title: The lncRNA MARS modulates the epigenetic reprogramming of the marneral cluster in response to ABA

abstract: Clustered organization of biosynthetic non-homologous genes is emerging as a characteristic feature of plant genomes. The co-regulation of clustered genes seems to largely depend on epigenetic reprogramming and three-dimensional chromatin conformation. Here we identified the long noncoding RNA (lncRNA) MARneral Silencing (MARS), localized inside the Arabidopsis marneral cluster, which controls the local epigenetic activation of its surrounding region in response to ABA. MARS modulates the POLYCOMB REPRESSIVE COMPLEX 1 (PRC1) component LIKE-HETEROCHROMATIN PROTEIN 1 (LHP1) binding throughout the cluster in a dose-dependent manner, determining H3K27me3 deposition and chromatin condensation. In response to ABA, MARS decoys LHP1 away from the cluster and promotes the formation of a chromatin loop bringing together the MARNERAL SYNTHASE 1 (MRN1) locus and a distal ABA-responsive enhancer. The enrichment of co-regulated lncRNAs in clustered metabolic genes in Arabidopsis suggests that the acquisition of novel noncoding transcriptional units may constitute an additional regulatory layer driving the evolution of biosynthetic pathways.


title: Dissecting the microenvironment around biosynthetic scaffolds in murine skin wound healing

abstract: Structural properties of biomaterials play critical roles in guiding cell behaviors and influence the immune response against them. We fabricated electrospun membranes with three types of surface topography (Random, Aligned, and Latticed). The aligned membranes showed immunomodulatory ability, and led to faster wound healing, reduced fibrotic response and enhanced regeneration of cutaneous appendages when used in skin wound repair. Based on that, we performed single-cell RNA sequencing analysis on cells from wounded mouse skin in the presence or absence of the Aligned scaffold. Keratinocytes, fibroblasts, and immune cells including neutrophils, monocytes, macrophages, dendritic cells, and T cells showed diverse cellular heterogeneity. More hair follicle progenitor cells, inner root sheath cells (anagen-related) and fibroblast subsets were found in the Aligned group, which corresponded to the improved regeneration of hair follicles and faster wound closure in the presence of scaffold. Immune responses towards the biomaterial differed from that of control group. In aligned samples, infiltrated macrophages and neutrophils were reduced, whereas more effector T cells were recruited. The time course of immune response was possibly advanced towards an adaptive immunity-dominant stage by the scaffold. The microenvironment around scaffold involved intricate interplay of immune cells and cutaneous cells, and wound healing was the comprehensive results of numerous influencing factors working together.

category: immunology


title: Quantity and quality of suitable matrices matter in reducing the negative effect of fragmentation on populations' extinction risk

abstract: The negative effect of fragmentation is one of the main concerns in the study of biodiversity loss in landscape ecology. The use of the matrix has been considered an important factor because it can change the relationship of a population with the configuration of the landscape. A systematic way to assess the effect of matrix quality in fragmented landscapes could lead to a better understanding of how matrices can be used to suppress the negative effect of fragmentation. We built a computational individual-based model capable of simulating bi-dimensional landscapes with three types of land cover (habitat, suitable matrix and hostile matrix) and individuals that inhabit those landscapes. We explored in which situations changes in the proportion of the suitable matrix in the landscape and the degree of usability of this suitable matrix can mitigate the negative effect of fragmentation per se. We observed that (i) an increase in the matrix quality (increases in the suitable matrix proportion and/or usability) can suppress the fragmentation effect in 47% of the simulated scenarios; (ii) the less usable the matrix is the more of it is needed to suppress the fragmentation effect; (iii) there is a level of usability below which increasing the suitable matrix proportion does cause the fragmentation effect to cease. These results point toward a landscape management that considers the similarity of the matrix to the native habitat under management. We suggest that an index to measure the usability of elements of the matrix could be an important tool to further the use of computational models in landscape management.

category: ecology


title: A comprehensive transcriptome signature of murine hematopoietic stem cell aging

abstract:
We surveyed 16 published and unpublished data sets to determine whether a consistent pattern of transcriptional deregulation in aging murine hematopoietic stem cells (HSC) exists. Despite substantial heterogeneity between individual studies, we uncovered a core and robust HSC aging signature. We detected increased transcriptional activation in aged HSCs, further confirmed by chromatin accessibility analysis. Unexpectedly, using two independent computational approaches, we established that deregulated aging genes consist largely of membrane-associated transcripts, including many cell surface molecules previously not associated with HSC biology. We show that Selp, the most consistent deregulated gene, is not merely a marker for aged HSCs but is associated with HSC functional decline. Additionally, single-cell transcriptomics analysis revealed increased heterogeneity of the aged HSC pool. We identify the presence of transcriptionally "young-like" HSCs in aged bone marrow. We share our results as an online resource and demonstrate its utility by confirming that exposure to sympathomimetics, and deletion of Dnmt3a/b, molecularly resembles HSC rejuvenation or aging, respectively.

Key PointsO_LIA comprehensive transcriptome analysis of aged murine hematopoietic stem cells identifies an aging signature;
C_LIO_LIThe HSC aging signature is highly enriched for cell membrane-related transcripts and identifies age-associated heterogeneity.
C_LI

category: cell biology


title: The record of Deinotheriidae from the Miocene of the Swiss Jura Mountains (Jura Canton, Switzerland)

abstract: The Miocene sands of the Swiss Jura Mountains, long exploited in quarries for the construction industry, have yielded abundant fossil remains of large mammals. Among Deinotheriidae (Proboscidea), two species, Prodeinotherium bavaricum and Deinotherium giganteum, had previously been identified in the Delemont valley, but never described. A third species, Deinotherium levius, from the locality of Charmoille in Ajoie, is reported herein for the first time in Switzerland. These occurrences are dated from the middle to the late Miocene, correlating to the European Mammal biozones MN5 to MN9. The study is completed by a discussion on the palaeobiogeography of deinotheres at the European scale.

category: paleontology


title: Probabilistic, entropy-maximizing control of large-scale neural synchronization

abstract: Oscillatory neural activity is dynamically controlled to coordinate perceptual, attentional and cognitive processes. On the macroscopic scale, this control is reflected in the U-shaped deviations of EEG spectral-power dynamics from stochastic dynamics, characterized by disproportionately elevated occurrences of the lowest and highest ranges of power. To understand the mechanisms that generate these low- and high-power states, we fit a simple mathematical model of synchronization of oscillatory activity to human EEG data. The results consistently indicated that the majority (~95%) of synchronization dynamics is controlled by slowly adjusting the probability of synchronization while maintaining maximum entropy within the timescale of a few seconds. This strategy appears to be universal as the results generalized across oscillation frequencies, EEG current sources, and participants (N = 52) whether they rested with their eyes closed, rested with their eyes open in a darkened room, or viewed a silent nature video. Given that precisely coordinated behavior requires tightly controlled oscillatory dynamics, the current results suggest that the large-scale spatial synchronization of oscillatory activity is controlled by the relatively slow, entropy-maximizing adjustments of synchronization probability (demonstrated here) in combination with temporally precise phase adjustments (e.g., phase resetting generated by sensorimotor interactions). Interestingly, we observed a modest but consistent spatial pattern of deviations from the maximum-entropy rule, potentially suggesting that the mid-central-posterior region serves as an "entropy dump" to facilitate the temporally precise control of spectral-power dynamics in the surrounding regions.

category: neuroscience


title: Dysregulation of the secretory pathway connects Alzheimer's disease genetics to aggregate formation

abstract: A hallmark of amyloid disorders, such as Alzheimers disease, is aggregation of secreted proteins. However, it is largely unclear how the hundreds of secretory pathway proteins contribute to amyloid formation. We developed a systems biology framework that integrates expression data with protein-protein interaction networks to successfully estimate a tissues fitness for producing specific secreted proteins. Using this framework, we analyzed the fitness of the secretory pathway of various brain regions and cell types for synthesizing the Alzheimers disease-associated amyloid-precursor protein (APP). While none of the key amyloidogenic pathway components were differentially expressed in AD brain, we found the deposition of A{beta} is associated with repressed expression of the secretory pathway components proximal to APP. Concurrently, we detected systemic up-regulation of the secretory pathway components proximal to {beta}- and {gamma}-secretases in AD brains. Our analyses suggest that perturbations from 3 high confidence AD risk genes cascade through the secretory machinery support network for APP and into the endocytosis pathway. Thus, we present a model where amyloidogenesis is associated with dysregulation of dozens of secretory pathway components supporting APP, which could yield novel therapeutic targets for the treatment of AD.


title: Predictive coding of natural images by V1 activity revealed by self-supervised deep neural networks

abstract: Predictive coding is an important candidate theory of self-supervised learning in the brain. Its central idea is that neural activity results from an integration and comparison of bottom-up inputs with contextual predictions, a process in which firing rates and synchronization may play distinct roles. Here, we quantified stimulus predictability for natural images based on self-supervised, generative neural networks. When the precise pixel structure of a stimulus falling into the V1 receptive field (RF) was predicted by the spatial context, V1 exhibited characteristic{gamma} -synchronization (30-80Hz), despite no detectable modulation of firing rates. In contrast to{gamma} , {beta}-synchronization emerged exclusively for unpredictable stimuli. Natural images with high structural predictability were characterized by high compressibility and low dimensionality. Yet, perceptual similarity was mainly determined by higher-level features of natural stimuli, not by the precise pixel structure. When higher-level features of the stimulus in the receptive field were predicted by the context, neurons showed a strong reduction in firing rates and an increase in surround suppression that was dissociated from synchronization patterns. These findings reveal distinct roles of synchronization and firing rates in the predictive coding of natural images.


