA-ssDNA filament to locate the homologous repair template on the sister chromosome. The mechanism by which the homology is located among vast amounts of heterologous DNA is not yet understood, despite a long history of research. Here, we directly visualize the repair of DSBs in hundreds of individual cells, using high-throughput microfluidics and fluorescence microscopy. We find that in E. coli, DSB repair is completed in 15 minutes without fitness loss. We further show that the search takes less than 10 minutes and is mediated by a thin, highly dynamic RecA filament that stretches throughout the cell. We propose a model in which the architecture of the RecA filament effectively reduces search dimensionality to two dimensions. The model is corroborated by the observation that the search time does not depend on the length of the cell or the amount of DNA, and also predicts a search time that is consistent with our measurement. Since the RecA family proteins are conserved in all organisms, our results also translate to other systems that rely on homologous recombination.


title: Jointing analysis of scATAC-seq datasets using epiConv

abstract: Technical improvement in ATAC-seq makes it possible to profile the chromatin states of single cells at high throughput, but currently no method is available to integrate datasets from multiple sources (different batches of same protocol or multiple experimental protocols). Here we present an algorithm to perform joint analyses on scATAC-seq datasets from multiple sources. In addition to batch correction, we also demonstrate that epiConv is capable of aligning co-assay data (simultaneous profiling of transcriptome and chromatin) onto high-quality ATAC-seq reference or integrating cells in different biological conditions (malignant vs. normal), which increases the statistical power of downstream analyses and reveals hidden hierarchy of malignant cells.

category: bioinformatics


title: ROS-triggered AMPK de-SUMOylation promotes Warburg effect in hepatocellular carcinoma cells

abstract: The authors have withdrawn this manuscript as they no longer stand by the conclusions. As found in previous literature review, the regulation effect and mechanism of reactive oxygen species (ROS) on the metabolism and proliferation of tumor cells are very complex. The preliminary results in the preprint may be just one front of "ROS-AMPK-tumor cell metabolism". After further experiments, the effects of different ROS concentrations on the metabolism of tumor cells as the cell passage increased were not completely consistent with the results shared in the preprint, so the author decided to withdraw the data in this preprint. The author do not wish this version to be cited as reference for this study. Subsequent investigators should carefully evaluate the consistency of the role of ROS stimulation in cell studies in vitro.


title: Endocrine fine-tuning of daily locomotor activity patterns under non-starving conditions in Drosophila

abstract:
1.Animals need to balance competitive behaviours to maintain internal homeostasis. The underlying mechanisms are complex, but typically involve neuroendocrine signalling. Using Drosophila, we systematically manipulated signalling between energy-mobilising endocrine cells producing adipokinetic hormone (AKH), octopaminergic neurons and the energy-storing fat body to assess whether this neuroendocrine axis involved in starvation-induced hyperactivity also balances activity levels under ad libitum access to food.

Our results suggest that AKH signals via two divergent pathways that are mutually competitive in terms of activity and rest. AKH increases activity via the octopaminergic system during the day, while it prevents high activity levels during the night by signalling to the fat body. This regulation involves feedback signalling from octopaminergic neurons to AKH-producing cells (APCs). APCs are known to integrate a multitude of metabolic and endocrine signals. Our results add a new facet to the versatile regulatory functions of APCs by showing that their output contributes to shape the daily activity pattern under ad libitum access to food.


title: Extraembryonic endoderm cells induce neuroepithelial tissue in gastruloids

abstract: Stem-cell derived in vitro systems, such as organoids or embryoids, hold great potential for modeling in vivo biology and engineering living systems with novel functions. To unlock that potential, we need new ways to elicit higher-level organization. Here we show that adding extraembryonic endoderm (XEN) cells to mouse gastruloids leads to the formation of neural epithelia. By single-cell RNA-seq, imaging and differentiation experiments, we demonstrate the neural characteristics and spatial patterning of the epithelial tissue. We further show that the XEN cells differentiate reciprocally to a visceral endoderm-like state. Finally, we demonstrate that local inhibition of WNT signaling and production of a basement membrane by the XEN cells underlie the formation of the neuroepithelial tissue. In summary, we establish "XEN Enhanced Gastruloids" (XEGs) to explore heterotypic cellular interactions as a means to achieve complex, tissue-level organization in vitro.


title: Distinct regionalization patterns of cortical morphology are associated with cognitive performance across different domains

abstract: Cognitive performance in children is predictive of academic and social outcomes; therefore, understanding neurobiological mechanisms underlying individual differences in cognition during development may be important for improving quality of life. The belief that a single, psychological construct underlies many cognitive processes is pervasive throughout society. However, it is unclear if there is a consistent neural substrate underlying many cognitive processes. Here we show that a distributed configuration of cortical surface area and apparent thickness, when controlling for global imaging measures, is differentially associated with cognitive performance on different types of tasks in a large sample (N=10,145) of 9-11 year old children from the Adolescent Brain and Cognitive DevelopmentSM (ABCD) study. The minimal overlap in these regionalization patterns of association has implications for competing theories about developing intellectual functions. Surprisingly, not controlling for sociodemographic factors increased the similarity between these regionalization patterns. This highlights the importance of understanding the shared variance between sociodemographic factors, cognition and brain structure, particularly with a population-based sample such as ABCD.


title: Spindle-slow oscillation coupling during sleep predicts sequence-based language learning

abstract: Language is one of the most defining human capabilities, involving the coordination of brain networks that generalise the meaning of linguistic units of varying complexity. On a neural level, neocortical slow oscillations and thalamic spindles during sleep facilitate the reactivation of newly encoded memory traces, manifesting in distinct oscillatory activity during retrieval. However, it is currently unknown if the effect of sleep on memory extends to the generalisation of the mechanisms that subserve sentence comprehension. We address this question by analysing electroencephalogram data recorded from 35 participants during an artificial language learning task and an 8hr nocturnal sleep period. We found that a period of sleep was associated with increased alpha/beta power and improved behavioural performance. Phase amplitude coupling analyses also revealed that spindle-slow oscillation coupling predicted the consolidation of sequence-based word orders, which was associated with distinct patterns of oscillatory activity during sentence processing. Taken together, this study presents converging behavioural and neurophysiological evidence for a role of sleep in the consolidation of higher order language learning and associated oscillatory neural activity.


title: Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy

abstract:
In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is due to a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation and cognition in the same mice advance our understanding of episodic memory mechanisms and their dysfunction in epilepsy.