title: Unification of Sparse Bayesian Learning Algorithms for Electromagnetic Brain Imaging with the Majorization Minimization Framework

abstract: Methods for electro- or magnetoencephalography (EEG/MEG) based brain source imaging (BSI) using sparse Bayesian learning (SBL) have been demonstrated to achieve excellent performance in situations with low numbers of distinct active sources, such as event-related designs. This paper extends the theory and practice of SBL in three important ways. First, we reformulate three existing SBL algorithms under the majorization-minimization (MM) framework. This unification perspective not only provides a useful theoretical framework for comparing different algorithms in terms of their convergence behavior, but also provides a principled recipe for constructing novel algorithms with specific properties by designing appropriate bounds of the Bayesian marginal likelihood function. Second, building on the MM principle, we propose a novel method called LowSNR-BSI that achieves favorable source reconstruction performance in low signal-to-noise-ratio (SNR) settings. Third, precise knowledge of the noise level is a crucial requirement for accurate source reconstruction. Here we present a novel principled technique to accurately learn the noise variance from the data either jointly within the source reconstruction procedure or using one of two proposed cross-validation strategies. Empirically, we could show that the monotonous convergence behavior predicted from MM theory is confirmed in numerical experiments. Using simulations, we further demonstrate the advantage of LowSNR-BSI over conventional SBL in low-SNR regimes, and the advantage of learned noise levels over estimates derived from baseline data. To demonstrate the usefulness of our novel approach, we show neurophysiologically plausible source reconstructions on averaged auditory evoked potential data.


title: A hardware/software system for electrophysiology "supersessions" in marmosets

abstract: We introduce a straightforward, robust method for recording and analyzing spiking activity over timeframes longer than a single session, with primary application to the marmoset (Callithrix jacchus). Although in theory the marmosets smooth brain allows for broad deployment of powerful tools in primate cortex, in practice marmosets do not typically engage in long experimental sessions akin to rhesus monkeys. This potentially limits their value for detailed, quantitative neurophysiological study. Here we describe chronically-implanted arrays with a 3D arrangement of electrodes yielding stable single and multi-unit responses, and an analytic method for creating "supersessions" combining that array data across multiple experiments. We could match units across different recording sessions over several weeks, demonstrating the feasibility of pooling data over sessions. This could be a key tool for extending the viability of marmosets for dissecting neural computations in primate cortex.


title: Cell-specific imputation of drug connectivity mapping with incomplete data

abstract:
MotivationDrug repositioning allows expedited discovery of new applications for existing compounds, but re-screening vast compound libraries is often prohibitively expensive. "Connectivity mapping" is a process that links drugs to diseases by identifying compounds whose impact on expression in a collection of cells reverses the diseases impact on expression in disease-relevant tissues. The high throughput LINCS project has expanded the universe of compounds and cell types for which data are available, but even with this effort, many potentially clinically useful combinations are missing. To evaluate the possibility of repurposing drugs this way despite missing data, we compared collaborative filtering with either neighborhood-based or SVD imputation methods to two naive approaches via cross-validation.

ResultsMethods were evaluated for their ability to predict drug connectivity despite missing data. Predictions improved when cell type was taken into account. Neighborhood-based collaborative filtering was the most successful method, with the best improvements in non-immortalized primary cells. We also explored which classes of compounds are most and least reliant on cell type for accurate imputation, and we identified connections between related compounds even when many were not measured in the relevant cells. We conclude that even for cells in which drug responses have not been fully characterized, it is possible to identify unassayed drugs that reverse in those cells the expression signatures observed in disease.

Contactdonna.slonim@tufts.edu

category: bioinformatics


title: Inhibition of histone readers bromodomain extra-terminal proteins alleviates skin fibrosis in experimental models of scleroderma

abstract: Binding of the bromodomain and extra-terminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. This study sought to determine the anti-fibrotic efficacy and potential mechanisms of BET inhibition in systemic sclerosis (SSc). Blockade of BETs was done using a pan BET inhibitor JQ1, BRD2 inhibitor BIC1, or BRD4 inhibitors AZD5153 or ARV825. BET inhibition, specifically BRD4 blockade, showed anti-fibrotic effects in an animal model of scleroderma and in patient-derived diffuse cutaneous (dc)SSc fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium signaling. The anti-fibrotic effect of BRD4 inhibition was at least in part mediated by downregulation of Ca2+/calmodulin-dependent protein kinase II  (CaMKII-) and reduction of intracellular calcium concentrations. These results suggest that targeting calcium pathways or BRD4 might be novel therapeutic approaches for progressive tissue fibrosis.

category: pharmacology and toxicology


title: SDC3 acts as a timekeeper of myogenic differentiation by regulating the insulin/AKT/mTOR axis in muscle stem cell progeny

abstract: Muscle stem cells (MuSCs) are indispensable for muscle regeneration. A multitude of extracellular stimuli direct MuSC fate decisions from quiescent progenitors to differentiated myocytes. The activity of these signals is modulated by coreceptors such as syndecan-3 (SDC3). We investigated the global landscape of SDC3-mediated regulation of myogenesis using a phosphoproteomics approach which revealed, with the precision level of individual phosphosites, the large-scale extent of SDC3-mediated regulation of signal transduction in MuSCs. We then focused on INSR/AKT/mTOR as a key pathway regulated by SDC3 during myogenesis and mechanistically dissected SDC3-mediated inhibition of insulin signaling in MuSCs. SDC3 interacts with INSR limiting insulin signal transduction via AKT/mTOR. Both knockdown of INSR and inhibition of AKT rescue Sdc3-/- MuSC differentiation to wild type levels. Since SDC3 is rapidly downregulated at the onset of differentiation, our study suggests that SDC3 acts a timekeeper to restrain proliferating MuSC response to insulin and prevent premature differentiation.


title: Rapid SARS-CoV-2 Adaptation to Available Cellular Proteases

abstract:
Since the pandemic spread of SARS-CoV-2, the virus has exhibited remarkable genome stability, but recent emergence of novel variants show virus evolution potential. Here we show that SARS-CoV-2 rapidly adapts to Vero E6 cells that leads to loss of furin cleavage motif in spike protein. The adaptation is achieved by asymptotic expansion of minor virus subpopulations to dominant genotype, but wildtype sequence is maintained at low percentage in the virus swarm, and mediate reverse adaptation once the virus is passaged on human lung cells. The Vero E6-adapted virus show defected cell entry in human lung cells and the mutated spike variants cannot be processed by furin or TMPRSS2. However, the mutated S1/S2 site is cleaved by cathepsins with higher efficiency. Our data show that SARS-CoV-2 can rapidly adapt spike protein to available proteases and advocate for deep sequence surveillance to identify virus adaptation potential and novel variant emergence.

Significance StatementRecently emerging SARS-CoV-2 variants B1.1.1.7 (UK), B.1.351 (South Africa) and B.1.1.248 (Brazil) harbor spike mutation and have been linked to increased virus pathogenesis. The emergence of these novel variants highlight coronavirus adaptation and evolution potential, despite the stable consensus genotype of clinical isolates. We show that subdominant variants maintained in the virus population enable the virus to rapidly adapt upon selection pressure. Although these adaptations lead to genotype change, the change is not absolute and genome with original genotype are maintained in virus swarm. Thus, our results imply that the relative stability of SARS-CoV-2 in numerous independent clinical isolates belies its potential for rapid adaptation to new conditions.

category: microbiology


title: ATP-responsive biomolecular condensates tune bacterial kinase signaling

abstract:
Biomolecular condensates formed via phase separation enable spatial and temporal organization of enzyme activity. The emergent properties of many condensates have been shown to be responsive to intracellular Adenosine triphosphate (ATP) levels, although the consequences of such mechanisms on enzyme activity are unknown. Here, we show that ATP depletion promotes phase separation in condensates composed of a disordered protein, thereby enhancing the activity of a client kinase enabling robust signaling and maintenance of viability under the stress posed by nutrient scarcity. We propose that a diverse repertoire of condensates can serve as control knobs to tune multivalency and reactivity in response to the metabolic state of bacterial cells.

One Sentence SummaryBacterial condensates boost kinase activity under ATP depletion


title: Petabase-scale sequence alignment catalyses viral discovery

abstract: Public databases contain a planetary collection of nucleic acid sequences, but their systematic exploration has been inhibited by a lack of efficient methods for searching this corpus, now exceeding multiple petabases and growing exponentially [1, 2]. We developed a cloud computing infrastructure, Serratus, to enable ultra-high throughput sequence alignment at the petabase scale. We searched 5.7 million biologically diverse samples (10.2 petabases) for the hallmark gene RNA dependent RNA polymerase, identifying well over 105 novel RNA viruses and thereby expanding the number of known species by roughly an order of magnitude. We characterised novel viruses related to coronaviruses and to hepatitis{delta} virus, respectively and explored their environmental reservoirs. To catalyse a new era of viral discovery, we established a free and comprehensive database of these data and tools. Expanding the known sequence diversity of viruses can reveal the evolutionary origins of emerging pathogens and improve pathogen surveillance for the anticipation and mitigation of future pandemics.


title: Discovery of a protein uptake pathway in lysosomes

abstract:
The degradation of cellular components plays an essential role in homeostasis. However, the known degradation pathways cannot account for the levels of proteolysis in cells. Here, we demonstrate that cytosolic proteins are imported into lysosomes in an ATP-dependent manner for degradation through a direct uptake mechanism distinct from any known pathway. SIDT2, a lysosomal membrane protein previously reported as an RNA transporter, translocates substrate proteins across the lysosomal membrane. Furthermore, we identify a dominant-negative mutation in SIDT2 that causes neuropathy and distal myopathy with rimmed vacuoles, a protein aggregation disease in humans. We generate Sidt2 knockout mice, recapitulating the characteristic features of this disease. Our results reveal a novel degradation pathway and illustrate its crucial role in cellular proteostasis, physiology, and pathophysiology.