Significance StatementPeople with temporal lobe epilepsy (TLE) often have learning and memory impairments, sometimes occurring earlier than the first seizure, but those symptoms and their biological underpinnings are poorly understood. We focused on the dentate gyrus, a brain region that is critical to avoid confusion between similar memories and is anatomically disorganized in TLE. We show that both humans and mice with TLE experience confusion between similar situations. This impairment coincides with a failure of the dentate gyrus to disambiguate similar input signals because of pathological bursting in a subset of neurons. Our work bridges seizure-oriented and memory-oriented views of the dentate gyrus function, suggests a mechanism for cognitive symptoms in TLE and supports a long-standing hypothesis of episodic memory theories.


title: Autophagic degradation of the Cucumber mosaic virus virulence factor 2b balances antiviral RNA silencing with proviral plant fitness and virus seed transmission

abstract:
Autophagy is a conserved intracellular degradation pathway that has recently emerged as an integral part of plant responses to virus infection. The elucidated mechanisms of autophagy range from the selective degradation of viral components to a more general attenuation of disease symptoms. In addition, several viruses are able to manipulate the autophagy machinery and counteract autophagy-dependent resistance. Despite these findings, the complex interplay of autophagy activities, viral pathogenicity factors, and host defence pathways in disease development remains poorly understood. In the current study, we analysed the interaction between autophagy and Cucumber mosaic virus (CMV) in Arabidopsis thaliana. We show that autophagy is induced during CMV infection and promotes the turnover of the major CMV virulence protein and RNA silencing suppressor 2b. Intriguingly, 2b itself dampens plant autophagy. In accordance with 2b degradation, we found that autophagy provides resistance against CMV by reducing viral RNA accumulation in an RNA silencing-dependent manner. Moreover, autophagy and RNA silencing pathways contribute to plant longevity and fecundity of CMV infected plants in an additive manner, uncoupling it from resistance. In addition to reduced fecundity, autophagy-deficient plants also failed to support seed transmission of the virus. We propose that autophagy attenuates CMV virulence via 2b degradation and thereby increases both plant and virus fitness with a trade-off penalty arising from increased RNA silencing-mediated resistance.

Author summaryThe capacity of plants to fight pathogenic viruses in order to survive and minimize damage relies on profound cellular reprogramming events. These include the synthesis of new as well as the degradation of pre-existing cellular components, together shifting cellular homeostasis towards a better tolerance of disease and fortification of antiviral defence mechanisms. Autophagy is a prominent and highly conserved cellular degradation pathway that supports plant stress resilience. Autophagy functions vary broadly and range from rather unspecific renewal of cytoplasm to highly selective degradation of a wide collection of specific substrates. Autophagy is well established to be involved during virus infections in animals, and its importance has also recently emerged in virus diseases of plants. However, we are still far from a comprehensive understanding of the complexity of autophagy activities in host-virus interactions and how autophagy pathway engineering could be applied against viruses. Here, we have analyzed one of the traditional model plant viruses, Cucumber mosaic virus (CMV), and its interactions with autophagy. Our study revealed that autophagy is tightly integrated into CMV disease, influencing processes from plant health to CMV epidemiology.


title: Cell-cell communication through FGF4 generates and maintains robust proportions of differentiated cell types in embryonic stem cells

abstract: During embryonic development and tissue homeostasis, reproducible proportions of differentiated cell types are specified from populations of multipotent precursor cells. Molecular mechanisms that enable both robust cell type proportioning despite variable initial conditions in the precursor cells, as well as the re-establishment of these proportions upon perturbations in a developing tissue remain to be characterized. Here we report that the differentiation of robust proportions of epiblast-like and primitive endoderm-like cells in mouse embryonic stem cell cultures emerges at the population level through cell-cell communication via a short-range FGF4 signal. We characterize the molecular and dynamical properties of the communication mechanism, and show how it controls both robust cell type proportioning from a wide range of experimentally controlled initial conditions, as well as the autonomous re-establishment of these proportions following the isolation of one cell type. The generation and maintenance of reproducible proportions of discrete cell types is a new function for FGF signaling that may operate in a range of developing tissues.


title: High Sucrose Diets Contribute to Brain Angiopathy with Impaired Glucose Uptake, and Psychosis-related Higher Brain Dysfunctions in Mice

abstract: Metabolic dysfunction is thought to contribute to the severity of psychiatric disorders; however, it has been unclear whether current high-simple-sugar diets contribute to pathogenesis of these diseases. Here we demonstrate that a high-sucrose diet during adolescence induces psychosis-related behavioral endophenotypes, including hyperactivity, poor working memory, impaired sensory gating, and disrupted interneuron function in mice deficient for glyoxalase-1 (Glo1), an enzyme involved in detoxification of sucrose metabolites. Further, the high-sucrose diet induced microcapillary impairments and reduced brain glucose uptake in brains of Glo1 deficient mice. Aspirin protected against this angiopathy, enhancing brain glucose uptake, and preventing abnormal behavioral phenotypes. Similar vascular damage to our model mice was found in the brains of randomly collected schizophrenia and bipolar disorder patients, suggesting that psychiatric disorders are associated with angiopathy in the brain caused by various environmental stresses, including metabolic stress.


title: Model Reduction Tools For Phenomenological Modeling of Input-Controlled Biological Circuits

abstract: We present a Python-based software package to automatically obtain phenomenological models of input-controlled synthetic biological circuits from descriptive models. From the parts and mechanism description of a synthetic biological circuit, it is easy to obtain a chemical reaction model of the circuit under the assumptions of mass-action kinetics using various existing tools. However, using these models to guide design decisions during an experiment is difficult due to a large number of reaction rate parameters and species in the model. Hence, phenomenological models are often developed that describe the effective relationships among the circuit inputs, outputs, and only the key states and parameters. In this paper, we present an algorithm to obtain these phenomenological models in an automated manner using a Python package for circuits with inputs that control the desired outputs. This model reduction approach combines the common assumptions of time-scale separation, conservation laws, and species abundance to obtain the reduced models that can be used for design of synthetic biological circuits. We consider an example of a simple gene expression circuit and another example of a layered genetic feedback control circuit to demonstrate the use of the model reduction procedure.

category: synthetic biology


title: Pou5f3 and Sox19b determine gene expression repertoire at Zygotic Genome Activation

abstract: Awakening of zygotic transcription in animal embryos relies on maternal pioneer transcription factors. The interplay of global and specific functions of these proteins remains poorly understood. Here, we analyze chromatin accessibility and time-resolved transcription in single and double mutant zebrafish embryos lacking pluripotency factors Pou5f3 and Sox19b. We show that two factors modify chromatin in a largely independent manner. We distinguish four types of direct enhancers by differential requirements for Pou5f3 or Sox19b. We demonstrate that changes in chromatin accessibility of enhancers underlie the changes in zygotic expression repertoire in the double mutants. Pou5f3 or Sox19b promote chromatin accessibility of enhancers linked to the genes involved in gastrulation and ventral fate specification. The genes regulating mesendodermal and dorsal fates are primed for activation independently of Pou5f3 and Sox19b. Strikingly, simultaneous loss of Pou5f3 and Sox19b leads to premature expression of genes, involved in regulation of organogenesis and differentiation.


title: Distinct natural syllable-selective neuronal ensembles in the primary auditory cortex of awake marmosets

abstract: Marmosets are highly social non-human primates living in families. They exhibit rich vocalization, but neural basis underlying complex vocal communication is largely unknown. Here we report the existence of specific neuronal ensembles in marmoset A1 that respond selectively to distinct monosyllable or disyllable calls made by conspecific marmosets. These neurons were spatially dispersed within A1 but distinct from those responsive to pure tones. Syllable-selective responses were markedly diminished when individual domains of the syllable were deleted or the domain sequence was altered, indicating the importance of global rather than local spectral-temporal properties of the sound. Disyllable-selective responses also disappeared when the sequence of the two monosyllable components was reversed or their interval was extended beyond 1 second. Light anesthesia largely abolished disyllable-selective responses. Our findings demonstrate extensive inhibitory and facilitory interactions among syllable-evoked responses, and provide the basis for further study of circuit mechanisms underlying vocal communication in awake non-human primates.


title: Eukaryotic rather than prokaryotic microbiomes change over seasons in rewetted fen peatlands

abstract: In the last decades, rewetting of drained peatlands is on the rise worldwide, to restore the significant carbon sink function. Rewetted peatlands differ substantially from their pristine counterparts and can, thus, be considered as novel ecosystems. Despite the increasing understanding of peat microbiomes, little is known about the seasonal dynamics and network interactions of the microbial communities in these novel ecosystems, especially in rewetted groundwater-fed peatlands, i.e. fens. Here, we investigated the seasonal dynamics in both prokaryotic and eukaryotic microbiomes in three common types of fens in Northern Germany, namely percolation fen, alder forest and coastal fen. The eukaryotic microbiomes, including fungi, protists and metazoa, showed significant changes of their community structures across the seasons in contrast to largely unaffected prokaryotic microbiomes. The co-occurrence network in the summer showed a distinct topology compared to networks in the other seasons, which was driven by the increased connections among protists, as well as between protists and the other microbial groups. Our results also indicated that the dynamics in eukaryotic microbiomes differed between fen types, specifically in terms of saprotrophs, arbuscular mycorrhiza and grazers of bacteria. Our study provides the insight that microbial eukaryotes mainly define the seasonal dynamics of microbiomes in rewetted fen peatlands. Accordingly, future research should unravel the importance of eukaryotes for biogeochemical processes, especially the under-characterized protists and metazoa, in these novel yet poorly understood ecosystems.


title: Regulatory architecture of the RCA gene cluster captures an intragenic TAD boundary, CTCF-mediated chromatin looping and a long-range intergenic enhancer

abstract:
The Regulators of Complement Activation (RCA) gene cluster comprises several tandemly arranged genes with shared functions within the immune system. RCA members, such as complement receptor 2 (CR2), are well-established susceptibility genes in complex autoimmune diseases. Altered expression of RCA genes has been demonstrated at both the functional and genetic level, but the mechanisms underlying their regulation are not fully characterised. We aimed to investigate the structural organisation of the RCA gene cluster to identify key regulatory elements that influence the expression of CR2 and other genes in this immunomodulatory region. Using 4C, we captured extensive CTCF-mediated chromatin looping across the RCA gene cluster in B cells and showed these were organised into two topologically associated domains (TADs). Interestingly, an inter-TAD boundary was located within the CR1 gene at a well-characterised segmental duplication. Additionally, we mapped numerous gene-gene and gene-enhancer interactions across the region, revealing extensive co-regulation. Importantly, we identified an intergenic enhancer and functionally demonstrated this element upregulates two RCA members (CR2 and CD55) in B cells. We have uncovered novel, long-range mechanisms whereby autoimmune disease susceptibility may be influenced by genetic variants, thus highlighting the important contribution of chromatin topology to gene regulation and complex genetic disease.

SIGNIFICANCEThe complement system is a complex network of protein effectors and regulators that play a key role in immunity. Several regulators of complement response are clustered within Regulators of Complement Activation (RCA) gene family. Its members are all functionally, structurally, and genetically related. However, the functional relevance of this close gene organisation is unknown. We show that the clustering of the RCA members is due to shared long-range regulatory elements and physical chromatin looping. We also reveal that the RCA genes are divided into two adjacent chromatin domains and a domain boundary falls within the body of an expressed gene (CR1). Overall, our findings in the RCA cluster offer insights into their evolution, biology and roles in disease.


title: Common postzygotic mutational signature in multiple healthy adult tissues related to embryonic hypoxia

abstract: Postzygotic mutations are acquired in all of the normal tissues throughout an individuals lifetime and hold clues for identifying mutagenesis causing factors. The process and underlying mechanism of postzygotic mutations in normal tissues is still poorly understood. In this study, we investigated postzygotic mutation spectra in healthy individuals by optimized ultra-deep exome sequencing of time series samples from the same volunteer and samples from different individuals. In cells of blood, sperm, and muscle, we resolved three common types of mutational signature. Two of them are known to represent clock-like mutational processes, and their proportions in mutation profiles associated with polymorphisms of epigenetic regulation genes, suggesting the contribution of personal genetic backgrounds to underlying biological process. Notably, the third signature, characterized by C>T transitions at GpCpN sites, tends to be a feature of diverse normal tissues. Mutations of this type were likely to occur early in embryo development even before the tissue differentiation, as indicated by their relatively high allele frequencies, sharing variants between multiple tissues, and lacking of age-related accumulation. Almost all tumors shown in public datasets did not have this signature detected except for 19.6% of clear cell renal cell carcinoma samples, which featured by activation of the hypoxia-induced signaling pathway. Moreover, in vitro activation of HIF signaling pathway successfully introduced the corresponding mutation profile of this signature in a culture-expanded human embryonic stem cell line. Therefore, embryonic hypoxia may explain this novel signature across multiple normal tissues. Our study suggest hypoxic conditions in the early stage of embryo development may be a crucial factor for the C>T transitions at GpCpN sites and individual genetic background also related to shaping human postzygotic mutation profiles.


title: Trans-generational effect of protein restricted diet on adult body and wing size of Drosophila melanogaster

abstract:
Dietary Restriction (DR) via protein restriction (PR) has become an inquisitive field and has established feasible trade-offs between various fitness and behavioral traits in Drosophila melanogaster to understand lifespan or aging in a nutritionally challenged environment. However, the phenotypes of body size, weight and wing length respond according to factors such as flies genotype, environmental exposure, and parental diet. Hence, understanding the long-term effect of PR on these phenotypes is essential. Here, we demonstrate the effect of PR diet on body size, weight and normal & dry wing length of flies subjected to PR50 and PR70 (50% and 70% protein content present in control food respectively) for 20 generations from pre-adult stage. We found that PR fed flies have lower body weight, relative water content (in males), unaltered (PR50%) and higher (PR70%) relative fat content in males, smaller normal and dry body size as compared to control and generations 1 and 2. Interestingly, wing size and pupal size of PR flies are smaller and showed significant effects of diet and generation. Thus, these traits are sex and generation dependent along with an interaction of diet, which is capable of modulating these results variably. Our study suggests that trans-generational effect is more prominent in influencing these traits and wing length might not be a predictor for body size. Taken together, the trans-generational effect of PR on fitness and fitness-related traits might be helpful to understand the underpinning mechanisms of evolution and aging in fruit flies D. melanogaster.