One Sentence SummaryDiscovery of a novel proteolytic pathway in cells, the dysfunction of which leads to protein aggregation disease in humans.


title: FAIRSCAPE: A Framework for FAIR and Reproducible Biomedical Analytics

abstract:
Results of computational analyses require transparent disclosure of their supporting resources, while the analyses themselves often can be very large scale and involve multiple processing steps separated in time. Evidence for the correctness of any analysis should include not only a textual description, but also a formal record of the computations which produced the result, including accessible data and software with runtime parameters, environment, and personnel involved.

This article describes FAIRSCAPE, a reusable computational framework, enabling simplified access to modern scalable cloud-based components. FAIRSCAPE fully implements the FAIR data principles and extends them to provide fully FAIR Evidence, including machine-interpretable provenance of datasets, software and computations, as metadata for all computed results.

The FAIRSCAPE microservices framework creates a complete Evidence Graph for every computational result, including persistent identifiers with metadata, resolvable to the software, computations, and datasets used in the computation; and stores a URI to the root of the graph in the results metadata. An ontology for Evidence Graphs, EVI (https://w3id.org/EVI), supports inferential reasoning over the evidence.

FAIRSCAPE can run nested or disjoint workflows and preserves provenance across them. It can run Apache Spark jobs, scripts, workflows, or user-supplied containers. All objects are assigned persistent IDs, including software. All results are annotated with FAIR metadata using the evidence graph model for access, validation, reproducibility, and re-use of archived data and software.


title: A Proteome-scale Analysis of Vertebrate Protein Amino Acid Occurrence: Thermoadaptation shows a Correlation with Protein Solvation but less so with Dynamics

abstract: Despite differences in behaviors and living conditions, vertebrate organisms share the great majority of proteins, often with subtle differences in amino acid sequence. Here, we present a simple way to analyze the difference in amino acid occurrence by comparing highly homologous proteins on a sub-proteome level between several vertebrate model organisms. Specifically, we use this method to identify a pattern of amino acid conservation as well as a shift in amino acid occurrence between homeotherms (warm-blooded species) and poikilotherms (cold-blooded species). Importantly, this general analysis and a specific example further establish a correlation, if not likely connection between the thermoadaptation of protein sequences and two of their physical features: a possible change in their protein dynamics and, even more strongly, in their solvation. For poikilotherms, such as frog and fish, the lower body temperature is expected to increase the association of proteins due to a decrease in protein internal dynamics. In order to prevent overly-sticky protein association at low temperatures, the use of amino acids suggests that poikilotherms enhance the solvation of their proteins by favoring polar groups on their proteins surface. This feature appears to dominate over possible changes in dynamics. The results suggest that a general trend for amino acid choice is part of the mechanism for thermoadaptation of vertebrate organisms at the molecular level.

category: biophysics


title: C/EBPB-dependent Adaptation to Palmitic Acid Promotes Stemness in Hormone Receptor Negative Breast Cancer

abstract:
Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network.

SignificanceCellular adaptation to obesity-induced palmitic acid drives tumor initiation through activation of a C/EBPB-dependent transcriptional network. This highlights a cell-autonomous mechanistic connection between obesity and postmenopausal hormone receptor negative breast cancer.

category: cancer biology


title: Jasmonic Acid coordinates with Light, Glucose and Auxin signalling in Regulating Branching Angle of Arabidopsis Lateral Roots

abstract: The role of jasmonates (JAs) in primary root growth and development and in plant response to external stimuli is already known. However, its role in lateral root (LR) development remains to be explored. Our work identified methyl jasmonate (MeJA) as a key phytohormone in determining the branching angle of Arabidopsis LRs. MeJA inclines the LRs to a more vertical orientation, which was dependent on the canonical JAR1-COI1-MYC2, 3, 4 signalling. Our work also highlights the dual roles of light in governing LR angle. Light signalling enhances JA biosynthesis, leading to erect root architecture; whereas, glucose (Glc) induces wider branching angles. Combining physiological and molecular assays, we revealed that Glc antagonizes the MeJA response via TARGET OF RAPAMYCIN (TOR) signalling. Moreover, physiological assays using auxin mutants, MYC2-mediated transcriptional activation of LAZY2, LAZY4 and auxin biosynthetic gene CYP79B2, and asymmetric distribution of DR5::GFP and PIN2::GFP pinpointed the role of an intact auxin mechanism required by MeJA for vertical growth of LRs. We also demonstrated that light perception and signalling are indispensable for inducing vertical angles by MeJA. Thus, our investigation highlights antagonism between light and Glc signalling and how they interact with JA-auxin signals to optimize the branching angle of LRs.

category: plant biology


title: Mycobacterium tuberculosis SufR Responds to Nitric oxide via its 4Fe-4S cluster and Regulates Fe-S cluster Biogenesis for Persistence in Mice

abstract:
The persistence of Mycobacterium tuberculosis (Mtb) is a major problem in managing tuberculosis (TB). Host-generated nitric oxide (NO) is perceived as one of the signals by Mtb to reprogram metabolism and respiration for persistence. However, the mechanisms involved in NO sensing and reorganizing Mtbs physiology are not fully understood. Since NO damages Fe-S clusters of essential enzymes, the mechanism(s) involved in regulating iron-sulfur (Fe-S) cluster biogenesis could help Mtb persist in host tissues. Here, we show that a transcription factor SufR (Rv1460) senses NO via its 4Fe-4S cluster and promotes persistence of Mtb by mobilizing the Fe-S cluster biogenesis system; suf operon (Rv1460-Rv1466). Analysis of anaerobically purified SufR by UV-visible spectroscopy, circular dichroism, and iron-sulfide estimation confirms the presence of a 4Fe-4S cluster. Atmospheric O2 and H2O2 gradually degrade the 4Fe-4S cluster of SufR. Furthermore, electron paramagnetic resonance (EPR) analysis demonstrates that NO directly targets SufR 4Fe-4S cluster by forming a protein-bound dinitrosyl-iron-dithiol complex. DNase I footprinting, gel-shift, and in vitro transcription assays confirm that SufR directly regulates the expression of the suf operon in response to NO. Consistent with this, RNA- sequencing of Mtb{Delta}sufR demonstrates deregulation of the suf operon under NO stress. Strikingly, NO inflicted irreversible damage upon Fe-S clusters to exhaust respiratory and redox buffering capacity of Mtb {Delta}sufR. Lastly, Mtb{Delta} sufR failed to recover from a NO-induced non-growing state and displayed persistence defect inside immune-activated macrophages and murine lungs in a NO-dependent manner. Data suggest that SufR is a sensor of NO that supports persistence by reprogramming Fe-S cluster metabolism and bioenergetics.

HighlightsO_LIMycobacterium tuberculosis (Mtb) induces the expression of suf operon for Fe-S cluster biogenesis in response to nitric oxide (NO).
C_LIO_LIWe found that a transcription factor SufR senses NO via its 4Fe-4S cluster and regulates the expression of the suf operon for Fe-S cluster biogenesis.
C_LIO_LISufR-regulated Fe-S cluster biogenesis confers respiratory and redox features that promote recovery of Mtb from NO stress.
C_LIO_LISufR activity is required to support the NO-dependent persistence of Mtb in macrophages and mice.
C_LI


title: Dengue emergence in the temperate Argentinian province of Santa Fe, 2009-2020.

abstract: Dengue virus (DENV) transmission occurs primarily in tropical and subtropical climates, but within the last decade it has extended to temperate regions. Santa Fe, a temperate province in Argentina, has experienced an increase in dengue cases and virus circulation since 2009, with the recent 2020 outbreak being the largest in the province to date. The aim of this work is to describe spatio-temporal fluctuations of dengue cases from 2009 to 2020 in Santa Fe Province. The data presented in this work provide a detailed description of DENV transmission for Santa Fe Province by department. These data are useful to assist in investigating drivers of dengue emergence in Santa Fe Province and for developing a better understanding of the drivers and the impacts of ongoing dengue emergence in temperate regions across the world. This work provides data useful for future studies including those investigating socio-ecological, climate, and environmental factors associated with DENV transmission, as well as those investigating other variables related to the biology and the ecology of vector-borne diseases.


title: Co-evolutionary signals from Burkholderia pseudomallei genomics identify its survival strategies and highlight improving environmental health as prevention policy

abstract:
BackgroundThe soil bacterium Burkholderia pseudomallei is the causative agent of melioidosis. It kills up to 40% of cases and contributes to human morbidity and mortality in many tropical and sub-tropical countries. As no vaccines are currently available, prevention is the key health policy and is achieved by avoiding direct contact with soil and standing water. The pathogen notoriously persists in ranges of environmental conditions which make disease prevention difficult. We aimed to scan B. pseudomallei genomes for signals of evolutionary adaptations that allow it to thrive across environmental conditions, which should ultimately inform prevention policy.

MethodsWe conducted three layers of analyses: a genome-wide epistasis and co-selection study (GWES) on 2,011 B. pseudomallei genomes to detect signals of co-selection; gene expression analyses across 82 diverse physical, chemical, biological and infectious conditions to identify specific conditions in which such selection might have acted; and gene knockout assays to confirm the function of the co-selection hotspot.

FindingsWe uncovered 13,061 mutation pairs in distinct genes and non-coding RNA that have been repeatedly co-selected through B. pseudomallei evolution. Genes under co-selection displayed marked expression correlation when B. pseudomallei was subjected to physical stress conditions including temperature stress, osmotic stress, UV radiation, and nutrient deprivation; highlighting these conditions as the major evolutionary driving forces for this bacterium. We identified a putative adhesin (BPSL1661) as a hub of co-selection signals, experimentally confirmed the role of BPSL1661 under nutrient deprivation, and explored the functional basis of the co-selection gene network surrounding BPSL1661 in facilitating bacterial survival under nutrient depletion.

InterpretationOur findings suggest that B. pseudomallei has a selective advantage to survive nutrient-limited conditions. Anthropogenic activities such as shifting cultivation systems with more frequent rotations of cropping and shortened fallow periods or continuous cultivation of cash crops could directly or indirectly contribute to loss of soil nutrient; these may lead to the preferential survival of B. pseudomallei and a subsequent rise of melioidosis. Successful disease control for melioidosis needs to consider improving environmental health in addition to current preventive efforts.

FundingWellcome Trust, European Research Council, UK Department of Health, Thailand Research Fund and Khon Kaen University

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed with terms (co-selection AND bacteria AND population) with no date or language restrictions from database inception until April 11, 2021. We identified 44 publications of which four were conducted at a genome-wide scale. These four studies were performed on human-restricted pathogens, detected co-selection of antibiotic resistance gene networks which highlight the use of antibiotics as major selection pressures and further inform treatment options. However, none of these studies were performed on Burkholderia pseudomallei or other opportunistic pathogens that have been adapted to both natural and host environments. The selection pressures exerted on these pathogens and the genetic determinants allowed for their adaptations remain unclear, which limit our understanding on the bacterial biology and the information used for disease control.

Added value of this studyBased on genomes of 2,011 B. pseudomallei collected from melioidosis endemic areas, we identified and confirmed genetic signals for co-selection. Using transcriptome profiling covering a broad spectrum of conditions and exposures, we showed that genes under co-selection displayed marked expression correlation under physical stress conditions with the gene at the co-selection hotspot conditionally expressed under nutrient starvation. Furthermore, we experimentally validated the function of the hotspot gene and demonstrated that unlike host-restricted pathogens, the B. pseudomallei co-selection network does not facilitate host infection but is focused on bacterial survival in a harsh environment, particularly under nutrient depletion. Aside from providing a data resource, the study also showcases the power of combined genetics, transcriptomics and functional analysis as a tool for biology discovery.

Implications of all available evidenceOur findings provide evolutionary and biological evidence for preferential survival of B. pseudomallei under nutrient starvation. Agricultural practice that induces soil loss, which is not uncommon in melioidosis endemic areas has been linked to soil nutrient depletion and may contribute to the prevalence of B. pseudomallei and a consequent rise of melioidosis in these regions. Successful melioidosis control has to consider environmental health in addition to existing prevention policy.


title: Perceptual difficulty modulates the direction of information flow in familiar face recognition

abstract: Humans are fast and accurate when they recognize familiar faces. Previous neurophysiological studies have shown enhanced representations for the dichotomy of familiar vs. unfamiliar faces. As familiarity is a spectrum, however, any neural correlate should reflect graded representations for more vs. less familiar faces along the spectrum. By systematically varying familiarity across stimuli, we show a neural familiarity spectrum using electroencephalography. We then evaluated the spatiotemporal dynamics of familiar face recognition across the brain. Specifically, we developed a novel informational connectivity method to test whether peri-frontal brain areas contribute to familiar face recognition. Results showed that feed-forward flow dominates for the most familiar faces and top-down flow was only dominant when sensory evidence was insufficient to support face recognition. These results demonstrate that perceptual difficulty and the level of familiarity influence the neural representation of familiar faces and the degree to which peri-frontal neural networks contribute to familiar face recognition.


title: Investigating molecular mechanisms of 2A-stimulated ribosomal pausing and frameshifting in Theilovirus

abstract: The 2A protein of Theilers murine encephalomyelitis virus (TMEV) acts as a switch to stimulate programmed -1 ribosomal frameshifting (PRF) during infection. Here we present the X-ray crystal structure of TMEV 2A and define how it recognises the stimulatory RNA element. We demonstrate a critical role for bases upstream of the originally predicted stem-loop, providing evidence for a pseudoknot-like conformation and suggesting that the recognition of this pseudoknot by beta-shell proteins is a conserved feature in cardioviruses. Through examination of PRF in TMEV-infected cells by ribosome profiling, we identify a series of ribosomal pauses around the site of PRF induced by the 2A-pseudoknot complex. Careful normalisation of ribosomal profiling data with a 2A knockout virus facilitated the identification, through disome analysis, of ribosome stacking at the TMEV frameshifting signal. These experiments provide unparalleled detail of the molecular mechanisms underpinning Theilovirus protein-stimulated frameshifting.

category: molecular biology


title: Structural and molecular basis for Cardiovirus 2A protein as a viral gene expression switch

abstract: Programmed -1 ribosomal frameshifting (PRF) in cardioviruses is activated by the 2A protein: a multi-functional virulence factor that also inhibits cap-dependent translational initiation. Here we present the X-ray crystal structure of 2A and show that it selectively binds to and stabilises the PRF stimulatory RNA element in the viral genome. Using optical tweezers, we define the conformational repertoire of this element and measure changes in unfolding pathways arising from mutation and 2A binding. Next, we demonstrate a strong interaction between 2A and the small ribosomal subunit and present a cryo-EM structure of 2A bound to initiated 70S ribosomes. Multiple copies of 2A bind to the 16S rRNA where they may compete for binding with initiation and elongation factors. Together, these results define the structural basis for RNA recognition by 2A, expand our understanding of the 2A-dependent gene expression switch and reveal how 2A accumulation may shut down translation during virus infection.


title: Targeting KRAS-mutant stomach/colorectal tumours by disrupting the ERK2-p53 complex

abstract: KRAS is widely mutated in human cancers, resulting in nearly unchecked tumour proliferation and metastasis. No therapies have been developed for targeting KRAS-mutant tumours. Herein, we observed that mutant KRAS specifically promoted the formation of ERK2-p53 complex in stomach/colorectal tumour cells. Disruption of this complex by applying MEK1/2 and ERK2 inhibitors elicits strong apoptotic responses in a p53-dependent manner, validated by genome-wide knockout screening. Mechanistically, p53 physically associates with phosphorylated ERK2 through the hydrophobic interaction in the presence of mutant KRAS, which suppresses p53 activation by preventing the recruitment of p300/CBP; trametinib disrupts the ERK2-p53 complex by reducing ERK2 phosphorylation, allowing the acetylation of p53 protein by recruiting p300/CBP; acetylated p53 activates PUMA transcription and thereby kills KRAS-mutant tumours. Our study unveils an important role of the ERK2-p53 complex and provides a potential therapeutic strategy for treating KRAS-mutant cancer via ERK2 inhibition.


title: Heat-treated virus inactivation rate depends strongly on treatment procedure: illustration with SARS-CoV-2

abstract:
Decontamination helps limit environmental transmission of infectious agents. It is required for the safe re-use of contaminated medical, laboratory and personal protective equipment, and for the safe handling of biological samples. Heat treatment is a common decontamination method, notably used for viruses. We show that for liquid specimens (here, solution of SARS-CoV-2 in cell culture medium), virus inactivation rate under heat treatment at 70{degrees}C can vary by almost two orders of magnitude depending on the treatment procedure, from a half-life of 0.86 min (95% credible interval: [0.09, 1.77]) in closed vials in a heat block to 37.00 min ([12.65, 869.82]) in uncovered plates in a dry oven. These findings suggest a critical role of evaporation in virus inactivation via dry heat. Placing samples in open or uncovered containers may dramatically reduce the speed and efficacy of heat treatment for virus inactivation. Given these findings, we reviewed the literature temperature-dependent coronavirus stability and found that specimen containers, and whether they are closed, covered, or uncovered, are rarely reported in the scientific literature. Heat-treatment procedures must be fully specified when reporting experimental studies to facilitate result interpretation and reproducibility, and must be carefully considered when developing decontamination guidelines.

ImportanceHeat is a powerful weapon against most infectious agents. It is widely used for decontamination of medical, laboratory and personal protective equipment, and for biological samples. There are many methods of heat treatment, and methodological details can affect speed and efficacy of decontamination. We applied four different heat-treatment procedures to liquid specimens containing SARS-CoV-2. Our results show that the container used to store specimens during decontamination can substantially affect inactivation rate: for a given initial level of contamination, decontamination time can vary from a few minutes in closed vials to several hours in uncovered plates. Reviewing the literature, we found that container choices and heat treatment methods are only rarely reported explicitly in methods sections. Our study shows that careful consideration of heat-treatment procedure -- in particular the choice of specimen container, and whether it is covered -- can make results more consistent across studies, improve decontamination practice, and provide insight into the mechanisms of virus inactivation.


title: Why are rare variants hard to impute? Coalescent models reveal theoretical limits in existing algorithms.

abstract: Genotype imputation is an indispensable step in human genetic studies. Large reference panels with deeply sequenced genomes now allow interrogating variants with minor allele frequency < 1% without sequencing. While it is critical to consider limits of this approach, imputation methods for rare variants have only done so empirically; the theoretical basis of their imputation accuracy has not been explored. To provide theoretical consideration of imputation accuracy under the current imputation framework, we develop a coalescent model of imputing rare variants, leveraging the joint genealogy of the sample to be imputed and reference individuals. We show that broadly used imputation algorithms includes model misspecifications about this joint genealogy that limit the ability to correctly impute rare variants. We develop closed-form solutions for the probability distribution of this joint genealogy and quantify the inevitable error rate resulting from the model misspecification across a range of allele frequencies and reference sample sizes. We show that the probability of a falsely imputed minor allele decreases with reference sample size, but the proportion of falsely imputed minor alleles mostly depends on the allele count in the reference sample. We summarize the impact of this error on genotype imputation on association tests by calculating the r2 between imputed and true genotype and show that even when modeling other sources of error, the impact of the model misspecification have a significant impact on the r2 of rare variants. To evaluate these predictions in practice, we compare the imputation of the same dataset across imputation panels of different sizes. While this empirical imputation accuracy is substantially lower than our theoretical prediction, modeling misspecification seems to further decrease imputation accuracy for variants with low allele counts in the reference. These results provide a framework for developing new imputation algorithms and for interpreting rare variant association analyses.