Summary statementTwenty generations of protein restricted diet have a diet and generation dependent effect on adult body size, wing length and body weight.

category: evolutionary biology


title: A predictive processing model of episodic memory and time perception

abstract:
Human perception and experience of time is strongly influenced by ongoing stimulation, memory of past experiences, and required task context. When paying attention to time, time experience seems to expand; when distracted, it seems to contract. When considering time based on memory, the experience may be different than in the moment, exemplified by sayings like "time flies when youre having fun". Experience of time also depends on the content of perceptual experience - rapidly changing or complex perceptual scenes seem longer in duration than less dynamic ones. The complexity of interactions between attention, memory, and perceptual stimulation is a likely reason that an overarching theory of time perception has been difficult to achieve. Here, we introduce a model of perceptual processing and episodic memory that makes use of hierarchical predictive coding, short-term plasticity, spatio-temporal attention, and episodic memory formation and recall, and apply this model to the problem of human time perception. In an experiment with ~ 13, 000 human participants we investigated the effects of memory, cognitive load, and stimulus content on duration reports of dynamic natural scenes up to ~ 1 minute long. Using our model to generate duration estimates, we compared human and model performance. Model-based estimates replicated key qualitative biases, including differences by cognitive load (attention), scene type (stimulation), and whether the judgement was made based on current or remembered experience (memory). Our work provides a comprehensive model of human time perception and a foundation for exploring the computational basis of episodic memory within a hierarchical predictive coding framework.

Author summaryExperience of the duration of present or past events is a central aspect of human experience, the underlying mechanisms of which are not yet fully understood. In this work, we combine insights from machine learning and neuroscience to propose a combination of mathematical models that replicate human perceptual processing, long-term memory, attention, and duration perception. Our computational implementation of this framework can process information from video clips of ordinary life scenes, record and recall important events, and report the duration of these clips. To assess the validity of our proposal, we conducted an experiment with ~ 13, 000 human participants. Each was shown a video between 1-64 seconds long and reported how long they believed it was. Reports of duration by our computational model qualitatively matched these human reports, made about the exact same videos. This was true regardless of the video content, whether time was actively judged or based on memory of the video, or whether the participants focused on a single task or were distracted - all factors known to influence human time perception. Our work provides the first model of human duration perception to incorporate these diverse and complex factors and provides a basis to probe the deep links between memory and time in human experience.


title: Synaptomic analysis of dopaminergic inputs reveal hub synapses in the mouse striatum.

abstract:
Dopamine is a monoamine involved in reward processing and motor control. Volume transmission is thought to be the mechanism by which monoamines modulate effector systems at glutamate and GABA synapses. Hence, dopamine synapses are scarcely described. We applied fluorescence activated synaptosome sorting to explore the features of the dopaminergic synaptome. We provide the proteome of striatal dopaminergic synapses with 57 proteins specifically enriched. Beyond canonical markers of dopamine neurotransmission (Th, Slc6a3/DAT, Slc18a2/VMAT2), we validated 6 proteins belonging to pre- and postsynaptic sides (Cpne7, Apba1/Mint1, Cadps2, Cadm2/SynCAM 2, Stx4 and Mgll). Moreover, dopaminergic varicosities adhere to both a post-synapse with cognate receptors and glutamatergic, GABAergic or cholinergic synapses in structures we named dopaminergic "hub synapses". Markers of presynaptic vesicles and active zone, post-synaptic density and spine apparatus, are significantly increased upon association with dopamine inputs in hubs. Thus neuromodulation frequently operates from hub synapses affecting associated synapses and is not solely dependent on volume transmission. Finally, FASS provides a new framework for the exploration of dopaminergic synapses and more generally for discrete synapse populations ex-vivo.

HighlightsO_LIA first proteome of dopaminergic synapses in the striatum
C_LIO_LIStriatal dopaminergic synaptosomes display post-synaptic cognate receptors
C_LIO_LIDopaminergic projections build hub synapses with excitatory, inhibitory, and cholinergic projections.
C_LIO_LICortico-striatal synaptic scaffolds are strengthened upon association in hub synapses.
C_LI


title: Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis

abstract:
Chronic kidney disease (CKD) remains a major epidemiological, clinical and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) suffer a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine if FAO gain-of-function (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1 A (CPT1A) in TECs. Cpt1a knock-in (CPT1A KI) mice subjected to three different models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy-FAN and adenine induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted pro-inflammatory response and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restituted oxidative metabolism and mitochondrial number and enhanced bioenergetics increasing palmitate oxidation and ATP levels, changes also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients evidenced decreased CPT1 levels and increased accumulation of short and middle chain acyl-carnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD.

Graphical abstractOverexpression of CPT1A impedes tubular epithelial renal cell dedifferentiation and a pro-fibrotic phenotype by restoring mitochondrial metabolic bioenergetics.

O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

category: biochemistry


title: Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2

abstract:
The emergence of SARS-CoV-2 underscores the need to better understand the evolutionary processes that drive the emergence and adaptation of zoonotic viruses in humans. In the betacoronavirus genus, which also includes SARS-CoV and MERS-CoV, recombination frequently encompasses the Receptor Binding Domain (RBD) of the Spike protein, which, in turn, is responsible for viral binding to host cell receptors. Here, we find evidence of a recombination event in the RBD involving ancestral linages to both SARS-CoV and SARS-CoV-2. Although we cannot specify the recombinant nor the parental strains, likely due to the ancestry of the event and potential undersampling, our statistical analyses in the space of phylogenetic trees support such an ancestral recombination. Consequently, SARS-CoV and SARS-CoV-2 share an RBD sequence that includes two insertions (positions 432-436 and 460-472), as well as the variants 427N and 436Y. Both 427N and 436Y belong to a helix that interacts directly with the human ACE2 (hACE2) receptor. Reconstruction of ancestral states, combined with protein-binding affinity analyses using the physics-based trRosetta algorithm, reveal that the recombination event involving ancestral strains of SARS-CoV and SARS-CoV-2 led to an increased affinity for hACE2 binding, and that alleles 427N and 436Y significantly enhanced affinity as well. Structural modeling indicates that ancestors of SARS-CoV-2 may have acquired the ability to infect humans decades ago. The binding affinity with the human receptor was subsequently boosted in SARS-CoV and SARS-CoV-2 through further mutations in RBD. In sum, we report an ancestral recombination event affecting the RBD of both SARS-CoV and SARS-CoV-2 that was associated with an increased binding affinity to hACE2.