category: genetics


title: The Contributions from the Progenitor Genomes of the Mesopolyploid Brassiceae are Evolutionarily Distinct but Functionally Compatible

abstract: The members of the tribe Brassiceae share a whole genome triplication (WGT), and one proposed model for its formation is a "two-step" pair of hybridizations producing hexaploid descendants. However, evidence for this model is incomplete, and the evolutionary and functional constraints that drove evolution after the hexaploidy are even less understood. Here we report a new genome sequence of Crambe hispanica, a species sister to most sequenced Brassiceae. Using this new genome and three others that share the hexaploidy, we traced the history of gene loss after the WGT using POInT (the Polyploidy Orthology Inference Tool). We confirm the two-step formation model and infer that there was a significant temporal gap between those two allopolyploidizations, with about a third of the gene losses from the first two subgenomes occurring prior to the arrival of the third. We also, for the 90,000 individual genes in our study, make parental "subgenome" assignments, inferring, with measured uncertainty, which of the progenitor genomes of the allohexaploidy each gene derives from. We further show that each subgenome has a statistically distinguishable rate of homoeolog losses. There is little indication of functional distinction between the three subgenomes: the individual subgenomes show no patterns of functional enrichment, no excess of shared protein-protein or metabolic interactions between their members, and no biases in their likelihood of having experienced a recent selective sweep. We propose a "mix and match" model of allopolyploidy, where subgenome origin drives homoeolog loss propensities but where genes from different subgenomes function together without difficulty.

category: genomics


title: The contributions from the progenitor genomes of the mesopolyploid Brassiceae are evolutionarily distinct but functionally compatible


title: Highly-parallel microfluidics-based force spectroscopy on single cytoskeletal motors

abstract: Cytoskeletal motors transform chemical energy into mechanical work to drive essential cellular functions. Optical trapping experiments have provided crucial insights into the operation of these molecular machines under load. However, the throughput of such force spectroscopy experiments is typically limited to one measurement at a time. Here, we introduce a highly-parallel, microfluidics-based method that allows for rapid collection of force-dependent motility parameters of cytoskeletal motors with two orders of magnitude improvement in throughput compared to currently available methods. We apply tunable hydrodynamic forces to stepping kinesin-1 motors via DNA-tethered beads and utilize a large field of view to simultaneously track the velocities, run lengths and interaction times of hundreds of individual kinesin-1 molecules under varying resisting and assisting loads. Importantly, the 16-m long DNA tethers between the motors and the beads significantly reduces the vertical component of the applied force pulling the motors away from the microtubule. Our approach is readily applicable to other molecular systems and constitutes a new methodology for parallelized single-molecule force studies on cytoskeletal motors.


title: Individual heterogeneity and its importance for metapopulation dynamics.

abstract:
Landscape connectedness shapes the exchange of individuals among patches, and hence metapopulation connectivity and dynamics. Connectedness, and its resulting effects on connectivity are therefore rightfully central in conservation biology. However, besides determining demographic fluxes of individuals between patches, connectedness also generates phenotypic sorting and thus impacts local and regional eco-evolutionary dynamics. Despite the central role of connectedness, its effects on individual phenotypic heterogeneity and spatial organization are so far neglected in theory and applications.

Through experimental metapopulations of Tetranychus urticae (two-spotted spider mite) with three levels of landscape connectedness and by regularly removing phenotypic structure in a subset of these populations, we tested how regional and local population dynamics are determined both by network connectedness and phenotypic spatial organization.

We find that the self-organizing phenotypic spatial structure increases local equilibrium population sizes and variability. It in contrast dampens the effects of imposed connectedness differences on population sizes and is therefore anticipated to improve metapopulation persistence. Contrary to theoretical expectations, the most locally connected patches within the network showed an overall reduced local population size, possibly originating from a faster depletion of resources from immigrants or transiting individuals.

This experiment shows how metapopulation dynamics can significantly deviate from theoretical expectations due to individual heterogeneity. This potential rescue effect stemming from phenotypical self-organization in space is a key point to consider for conservation actions, especially based on translocations.


title: Adolescent Alcohol Binge-Drinking compromises behaviors during adulthood without triggering neuroinflammation

abstract: Adolescence is a developmental period characterized by significant changes in brain architecture and behavior. The immaturity of the adolescent brain is associated with heightened vulnerability to exogenous agents, including alcohol. Alcohol is the most consumed drug among teenagers, and binge-drinking during adolescence is a major public health concern. Studies have suggested that adolescent alcohol exposure (AAE) may interfere with the maturation of frontal brain regions and lead to long-lasting behavioral consequences. In this study, we used a mouse model of AAE in which adolescent mice reach high blood alcohol concentration after voluntary binge-drinking. In order to assess short- and long-term consequences of AAE, a battery of behavioral tests was performed during late adolescence and during adulthood. We showed that AAE had no short-term effect on young mice behavior but rather increased anxiety- and depressive-like behaviors, as well as alcohol consumption during adulthood. Moreover, alcohol binge-drinking during adolescence dramatically decreased recognition memory performances and behavioral flexibility in both adult males and females. Furthermore, we showed that voluntary consumption of alcohol during adolescence did not trigger any major activation of the innate immune system in the prefrontal cortex (PFC). Together, our data suggest that voluntary alcohol binge-drinking in adolescent mice induces a delayed appearance of behavioral impairments in adulthood.

category: animal behavior and cognition


title: Adolescent Alcohol Binge-Drinking induces delayed appearance of behavioral defects in mice


title: Red deer Cervus elaphus blink more in larger groups

abstract: Most animals need to spend time being vigilant for predators, at the expense of other activities such as foraging. Group-living animals can benefit from the shared vigilance effort of other group members, with individuals reducing personal vigilance effort as group size increases. Behaviours like active scanning or head lifting are usually used to quantify vigilance, but may not be accurate measures as the individual could be conducting them for other purposes. We suggest that measuring an animals blinking rate gives a meaningful measure of vigilance: increased blinking implies reduced vigilance, as the animal cannot detect predators when its eyes are closed. We demonstrate that as group size increases in red deer, individuals increase their blink rate, confirming the prediction that vigilance should decrease. Blinking is a simple non-invasive measure, and offers a useful metric for assessing the welfare of animals experiencing an increase in perceived predation risk or other stressors.


title: The sex-specific VC neurons are mechanically activated motor neurons that facilitate serotonin-induced egg laying in C. elegans

abstract:
Successful execution of behavior requires coordinated activity and communication between multiple cell types. Studies using the relatively simple neural circuits of invertebrates have helped to uncover how conserved molecular and cellular signaling events shape animal behavior. To understand the mechanisms underlying neural circuit activity and behavior, we have been studying a simple circuit that drives egg-laying behavior in the nematode worm C. elegans. Here we show that the sex-specific, Ventral C (VC) motor neurons are important for vulval muscle contractility and egg laying in response to serotonin. Ca2+ imaging experiments show the VCs are active during times of vulval muscle contraction and vulval opening, and optogenetic stimulation of the VCs promotes vulval muscle Ca2+ activity. Blocking VC neurotransmission inhibits egg laying in response to serotonin and increases the failure rate of egg-laying attempts, indicating that VC signaling facilitates full vulval muscle contraction and opening of the vulva for efficient egg laying. We also find the VCs are mechanically activated in response to vulval opening. Optogenetic stimulation of the vulval muscles is sufficient to drive VC Ca2+ activity and requires muscle contractility, showing the presynaptic VCs and the postsynaptic vulval muscles can mutually excite each other. Together, our results demonstrate that the VC neurons facilitate efficient execution of egg-laying behavior by coordinating postsynaptic muscle contractility in response to serotonin and mechanosensory feedback.

Significance StatementMany animal motor behaviors are modulated by the neurotransmitters serotonin and acetylcholine. Such motor circuits also respond to mechanosensory feedback, but how neurotransmitters and mechanoreceptors work together to coordinate behavior is not well understood. We address these questions using the egg-laying circuit in C. elegans where we can manipulate presynaptic neuron and postsynaptic muscle activity in behaving animals while recording circuit responses through Ca2+ imaging. We find that the cholinergic VC motoneurons are important for proper vulval muscle contractility and egg laying in response to serotonin. Muscle contraction also activates the VCs, forming a positive feedback loop that promotes full contraction for egg release. In all, mechanosensory feedback provides a parallel form of modulation that shapes circuit responses to neurotransmitters.


title: Convolutional neural networks do not develop brain-like transformation tolerant visual representations

abstract:
Forming transformation-tolerant object representations is critical to high-level primate vision. Despite its significance, many details of tolerance in the human brain remain unknown. Likewise, despite the ability of convolutional neural networks (CNNs) to exhibit human-like object categorization performance, whether CNNs form tolerance similar to that of the human brain is unknown. Here we provide the first comprehensive documentation and comparison of three tolerance measures in the human brain and CNNs. We measured fMRI responses from human ventral visual areas to real-world objects across both Euclidean and non-Euclidean feature changes. In single fMRI voxels in higher visual areas, we observed robust object response rank-order preservation across feature changes. This is indicative of functional smoothness in tolerance at the fMRI meso-scale level that has never been reported before. At the voxel population level, we found highly consistent object representational structure across feature changes towards the end of ventral processing. Rank-order preservation, consistency, and a third tolerance measure, cross-decoding success (i.e., a linear classifiers ability to generalize performance across feature changes) showed an overall tight coupling. These tolerance measures were lower for Euclidean than non-Euclidean feature changes in lower visual areas, but increased over the course of ventral processing in most cases. These characteristics of tolerance, however, were absent in eight CNNs pretrained with ImageNet images with varying network architecture, depth, the presence/absence of recurrent processing, or whether a network was pretrained with the original or stylized ImageNet images that encouraged shape processing. Most notably, CNNs do not show increased representational consistency across feature changes at the higher layers. CNNs thus do not appear to develop the same kind of tolerance as the human brain over the course of visual processing.

Significant StatementPerceiving object identity among changes in non-identity features and forming transformation-tolerant object representations is essential to high-level primate vision. Here we provide a comprehensive documentation and comparison of three tolerance measures between the human brain and CNNs pretrained for object classification. While all three measures show increased tolerance in the human brain across four types of feature changes towards the end of ventral visual processing, CNNs fail to develop the same kind of tolerance with visual processing.


title: Understanding transformation tolerant visual object representations in the human brain and convolutional neural networks


title: A flexible Bayesian framework for unbiased estimation of timescales

abstract: Timescales characterize the pace of change for many dynamic processes in nature. Timescales are usually estimated by fitting the exponential decay of data autocorrelation in the time or frequency domain. We show that this standard procedure often fails to recover the correct timescales due to a statistical bias arising from the finite sample size. We develop an alternative approach to estimating timescales by fitting the sample autocorrelation or power spectrum with a generative model based on a mixture of Ornstein-Uhlenbeck processes using adaptive Approximate Bayesian Computations. Our method accounts for finite sample size and noise in data and returns a posterior distribution of timescales that quantifies the estimation uncertainty and can be used for model selection. We demonstrate the accuracy of our method on synthetic data and illustrate its application to recordings from the primate cortex. We provide a customizable Python package implementing our framework with different generative models suitable for diverse applications.


title: Two pathways drive meiotic chromosome axis assembly in Saccharomyces cerevisiae

abstract: Successful meiotic recombination, and thus fertility, depends on conserved axis proteins that organize chromosomes into arrays of anchored chromatin loops and provide a protected environment for DNA exchange. Here, we show that the stereotypic chromosomal distribution of axis proteins in S. cerevisiae is the additive result of two independent pathways: a cohesin-dependent pathway, which was previously identified and mediates focal enrichment of axis proteins at gene ends, and a parallel cohesin-independent pathway that recruits axis proteins to broad genomic islands with high gene density. These islands exhibit elevated markers of crossover recombination as well as increased nucleosome density, which we show is a direct consequence of the underlying DNA sequence. A predicted PHD domain in the center of the axis factor Hop1 specifically mediates cohesin-independent axis recruitment. Intriguingly, other chromosome organizers, including cohesin, condensin, and topoisomerases, are differentially depleted from the same regions even in non-meiotic cells, indicating that these DNA sequence-defined chromatin islands exert a general influence on the patterning of chromosome structure.


title: Integrative inference of transcriptional networks in Arabidopsis yields novel ROS signalling regulators

abstract: Gene regulation is a dynamic process in which transcription factors (TFs) play an important role to control spatiotemporal gene expression. While gene regulatory networks describe the interactions between TFs and their target genes, our global knowledge about the complexity of TF control for different genes and biological processes is incomplete. To enhance our global understanding of regulatory interactions in Arabidopsis thaliana, different regulatory input networks capturing complementary information about DNA motifs, open chromatin, TF binding and expression-based regulatory interactions, were combined using a supervised learning approach, resulting in an integrated gene regulatory network (iGRN) covering 1,491 TFs and 31,393 target genes (1.7 million interactions). This iGRN outperforms the different input networks to predict known regulatory interactions and has a similar performance to recover functional interactions compared to state-of-the-art experimental methods like yeast one-hybrid and ChIP-seq. The iGRN correctly inferred known functions for 681 TFs and predicted new gene functions for hundreds of unknown TFs. For regulators predicted to be involved in reactive oxygen species stress regulation, we confirmed in total 75% of TFs with a function in ROS and/or physiological stress responses. This includes 13 novel ROS regulators, previously not connected to any ROS or stress function, that were experimentally validated in our ROS-specific phenotypic assays of loss- or gain-of-function lines. In conclusion, the presented iGRN offers a high-quality starting point to enhance our understanding of gene regulation in plants by integrating different experimental data types at the network level.


title: Deep and superficial layers of the primary somatosensory cortex are critical for whisker-based texture discrimination in mice

abstract:
The neocortex, comprised of multiple distinct layers, processes sensory input from the periphery, makes decisions, and executes actions. Despite extensive investigation of cortical anatomy and physiology, the contributions of different cortical layers to sensory guided behaviors remain unknown. Here, we developed a two-alternative forced choice (2AFC) paradigm in which head-fixed mice use a single whisker to either discriminate textures of parametrically varied roughness or detect the same textured surfaces. Lesioning the barrel cortex revealed that 2AFC texture discrimination, but not detection, was cortex-dependent. Paralyzing the whisker pad had little effect on performance, demonstrating that passive can rival active perception and cortical dependence is not movement-related. Transgenic Cre lines were used to target inhibitory opsins to excitatory cortical neurons of specific layers for selective perturbations. Both deep and superficial layers were critical for texture discrimination. We conclude that even basic cortical computations require coordinated transformation of sensory information across layers.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/245381v2_ufig1.gif" ALT="Figure 1">
View larger version (22K):
org.highwire.dtl.DTLVardef@16c4d20org.highwire.dtl.DTLVardef@13b8832org.highwire.dtl.DTLVardef@16ac3aborg.highwire.dtl.DTLVardef@5426d8_HPS_FORMAT_FIGEXP  M_FIG C_FIG


title: Four new Scopalina from Southern California: the first Scopalinida (Porifera: Demospongiae) from the temperate Eastern Pacific

abstract: Sponges (phylum Porifera) are common inhabitants of kelp forest ecosystems in California, but their diversity and ecological importance are poorly characterized in this biome. Here I use freshly collected samples to describe the diversity of the order Scopalinida in California. Though previously unknown in the region, four new species are described here: Scopalina nausicae sp. nov., S. kuyamu sp. nov., S. goletensis sp. nov., and S. jali sp. nov.. These discoveries illustrate the considerable uncharacterized sponge diversity remaining in California kelp forests, and the utility of SCUBA-based collection to improve our understanding of this diversity.

category: zoology


title: Deletion of the voltage-gated calcium channel, CaV1.3, causes deficits in motor performance and associative learning

abstract: L-type voltage-gated calcium channels are important regulators of neuronal activity and are widely expressed throughout the brain. One of the major L-type voltage-gated calcium channel isoforms in the brain is CaV1.3. Mice lacking CaV1.3 are reported to have impairments in fear conditioning and depressive-like behaviors, which have been linked to CaV1.3 function in the hippocampus and amygdala. Genetic variation in CaV1.3 has been linked to a variety of psychiatric disorders, including autism and schizophrenia, which are associated with altered motor learning, associative learning, and social function. Here, we explored whether CaV1.3 plays a role in these behaviors. We found that CaV1.3 knockout mice have deficits in rotarod learning despite normal locomotor function. Deletion of CaV1.3 is also associated with impaired gait adaptation and associative learning on the Erasmus Ladder. We did not observe any impairments in CaV1.3 knockout mice on assays of anxiety-like, depression-like, or social preference behaviors. Our results suggest an important role for CaV1.3 in neural circuits involved in motor learning and concur with previous data showing its involvement in associative learning.


title: Interhemispheric transfer of working memories

abstract: Visual working memory (WM) storage is largely independent between the left and right visual hemifields/cerebral hemispheres, yet somehow WM feels seamless. We studied how WM is integrated across hemifields by recording neural activity bilaterally from lateral prefrontal cortex. An instructed saccade during the WM delay shifted the remembered location from one hemifield to the other. Before the shift, spike rates and oscillatory power showed clear signatures of memory laterality. After the shift, the lateralization inverted, consistent with transfer of the memory trace from one hemisphere to the other. Transferred traces initially used different neural ensembles from feedforward-induced ones but they converged at the end of the delay. Around the time of transfer, synchrony between the two prefrontal hemispheres peaked in theta and beta frequencies, with a directionality consistent with memory trace transfer. This illustrates how dynamics between the two cortical hemispheres can stitch together WM traces across visual hemifields.


title: A dynamic gradient architecture generates brain activity states

abstract: A central goal of systems neuroscience is to determine the functional-anatomical basis of brain-wide activity dynamics. While brain activity patterns appear to be low-dimensional and guided by spatial gradients, the set of gradients remains provisional and their mode of interaction is unclear. Here we applied deep learning-based dimensionality reduction to task-free fMRI images to derive an intrinsic latent space of human brain activity. Each dimension represented a discrete, dynamically fluctuating spatial activity gradient. The principal dimension was a novel unipolar sensory-association gradient underlying the global signal. A small set of gradients appeared to underlie key functional connectomics phenomena. Different task activation patterns were generated by gradients adopting task-specific configurations. Dynamical systems modelling revealed that gradients interact via state-specific coupling parameters, allowing accurate forecasts and simulations of task-specific brain activity. Together, these findings indicate that a small set of dynamic, interacting gradients create the repertoire of possible brain activity states.