ImportanceThis paper addresses critical questions about the origin of the SARS-CoV-2 virus: what are the evolutionary mechanisms that led to the emergence of the virus, and how can we leverage such knowledge to assess the potential of SARS-like viruses to become pandemic strains? In this work, we demonstrate common mechanisms involved in the emergence of human-infecting SARS-like viruses: first, by acquiring a common haplotype in the RBD through recombination, and further, through increased specificity to the human ACE2 receptor through lineage specific mutations. We also show that the ancestors of SARS-CoV-2 already had the potential to infect humans at least a decade ago, suggesting that SARS-like viruses currently circulating in wild animal species constitute a source of potential pandemic re-emergence.


title: Altered patterning of interneuron progenitors in Down syndrome

abstract: Individuals with Down syndrome (DS, Ts21), the most common genetic cause of intellectual disability, have smaller brains that reflect fewer neurons at pre- and post-natal stages, implicating impaired neurogenesis during development. Our stereological analysis of adult DS cortex indicates a reduction of calretinin expressing interneurons. Using Ts21 human induced pluripotent stem cells (iPSCs) and isogenic controls, we find Ts21 progenitors generate fewer COUP-TFII+ progenitors with reduced proliferation. Single cell RNA-sequencing of Ts21 progenitors confirms the altered specification of progenitor subpopulations and identifies reduced WNT signaling. Activation of WNT signaling partially restores the COUP-TFII+ progenitor population in Ts21, suggesting that altered WNT signaling contributes to the defective development of cortical interneurons in DS.


title: Consilience and the Peripheral Sensory Adaptation Response

abstract: Measurements of the peripheral sensory adaptation response were compared to a simple mathematical relationship involving the spontaneous, peak and steady-state activities. This relationship is based on the geometric mean and is found to be obeyed to good approximation in peripheral sensory units showing a sustained response to prolonged stimulation. From an extensive review of past studies, the geometric mean relationship is shown to be independent of modality and is satisfied in a wide range of animal species. The consilience of evidence, from nearly one hundred years of experiments beginning with the work of Edgar Adrian, suggests that this is a fundamental result of neurophysiology.


title: Hand-reared wolves show attachment comparable to dogs and use human caregiver as a social buffer in the Strange Situation Test

abstract: Domesticated animals are generally assumed to display increased sociability towards humans compared to their wild ancestors. Dogs (Canis familiaris) have a remarkable ability to form social relationships with humans, including lasting attachment, a social bond based on emotional dependency. Since it has specifically been suggested that the ability to form attachment with humans evolved post-domestication in dogs, attempts to quantify attachment in wolves (Canis lupus), the ancestor of dogs, have subsequently been performed. However, while these rare wolf studies do highlight the potential for wolves to express attachment behaviour towards humans, the varied, and in some cases, contrasting results also emphasize the need for further testing of wolves. Here we used the standardized Strange Situation Test to investigate attachment behaviour expressed in wolves and dogs hand-reared and socialized under identical conditions. We found that 23 weeks old wolves and dogs equally discriminated between a stranger and a familiar person, and expressed similar attachment behaviours toward a familiar person. Additionally, wolves, but not dogs, expressed significantly elevated stress behaviour during the test, but this stress response was buffered by the presence of a familiar person. Wolves also expressed quantifiable fear responses to the stranger, whereas no such response was detectable in dogs. Together, our results suggest that wolves can show attachment toward humans comparable to that of dogs. Importantly, our findings demonstrate that the ability to form attachment with humans exists in relatives of the wild ancestor of dogs, thus refuting claims that such attachment is unique to post-domestication dog lineages.

category: animal behavior and cognition


title: Altered GABAergic inhibition in CA1 pyramidal neurons modifies despair-like behavior in mice

abstract: Despair is a common human feeling characterized by the loss of hope and is a core symptom of depressive disorders. However, little is known regarding neural circuits mediating despair and their modulation by antidepressants. Here we show that alterations in inhibitory synaptic transmission in the hippocampus affect behavioral despair in mice. Reduced interneuron density, knockdown of GABAA receptor gamma 2 subunit gene (Gabrg2) or DREADD-mediated suppression of interneuron activity resulted in disinhibition of CA1 neurons and anti-despair-like behaviors in mice. Similarly, a low dose of pentylenetetrazol, a GABAAR antagonist, induced transient anti-despair-like behaviors, with rapid eukaryotic elongation factor 2 (eEF2) activation in the hippocampus. Conversely, pharmacological and chemogenetic potentiation of GABAergic transmission in CA1 neurons induced despair-like behaviors. The antidepressant ketamine rapidly increased c-Fos expression in CA1 neurons and induced anti-despair-like behaviors. These results suggest that the enhanced hippocampal CA1 neuron activity induces anti-despair-like behaviors and contributes to the antidepressant effects of ketamine.


title: Spatial maps in olfactory cortex during olfactory navigation

abstract: Odors are a fundamental part of the sensory environment used by animals to inform behaviors such as foraging and navigation1, 2. Primary olfactory (piriform) cortex is thought to be dedicated to encoding odor identity3-8. Here, using neural ensemble recordings in freely moving rats performing a novel odor-cued spatial choice task, we show that posterior piriform cortex neurons also carry a robust spatial map of the environment. Piriform spatial maps were stable across behavioral contexts independent of olfactory drive or reward availability, and the accuracy of spatial information carried by individual neurons depended on the strength of their functional coupling to the hippocampal theta rhythm. Ensembles of piriform neurons concurrently represented odor identity as well as spatial locations of animals, forming an "olfactory-place map". Our results reveal a previously unknown function for piriform cortex in spatial cognition and suggest that it is well-suited to form odor-place associations and guide olfactory cued spatial navigation.


title: Trait plasticity and covariance along a continuous soil moisture gradient

abstract: Water availability is perhaps the greatest environmental determinant of plant yield and fitness. However, our understanding of plant-water relations is limited because it is primarily informed by experiments considering soil moisture variability at two discrete levels - wet and dry - rather than as a continuously varying environmental gradient. Here we used experimental and statistical methods based on function-valued traits to explore responses to a continuous soil moisture gradient in physiological and morphological traits in two species and five genotypes each of the model grass Brachypodium. We find that most traits exhibit non-linear responses to soil moisture variability. We also observe differences in the shape of these non-linear responses between traits, species, and genotypes. Emergent phenomena arise from this variation including changes in trait correlations and evolutionary constraints as a function of soil moisture. These results point to the importance of considering non-linearity in plant-water relations to understand plastic and evolutionary responses to changing climates.


title: Spatial segregation and cooperation in radially expanding microbial colonies under antibiotic stress

abstract: Antibiotic resistance in microbial communities reflects a combination of processes operating at different scales. The molecular mechanisms underlying antibiotic resistance are increasingly understood, but less is known about how these molecular events give rise to spatiotemporal behavior on longer length scales. In this work, we investigate the population dynamics of bacterial colonies comprised of drug-resistant and drug-sensitive cells undergoing range expansion under antibiotic stress. Using the opportunistic pathogen E. faecalis with plasmid-encoded ({beta}-lactamase) resistance as a model system, we track colony expansion dynamics and visualize spatial pattern formation in fluorescently labeled populations exposed to ampicillin, a commonly-used {beta}-lactam antibiotic. We find that the radial expansion rate of mixed communities is approximately constant over a wide range of drug concentrations and initial population compositions. Fluorescence imaging of the final populations shows that resistance to ampicillin is cooperative, with sensitive cells surviving in the presence of resistant cells even at drug concentrations lethal to sensitive-only communities. Furthermore, despite the relative invariance of expansion rate across conditions, the populations exhibit a diverse range of spatial segregation patterns, with both the spatial structure and the population composition depending on drug concentration, initial composition, and initial population size. Agent based models indicate that the observed dynamics are consistent with long-range cooperation, despite the fact that {beta}-lactamase remains cell-associated in E. faecalis, and experiments confirm that resistant colonies provide a protective effect to sensitive cells on length scales multiple times the size of a single colony. Furthermore, in the limit of small inoculum sizes, we experimentally show that populations seeded with (on average) no more than a single resistant cell can produce mixed communities in the presence of drug. While biophysical models of diffusion-limited drug degradation suggest that individual resistant cells offer only short-range protection to neighboring sensitive cells, we show that long-range protection may arise from synergistic effects of multiple resistant cells, even when they represent only a small fraction of a colonys surface area. Our results suggest that {beta}-lactam resistance can be cooperative even in spatially extended systems where genetic segregation typically disfavors exploitation of locally produced public goods.


title: Efficient coding of numbers explains decision bias and noise

abstract: Human subjects differentially weight different stimuli in averaging tasks, which has been interpreted as reflecting encoding bias. We examine the alternative hypothesis that stimuli are encoded with noise, then optimally decoded. Under a model of efficient coding, the amount of noise should vary across stimuli, and depend on statistics of the stimuli. We investigate these predictions through a task in which participants are asked to compare the averages of two series of numbers, each sampled from a prior distribution that varies across blocks of trials. Subjects encode numbers with a bias and a noise that both depend on the number. Infrequently occurring numbers are encoded with more noise. We show how an efficient-coding, Bayesian-decoding model accounts for these patterns, and best captures subjects behaviour. Finally, our results suggest that Wei and Stockers "law of human perception", which relates the bias and variability of sensory estimates, also applies to number cognition.


title: Endosomes facilitate mitochondrial clearance by enhancing Parkin recruitment to mitochondria

abstract: Mutations in ubiquitin ligase Parkin are associated with Parkinsons disease and defective mitophagy. Conceptually, Parkin-dependent mitophagy is classified into two phases; 1. Parkin recruits to and ubiquitinates mitochondrial proteins, 2. Formation of autophagosome membrane, sequestering mitochondria for degradation. Recently, endosomal machineries were reported to contribute to the later stage for membrane assembly. We report a role for endosomes in the events upstream of phase 1. We demonstrate that an endosomal ubiquitin ligase CARP2 associates with damaged mitochondria, and this association precedes that of Parkin. CARP2 interacts with Parkin, and stable recruitment of Parkin to damaged mitochondria was substantially reduced in CARP2 KO cells. Our study unravels a novel role of endosomes in modulating upstream pathways of Parkin-dependent mitophagy initiation.

category: cell biology


title: The transcriptional landscape of Venezuelan equine encephalitis virus (TC-83) infection

abstract:
Venezuelan Equine Encephalitis Virus (VEEV) is a major biothreat agent that naturally causes outbreaks in humans and horses particularly in tropical areas of the western hemisphere, for which no antiviral therapy is currently available. The host response to VEEV and the cellular factors this alphavirus hijacks to support its effective replication or evade cellular immune responses are largely uncharacterized. We have previously demonstrated tremendous cell-to-cell heterogeneity in viral RNA (vRNA) and cellular transcript levels during flaviviral infection using a novel virus-inclusive single-cell RNA-Seq approach. Here, we used this unbiased, genome-wide approach to simultaneously profile the host transcriptome and vRNA in thousands of single cells during infection of human astrocytes with the live-attenuated vaccine strain of VEEV (TC-83). Host transcription was profoundly suppressed, yet "superproducer cells" with extremely high vRNA abundance emerged during the first viral life cycle and demonstrated an altered transcriptome relative to both uninfected cells and cells with high vRNA abundance harvested at later time points. Additionally, cells with increased structural-to-nonstructural transcript ratio exhibited upregulation of intracellular membrane trafficking genes at later time points. Loss- and gain-of-function experiments confirmed pro- and antiviral activities in both vaccine and virulent VEEV infections among the products of transcripts that positively or negatively correlated with vRNA abundance, respectively. Lastly, comparison with single cell transcriptomic data from other viruses highlighted common and unique pathways perturbed by infection across evolutionary scales. This study provides a high-resolution characterization of the VEEV (TC-83)-host interplay, identifies candidate targets for antivirals, and establishes a comparative single-cell approach to study the evolution of virus-host interactions.

Author SummaryLittle is known about the host response to Venezuelan Equine Encephalitis Virus (VEEV) and the cellular factors this alphavirus hijacks to support effective replication or evade cellular immune responses. Monitoring dynamics of host and viral RNA (vRNA) during viral infection at a single-cell level can provide insight into the virus-host interplay at a high resolution. Here, a single-cell RNA sequencing technology that detects host and viral RNA was used to investigate the interactions between TC-83, the vaccine strain of VEEV, with the human host during the course of infection of U-87 MG cells (human astrocytoma). Virus abundance and host transcriptome were heterogeneous across cells from the same culture. Subsets of differentially expressed genes, positively or negatively correlating with vRNA abundance, were identified and subsequently in vitro validated as candidate proviral and antiviral factors, respectively, in TC-83 and/or virulent VEEV infections. In the first replication cycle, "superproducer" cells exhibited rapid increase in vRNA abundance and unique gene expression patterns. At later time points, cells with increased structural-to-nonstructural transcript ratio demonstrated upregulation of intracellular membrane trafficking genes. Lastly, comparing the VEEV dataset with published datasets on other RNA viruses revealed unique and overlapping responses across viral clades. Overall, this study improves the understanding of VEEV-host interactions, reveals candidate targets for antiviral approaches, and establishes a comparative single-cell approach to study the evolution of virus-host interactions.


title: Social isolation modulates appetite and defensive behavior via a common oxytocinergic circuit in larval zebrafish

abstract: Animal brains have evolved to encode social stimuli and transform these representations into advantageous behavioral responses. The commonalities and differences of these representations across species are not well-understood. Here, we show that social isolation activates an oxytocinergic (OXT), nociceptive circuit in the larval zebrafish hypothalamus and that chemical cues released from conspecific animals are potent modulators of this circuits activity. We delineate an olfactory to subpallial pathway that transmits chemical social cues to OXT circuitry, where they are transformed into diverse outputs simultaneously regulating defensive and feeding behaviors. Our data allow us to propose a model through which social stimuli are integrated within a fundamental neural circuit to mediate diverse adaptive behaviours.


title: Quantitative dialing of gene expression via precision targeting of KRAB repressor

abstract: Human genes are regulated quantitatively, yet the ability to specify the expression level of a native gene accurately and specifically using a defined reagent has remained elusive. Here we show that precise targeting of KRAB repressive domain within regulatory DNA unlocks an endogenous quantitative  dial that can be engaged at nucleotide resolution to program expression levels across a wide physiologic range, with single-gene specificity and high reproducibly in primary cells.


title: Responses of tree species traits to soil variation in the Cerrado

abstract:
AimsThe Cerrado is a rich tropical savanna in plant species and to understand how key functional traits respond to soil variables can help to understand this hotspot functioning. This work aimed to answer i) whether the Cerrado tree species respond to soil by functional traits, ii) how the functional traits respond to soil variation in the Cerrado, and iii) whether the functional traits responses are interconnected.

MethodsWe used an RLQ method to associate soil variables to functional traits and GLMs for additional analysis. We used the nitrogen-fixing character as categorical trait and maximum plant height, maximum stem diameter, stem elongation, leaf nitrogen, leaf carbon, leaf C/N, leaf d15N and leaf d 13C as continuous traits.

ResultsThe RLQ showed that tree species responded to the soil variables with differences between nitrogen-fixing species and other species. The increase of CEC and decrease of aluminium saturation induced an increase of SLA and of stem elongation. CEC and aluminium saturation did not influence the leaf N% and C%. The increase of soil inorganic nitrogen is associated to an increase of leaf N% and of leaf C%. The C/N ratio explained negatively the {delta}13C and the stem elongation variation. Nitrogen fixing species presented low C/N ratios and high {delta}13C.

ConclusionsThe relative disassociation of the variation of SLA and stem elongation (mostly driven by CEC and aluminium variation) from the variation of N% and C% (mostly associated with inorganic nitrogen variation) can be a result of enhanced water use efficiency in N-enriched plants.


title: Hierarchical dinucleotide distribution in genome along evolution and its effect on chromatin packing

abstract: Dinucleotide densities and their distribution patterns vary significantly among species. Previous studies revealed that CpG is susceptible to methylation, enriched at topologically associating domains (TADs) boundaries and its distribution along the genome correlates with chromatin compartmentalization. However, the multi-scale organizations of CpG in the linear genome, their role in chromatin organization, and how they change along the evolution are only partially understood. By comparing the CpG distribution at different genomic length scales, we quantify the difference between the CpG distributions of different species and evaluate how the hierarchical uneven CpG distribution appears in evolution. The clustering of species based on the CpG distribution is consistent with the phylogenetic tree. Interestingly, we found the CpG distribution and chromatin structure to be correlated in many different length scales, especially for mammals and avians, consistent with the mosaic CpG distribution in the genomes of these species.


title: Distinct information-seeking modes in healthy and addicted individuals

abstract: As massive amounts of information are becoming available to people understanding the mechanisms underlying information-seeking is more pertinent today than ever. In this study, we investigate the underlying motivations to seek out information in healthy and addicted individuals. We developed a novel decision-making task and a novel computational model which allow to dissociate the relative contribution of two motivating factors to seek out information: a desire for novelty and a desire to reduce uncertainty. To investigate whether/how the motivations to seek out information vary between healthy and addicted individuals, in addition to healthy controls we included a sample of individuals with gambling disorder- a form of addiction without the confound of substance consumption and characterized by compulsive gambling. Our results indicate that healthy subjects and problem gamblers adopt distinct information-seeking "modes". Healthy information-seeking behavior was mostly motivated by a desire for novelty. Problem gamblers, on the contrary, displayed reduced novelty-seeking and an increased desire to reduce uncertainty (general information-seeking) compared to healthy controls. Our findings not only shed new light on the motivations driving healthy and addicted individuals to seek out information, but they also have important implications for treatment and diagnosis of behavioral addiction.


title: Distinct motivations to seek out information in healthy and addicted 1 individuals


title: The expression of hemagglutinin by a recombinant Newcastle disease virus causes structural changes and alters innate immune sensing

abstract: Recombinant Newcastle disease viruses (rNDV) have been used as bivalent vectors for vaccination against multiple economically important avian pathogens. NDV-vectored vaccines expressing the immunogenic H5 hemagglutinin (rNDV-H5) are considered attractive candidates to protect poultry from both highly pathogenic avian influenza (HPAI) and Newcastle disease (ND). However, the impact of the insertion of a recombinant protein, such as H5, on the biological characteristics of the parental NDV strain has been little investigated to date. The present study compared a rNDV-H5 vaccine and its parental NDV LaSota strain in terms of their structural and functional characteristics, as well as their recognition by the innate immune sensors. Structural analysis of the rNDV-H5 demonstrated a decreased number of fusion (F) and a higher number of hemagglutinin-neuraminidase (HN) glycoproteins compared to NDV LaSota. These structural differences were accompanied by increased hemagglutinating and neuraminidase activities of rNDV-H5. During in vitro rNDV-H5 infection, increased mRNA expression of TLR3, TLR7, MDA5, and LGP2 was observed, suggesting that the recombinant virus is recognized differently by sensors of innate immunity when compared with the parental NDV LaSota. Given the growing interest in using NDV as a vector against human and animal diseases, these data highlight the importance to thoroughly understand the recombinant vaccines structural organization, functional characteristics, and the immune responses elicited.


title: Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans

abstract: Complex I deficiency represents the most frequent pathogenetic cause of human mitochondriopathies. Therapeutic options for these neurodevelopmental life-threating disorders do not exist, partly due to the scarcity of appropriate model systems to study them. Caenorhabditis elegans is a genetically tractable model organism widely used to investigate neuronal pathologies. Here, we generated new C. elegans models for mitochondriopathies and showed that depletion of Complex I subunits recapitulates biochemical, cellular and neurodevelopmental aspects of the human diseases. Two models, nuo-5/NDUFS1- and lpd-5/NDUFS4-depleted animals, were exploited for a suppressor screening that identified lutein for its ability to rescue animals neurodevelopmental deficits. We uncovered overexpression of synaptic neuroligins as an evolutionarily conserved consequence of mitochondrial dysfunction, which we found to mediate an early cholinergic defect in C. elegans. We showed lutein exerts its beneficial effects by restoring neuroligin expression independently from its antioxidant activity, thus pointing to a possible novel pathogenetic target for the human disease.


title: ALG-2 And Peflin Stimulate or Inhibit COPII Targeting And Secretion In Response To Calcium Signaling

abstract: ER-to-Golgi transport is the first step in the constitutive secretory pathway which, unlike regulated secretion, is believed to proceed non-stop regardless of Ca2+ flux. Rowever, here we demonstrate that penta-EF hand (PEF) proteins ALG-2 and peflin constitute a hetero-bifunctional COPII regulator that responds to Ca2+ signaling by adjusting the ER export rate of COPII-sorted cargos up or down by ~50%. At steady-state Ca2+, ALG-2/peflin hetero-complexes bind to ER exit sites (ERES) through the ALG-2 subunit to confer a low, buffered secretion rate, while peflin-lacking ALG-2 complexes markedly stimulate secretion. During Ca2+ signaling, ALG-2 complexes lacking peflin can either increase or decrease the secretion rate depending on signaling intensity and duration-phenomena that could contribute to cellular growth and intercellular communication, following secretory increases, or protection from excitotoxicity and infection following decreases. In epithelial normal rat kidney (NRK) cells, the Ca2+-mobilizing agonist ATP causes ALG-2 to depress ER export, while in neuroendocrine PC12 cells, Ca2+ mobilization by ATP results in ALG-2-dependent enhancement of secretion. Within the NRK cell model, distinct Ca2+ signaling patterns can produce opposing ALG-2-dependent effects on secretion. Mechanistically, ALG-2-dependent depression of secretion involves decreased COPTT outer shell and increased peflin targeting to ERES, while ALG-2-dependent enhancement of secretion involves increased COPTT outer shell and decreased peflin at ERES. PEF protein complexes represent a true regulator of transport as they are dispensable for secretion yet adjust the secretion rate to physiological conditions. Their dynamics affects secretion of important physiological cargoes such as collagen T and significantly impacts ER stress.


title: Plant SYP12 syntaxins mediate an evolutionarily conserved general immunity to filamentous pathogens

abstract: Filamentous fungal and oomycete plant pathogens that invade by direct penetration through the leaf epidermal cell wall, cause devastating plant diseases. Towards non-adapted filamentous pathogens, plant pre-invasive immunity is highly effective and durable. Pre- and post-invasive immunity correlates with the formation of evolutionarily conserved and cell-autonomous cell wall structures, named papillae and encasements. Yet, it is still unresolved how papillae/encasements are formed and whether these defense structures prevent pathogen ingress. Here we show that in Arabidopsis, the two closely related members of the SYP12 clade of syntaxins (PEN1 and SYP122) are indispensable for the formation of papillae and encasements. Moreover, loss-of-function mutants were hampered in pre-invasive immunity towards a range of taxonomically distinct non-adapted filamentous pathogens, underlining the versatility and efficacy of this defense. Complementation studies using SYP12s from the early diverging land plant, Marchantia polymorpha, showed that the SYP12 clade immunity function has survived 470 My of independent evolution. These results suggest that ancestral land plants evolved the SYP12 clade to provide a broad and durable pre-invasive immunity to facilitate their life on land, and pave the way to a better understanding of how adapted pathogens overcome this ubiquitous plant defense strategy.


title: Predicting and Visualizing STK11 Mutation in Lung Adenocarcinoma Histopathology Slides Using Deep Learning

abstract: Studies have shown that STK11 mutation plays a critical role in affecting the lung adenocarcinoma (LUAD) tumor immune environment. By training an Inception-Resnet-v2 deep convolutional neural network model, we were able to classify STK11-mutated and wild type LUAD tumor histopathology images with a promising accuracy (per slide AUROC=0.795). Dimensional reduction of the activation maps before the output layer of the test set images revealed that fewer immune cells were accumulated around cancer cells in STK11-mutation cases. Our study demonstrated that deep convolutional network model can automatically identify STK11 mutations based on histopathology slides and confirmed that the immune cell density was the main feature used by the model to distinguish STK11-mutated cases.


title: Molecular epidemiology of third-generation cephalosporin-resistant Enterobacteriaceae from Southeast Queensland, Australia

abstract: SynopsisThird-generation cephalosporin-resistant (3GC-R) Enterobacteriaceae represent a major threat to human health. Here, we captured 288 3GC-R Enterobacteriaceae clinical isolates from 264 patients presenting at a regional Australian hospital over a 14-month period. Alongside routine mass spectrometry speciation and antibiotic sensitivity testing, isolates were examined using rapid ([~]40 min) real-time PCR assays targeting the most common extended spectrum {beta}-lactamases (ESBLs; CTX-M-1 and CTX-M-9 groups, plus TEM, SHV, and an internal 16S ribosomal DNA control). AmpC CMY {beta}-lactamase prevalence was also examined. Escherichia coli (80.2%) and Klebsiella pneumoniae (17.0%) were dominant, with Klebsiella oxytoca, Klebsiella aerogenes and Enterobacter cloacae infrequently identified. Ceftriaxone and cefoxitin resistance were identified in 97.0% and 24.5% of E. coli and K. pneumoniae isolates, respectively. Consistent with global findings in Enterobacteriaceae, most (98.3%) isolates harbored at least one {beta}-lactamase gene, with 144 (50%) encoding blaCTX-M-1 group, 92 (31.9%) blaCTX-M-9 group, 48 (16.7%) blaSHV, 133 (46.2%) blaTEM, and 34 (11.8%) blaCMY. A subset of isolates (n=98) were subjected to whole-genome sequencing (WGS) to identify the presence of cryptic resistance determinants, and to verify genotyping accuracy. WGS of {beta}-lactamase negative or carbapenem-resistant isolates identified uncommon ESBLs and carbapenemases, including blaNDM and blaIMP, and confirmed all PCR-positive genotypes. We demonstrate that our PCR assays enable the rapid and cost-effective identification of ESBLs in the hospital setting, which has important infection control and therapeutic implications.


title: Next-generation phylogeography resolves post-glacial colonization patterns in a widespread carnivore, the red fox (Vulpes vulpes), in Europe.

abstract: Carnivores tend to exhibit a lack of (or less pronounced) genetic structure at continental scales in both a geographic and temporal sense and this can confound the identification of post-glacial colonization patterns in this group. In this study we used genome-wide data (using Genotyping-by-Sequencing (GBS)) to reconstruct the phylogeographic history of a widespread carnivore, the red fox (Vulpes vulpes), by investigating broad-scale patterns of genomic variation, differentiation and admixture amongst contemporary populations in Europe. Using 15,003 single nucleotide polymorphisms (SNPs) from 524 individuals allowed us to identify the importance of refugial regions for the red fox in terms of endemism (e.g. Iberia). In addition, we tested multiple post-glacial re-colonization scenarios of previously glaciated regions during the Last Glacial Maximum using an Approximate Bayesian Computation (ABC) approach that were unresolved from previous studies. This allowed us to identify the role of admixture from multiple source population post-Younger Dryas in the case of Scandinavia and ancient land-bridges in the colonization of the British Isles. A natural colonization of Ireland was deemed more likely than an ancient human-mediated introduction as has previously been proposed and potentially points to an increased mammalian fauna on the island in the early post-glacial period. Using genome-wide data has allowed us to tease apart broad-scale patterns of structure and diversity in a widespread carnivore in Europe that was not evident from using more limited marker sets and provides a foundation for next-generation phylogeographic studies in other non-model species.


title: Ice2 promotes ER membrane biogenesis in yeast by inhibiting the conserved lipin phosphatase complex

abstract: Cells dynamically adapt organelle size to current physiological demand. Organelle growth requires membrane biogenesis and therefore needs to be coordinated with lipid metabolism. The endoplasmic reticulum (ER) can undergo massive expansion, but the regulatory mechanisms that govern ER membrane biogenesis are largely unclear. Here, we conduct a genetic screen for factors involved in ER membrane expansion in budding yeast and identify the ER transmembrane protein Ice2 as a strong hit. We show that Ice2 promotes ER membrane biogenesis by opposing the phosphatidic acid phosphatase Pah1, which is called lipin in metazoa. Ice2 inhibits the conserved Nem1-Spo7 complex, which dephosphorylates and thus activates Pah1. Furthermore, Ice2 cooperates with the transcriptional regulation of lipid synthesis genes and helps to maintain ER homeostasis during ER stress. These findings establish inhibition of the lipin phosphatase complex as an important mechanism for controlling ER membrane biogenesis.