title: Src-dependent NM2A tyrosine-phosphorylation regulates actomyosin dynamics

abstract: Non-muscle myosin 2A (NM2A) is a key cytoskeletal enzyme that along with actin assembles into actomyosin filaments inside cells. NM2A is fundamental in cellular processes requiring force generation such as cell adhesion, motility and cell division, and plays important functions in different stages of development and during the progression of viral and bacterial infections. We previously identified a novel tyrosine phosphorylation on residue 158 (pTyr158) in the motor domain of NM2A. This phosphorylation is dependent on Src kinase and is promoted by Listeria monocytogenes infection of epithelial cells, however its role is unknown. Here we show that Listeriolysin O (LLO), the pore-forming toxin (PFT) secreted by L. monocytogenes, is sufficient to trigger NM2A pTyr158 by activating Src, an upstream regulator of actomyosin remodeling. We further address the role of NM2A pTyr158 on the organization and dynamics of the actomyosin cytoskeleton and find that, by controlling the activation of the NM2A, the status of the pTyr158 alters cytoskeletal organization, dynamics of focal adhesions and cell motility. In vitro, we observe that non-phosphorylatable and phospho-mimetic versions of NM2A at Tyr158 display motor and ATPase activities similar to the wild-type NM2A, which indicates that the phenotype of these mutants in cells is independent of their ability to translocate actin filaments. Importantly, we find the regulation of this phosphorylation site to be of physiological relevance in Caenorhabditis elegans, in particular in response to intoxication by a PFT and to heat shock. We conclude that the control of the phosphorylation status at NM2A Tyr158 is a conserved trait that contributes to the regulation of actomyosin dynamics and the ability of cells to respond to bacterial infection. We propose Src-dependent NM2A pTyr158 as a novel layer of regulation of the actomyosin cytoskeleton.


title: APC/CFZR-1 Controls ZYG-1 Levels to Regulate Centrosome Assembly

abstract: Aberrant centrosome numbers are associated with human cancers. The levels of centrosome regulators positively correlate with centrosome number. Thus, tight control of centrosome protein levels is critical. In Caenorhabditis elegans, the anaphase-promoting complex/cyclosome and co-activator FZR-1 (APC/CFZR-1) ubiquitin ligase negatively regulates centrosome assembly through SAS-5 degradation. In this study, we identify the C. elegans ZYG-1 (Plk4 in human) as a new substrate of APC/CFZR-1. Inhibiting APC/CFZR-1 or mutating a ZYG-1 destruction (D)-box leads to elevated ZYG-1 levels at centrosomes, restoring bipolar spindles and embryonic viability to zyg-1 mutants, suggesting that APC/CFZR-1 targets ZYG-1 for proteasomal degradation via D-box motif. We also show the Slimb/{beta}TrCP-binding (SB) motif is critical for ZYG-1 degradation, substantiating a conserved mechanism by which ZYG-1/Plk4 stability is regulated by SCFSlimb/{beta}TrCP-dependent proteolysis via the conserved SB motif in C. elegans. Furthermore, inhibiting both APC/CFZR-1 and SCFSlimb/{beta}TrCP, by co-mutating ZYG-1 SB and D-box motifs, stabilizes ZYG-1 in an additive manner, conveying that APC/CFZR-1 and SCFSlimb/{beta}TrCP ubiquitin ligases function cooperatively for timely ZYG-1 destruction in C. elegans embryos where ZYG-1 activity remains at threshold level to ensure normal centrosome number.


title: On the effect of phylogenetic correlations in coevolution-based contact prediction in proteins

abstract:
Coevolution-based contact prediction, either directly by coevolutionary couplings resulting from global statistical sequence models or using structural supervision and deep learning, has found widespread application in protein-structure prediction from sequence. However, one of the basic assumptions in global statistical modeling is that sequences form an at least approximately independent sample of an unknown probability distribution, which is to be learned from data. In the case of protein families, this assumption is obviously violated by phylogenetic relations between protein sequences. It has turned out to be notoriously difficult to take phylogenetic correlations into account in coevolutionary model learning. Here, we propose a complementary approach: we develop strategies to randomize or resample sequence data, such that conservation patterns and phylogenetic relations are preserved, while intrinsic (i.e. structure- or function-based) coevolutionary couplings are removed. A comparison between the results of Direct Coupling Analysis applied to real and to resampled data shows that the largest coevolutionary couplings, i.e. those used for contact prediction, are only weakly influenced by phylogeny. However, the phylogeny-induced spurious couplings in the resampled data are compatible in size with the first false-positive contact predictions from real data. Dissecting functional from phylogeny-induced couplings might therefore extend accurate contact predictions to the range of intermediate-size couplings.

The code is available at https://github.com/ed-rodh/Null_models_I_and_II.

Author summaryMany homologous protein families contain thousands of highly diverged amino-acid sequences, which fold into close-to-identical three-dimensional structures and fulfill almost identical biological tasks. Global coevolutionary models, like those inferred by the Direct Coupling Analysis (DCA), assume that families can be considered as samples of some unknown statistical model, and that the parameters of these models represent evolutionary constraints acting on protein sequences. To learn these models from data, DCA and related approaches have to also assume that the distinct sequences in a protein family are close to independent, while in reality they are characterized by involved hierarchical phylogenetic relationships. Here we propose Null models for sequence alignments, which maintain patterns of amino-acid conservation and phylogeny contained in the data, but destroy any coevolutionary couplings, frequently used in protein structure prediction. We find that phylogeny actually induces spurious non-zero couplings. These are, however, significantly smaller that the largest couplings derived from natural sequences, and therefore have only little influence on the first predicted contacts. However, in the range of intermediate couplings, they may lead to statistically significant effects. Dissecting phylogenetic from functional couplings might therefore extend the range of accurately predicted structural contacts down to smaller coupling strengths than those currently used.


title: Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer's disease

abstract:
A predominant trigger and driver of sporadic Alzheimers disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences has remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind A{beta}1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that A{beta}1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide the first direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.

Single sentence summaryBeta-amyloid induces brain hypometabolism, network hyperactivity, and behavioral changes via NADPH oxidase-mediated oxidative stress, suggesting a novel therapeutic target for Alzheimers disease treatment.


title: Whole-Brain Longitudinal Profiling of Serotonergic Reuptake Inhibition

abstract: The serotonergic system is widely implicated in affect regulation, and a common target for psychopharmacological interventions. Selective Serotonin Reuptake Inhibitors (SSRIs) are the foremost drug class for treating depression, as well as anxiety, phobia and other affective disorders. However, the functional mechanisms determining SSRI efficacy remain elusive, hindering the targeted further development of serotonergic system interventions. Assays for longitudinal whole-brain interrogation of the serotonergic system are unavailable, yet such techniques are essential for identifying differential intervention effects across projection areas. We present a novel longitudinal opto-fMRI assay suitable for imaging longitudinal drug treatment effects on the mouse serotonergic system -- within-subject and with sub-millimetre spatial resolution. We apply this assay to a longitudinal fluoxetine treatment, and document reliable segmentation of brain-wide treatment effects, including identification of a brainstem cluster with a highly significant longitudinal trajectory, constituting a novel neurophenotype for psychopharmacological interventions. We differentiate serotonergic neuron activation from projection area activation, and offer brain-wide fMRI evidence for the prominent autoinhibition down-regulation theory of SSRI effects. Further, we show that given the sensitivity of the assay, SSRI treatment produces no persistent effects after treatment cessation in healthy subjects.


title: Learning an efficient hippocampal place map from entorhinal inputs using non-negative sparse coding

abstract:
Cells in the entorhinal cortex (EC) contain rich spatial information and projects strongly to the hippocampus where a cognitive map is supposedly created. These cells range from cells with structured spatial selectivity, such as grid cells in the medial entorhinal cortex (MEC) that are selective to an array of spatial locations that form a hexagonal grid, to weakly spatial cells, such as non-grid cells in the MEC and lateral entorhinal cortex (LEC) that contain spatial information but have no structured spatial selectivity. However, in a small environment, place cells in the hippocampus are generally selective to a single location of the environment, while granule cells in the dentate gyrus of the hippocampus have multiple discrete firing locations but lack spatial periodicity. Given the anatomical connection from the EC to the hippocampus, how the hippocampus retrieves information from upstream EC remains unclear. Here, we propose a unified learning model that can describe the spatial tuning properties of both hippocampal place cells and dentate gyrus granule cells based on non-negative sparse coding from EC input. Sparse coding plays an important role in many cortical areas and is proposed here to have a key role in the hippocampus. Our results show that the hexagonal patterns of MEC grid cells with various orientations, grid spacings and phases are necessary for the model to learn different place cells that efficiently tile the entire spatial environment. However, if there is a lack of diversity in any grid parameters or a lack of hippocampal cells in the network, this will lead to the emergence of hippocampal cells that have multiple firing locations. More surprisingly, the model can also learn hippocampal place cells even when weakly spatial cells, instead of grid cells, are used as the input to the hippocampus. This work suggests that sparse coding may be one of the underlying organising principles for the navigational system of the brain.

Significance StatementThe brain can perform extremely complex spatial navigation tasks, but how it does this remains unclear. Here we show that the principle of sparse coding can be used to learn the hippocampal place map in a way that efficiently tiles the entire spatial environment using EC inputs, namely either grid cells or weakly spatial cells. This demonstrates that the hippocampus can retrieve spatial information from the entorhinal cortex using an efficient representation and that sparse coding may be one of the underlying principles of the navigational system of the brain.


title: Molecular architecture of the endocytic TPLATE complex

abstract:
All eukaryotic cells rely on endocytosis to regulate the plasma membrane proteome and lipidome. Most eukaryotic groups, with the exception of fungi and animals, have retained the evolutionary ancient TSET complex as a regulator of endocytosis. Despite the presence of similar building blocks in TSET, compared to other coatomer complexes, structural insight into this adaptor complex is lacking. Here, we elucidate the molecular architecture of the octameric plant TSET complex (TPLATE complex/TPC) using an integrative structural approach. This allowed us to describe a plant-specific connection between the TML subunit and the AtEH/Pan1 proteins and show a direct interaction between the complex and the plasma membrane without the need for any additional protein factors. Furthermore, we identify the appendage of TPLATE as crucial for complex assembly. Structural elucidation of this ancient adaptor complex vastly advances our functional as well as evolutionary insight into the process of endocytosis.

Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY


title: The TPLATE subunit is essential for structural assembly of the endocytic TSET complex


title: Assessment of Neurovascular Coupling & Cortical Spreading Depression in Mixed Models of Atherosclerosis & Alzheimer's Disease

abstract: Neurovascular coupling is a critical brain mechanism whereby changes to blood flow accompany localised neural activity. The breakdown of neurovascular coupling is linked to the development and progression of several neurological conditions including dementia. In this study, we examined cortical haemodynamics in preparations that modelled Alzheimers disease (J20-AD) and atherosclerosis (PCSK9-ATH) between 9-12m of age. We report novel findings with atherosclerosis where neurovascular decline is characterised by significantly reduced blood volume, levels of oxyhaemoglobin & deoxyhaemoglobin, in addition to global neuroinflammation. In the comorbid mixed model (J20-PCSK9-MIX), we report a 3x fold increase in hippocampal amyloid-beta plaques. A key finding was that cortical spreading depression (CSD) due to electrode insertion into the brain was worse in the diseased animals and led to a prolonged period of hypoxia. These findings suggest that systemic atherosclerosis can be detrimental to neurovascular health and that having cardiovascular comorbidities can exacerbate pre-existing Alzheimers-related amyloid-plaques.


title: Mitogenomic Phylogeny of Callithrix with Special Focus on Human Transferred Taxa

abstract:
Callithrix marmosets are a relatively young primate radiation, whose phylogeny is not yet fully resolved. These primates are naturally para- and allopatric, but three species with highly invasive potential have been introduced into the southeastern Brazilian Atlantic Forest by the pet trade. There, these species hybridize with each other and endangered, native congeners. We aimed here to reconstruct a robust Callithrix phylogeny and divergence time estimates, and identify the biogeographic origins of autochthonous and allochthonous Callithrix mitogenome lineages. We sequenced 49 mitogenomes from four species (C. aurita, C. geoffroyi, C. jacchus, C. penicillata) and anthropogenic hybrids (C. aurita x Callithrix sp., C. penicillata x C. jacchus, Callithrix sp. x Callithrix sp., C. penicillata x C. geoffroyi) via Sanger and whole genome sequencing. We combined these data with previously published Callithrix mitogenomes to analyze five Callithrix species in total.

ResultsWe report the complete sequence and organization of the C. aurita mitogenome. Phylogenetic analyses showed that C. aurita was the first to diverge within Callithrix 3.54 million years ago (Ma), while C. jacchus and C. penicillata lineages diverged most recently 0.5 Ma as sister clades. MtDNA clades of C. aurita, C. geoffroyi, and C. penicillata show intraspecific geographic structure, but C. penicillata clades appear polyphyletic. Hybrids, which were identified by phenotype, possessed mainly C. penicillata or C. jacchus mtDNA haplotypes. The biogeographic origins of mtDNA haplotypes from hybrid and allochthonous Callithrix were broadly distributed across natural Callithrix ranges. Our phylogenetic results also evidence introgression of C. jacchus mtDNA into C. aurita.

ConclusionOur robust Callithrix mitogenome phylogeny shows C. aurita lineages as basal and C. jacchus lineages among the most recent within Callithrix. We provide the first evidence that parental mtDNA lineages of anthropogenic hybrid and allochthonous marmosets are broadly distributed inside and outside of the Atlantic Forest. We also show evidence of cryptic hybridization between allochthonous Callithrix and autochthonous C. aurita. Our results encouragingly show that further development of genomic resources will allow to more clearly elucidate Callithrix evolutionary relationships and understand the dynamics of Callithrix anthropogenic introductions into the Brazilian Atlantic Forest.


title: Conditional resampling improves calibration and sensitivity in single cell CRISPR screen analysis

abstract: Single-cell CRISPR screens are the most promising biotechnology for mapping regulatory elements to their target genes at genome-wide scale. However, the analysis of these screens presents significant statistical challenges. For example, technical factors like sequencing depth impact not only expression measurement but also perturbation detection, creating a confounding effect. We demonstrate on two recent high multiplicity of infection single-cell CRISPR screens how these challenges cause calibration issues among existing analysis methods. To address these challenges, we propose SCEPTRE: analysis of single-cell perturbation screens via conditional re-sampling. This methodology, designed to avoid calibration issues due to technical confounders and expression model misspecification, infers associations between perturbations and expression by resampling the former according to a working model for perturbation detection probability in each cell. SCEPTRE demonstrates excellent calibration and sensitivity on the CRISPR screen data and yields hundreds of new regulatory relationships, supported by orthogonal functional evidence.


title: Molluscan dorsal-ventral patterning relying on bmp2/4 and chordin provides insights into spiralian development and bilaterian evolution

abstract: Although a conserved mechanism relying on bmp2/4 and chordin is suggested in animal dorsal-ventral (DV) patterning, this mechanism has not been reported in spiralians, one of the three major clades of bilaterians. Studies on limited spiralian representatives have suggested markedly diverse DV patterning mechanisms, a considerable amount of which no longer deploy BMP signaling. Here, we showed that bmp2/4 and chordin regulated DV patterning in the mollusk Lottia goshimai, which was predicted in spiralians but not reported before. In the context of the diverse reports in spiralians, it conversely represents a relatively unusual case. We then showed that bmp2/4 and chordin coordinated to mediate signaling from the D-quadrant organizer to induce the DV axis, among which chordin transferred breakdown-of-symmetry information. Further investigations on the L. goshimai embryos with influenced DV patterning suggested roles of BMP signaling in regulating the localization of the blastopore and the organization of the nervous system, indicating a cooption of DV patterning and the transition of these key characteristics at the origin of bilaterians. These findings provide insights into the evolution of animal DV patterning, the unique development mode of spiralians driven by the D-quadrant organizer, and the evolution of bilaterian body plans.

category: developmental biology


title: The genetic variation landscape of African swine fever virus reveals frequent positive selection and adaptive flexibility

abstract: African swine fever virus (ASFV) is a lethal disease agent that causes high mortality in swine population and devastating loss in swine industries. The development of efficacious vaccines has been hindered by the gap in knowledge concerning genetic variation of ASFV and the genetic factors involved in host adaptation and virus-host interactions. In this study, we performed a meta-genetic study of ASFV aiming to profile the variation landscape and identify genetic factors with signatures of positive selection and relevance to host adaptation. Our data reveals a high level of genetic variability of ASFV shaped by both diversifying selection and selective sweep. The selection signatures are widely distributed across the genome with the diversifying selection falling within 29 genes and selection sweep within 25 genes, highlighting strong signals of adaptive evolution of ASFV. Further examination of the sequence properties reveals the link of the selection signatures with virus-host interactions and adaptive flexibility. Specifically, we discovered a site at 157th of the key antigen protein EP402R under diversifying selection, which is located in the cytotoxic T-cell epitope related with the low level of cross-reaction in T-cell response. Importantly, two multigene families MGF360 and MGF505, the host range factors of ASFV, exhibit divergent selection among the paralogous members, conferring sequence pools for genetic diversification and adaptive capability. By integrating the genes with selection signatures into a unified framework of interactions between ASFV and hosts, we showed that the genes are involved in multiple processes of host immune interaction and virus life cycles, and may play crucial roles in circumventing host defense systems and enhancing adaptive fitness. Our findings will allow enhanced understanding of genetic basis of rapid spreading and adaptation of ASFV among the hosts.

category: evolutionary biology


title: Profiling variable-number tandem repeat variation across populations using repeat-pangenome graphs

abstract: Variable number tandem repeat sequences (VNTR) are composed of consecutive repeats of short segments of DNA with hypervariable repeat count and composition. They include protein coding sequences and associations with clinical disorders. It has been difficult to incorporate VNTR analysis in disease studies that use short-read sequencing because the traditional approach of mapping to the human reference is less effective for repetitive and divergent sequences. We solve VNTR mapping for short reads with a repeat-pangenome graph (RPGG), a data structure that encodes both the population diversity and repeat structure of VNTR loci from multiple haplotype-resolved assemblies. We developed software to build a RPGG, and use the RPGG to estimate VNTR composition with short reads. We used this to discover VNTRs with length stratified by continental population, and novel expression quantitative trait loci, indicating that RPGG analysis of VNTRs will be critical for future studies of diversity and disease.


title: Comparing spatial null models for brain maps

abstract: Technological and data sharing advances have led to a proliferation of high-resolution structural and functional maps of the brain. Modern neuroimaging research increasingly depends on identifying correspondences between the topographies of these maps; however, most standard methods for statistical inference fail to account for their spatial properties. Recently, multiple methods have been developed to generate null distributions that preserve the spatial autocorrelation of brain maps and yield more accurate statistical estimates. Here, we comprehensively assess the performance of ten published null frameworks in statistical analyses of neuroimaging data. To test the efficacy of these frameworks in situations with a known ground truth, we first apply them to a series of controlled simulations and examine the impact of data resolution and spatial autocorrelation on their family-wise error rates. Next, we use each framework with two empirical neuroimaging datasets, investigating their performance when testing (1) the correspondence between brain maps (e.g., correlating two activation maps) and (2) the spatial distribution of a feature within a partition (e.g., quantifying the specificity of an activation map within an intrinsic functional network). Finally, we investigate how differences in the implementation of these null models may impact their performance. In agreement with previous reports, we find that naive null models that do not preserve spatial autocorrelation consistently yield elevated false positive rates and unrealistically liberal statistical estimates. While spatially-constrained null models yielded more realistic, conservative estimates, even these frameworks suffer from inflated false positive rates and variable performance across analyses. Throughout our results, we observe minimal impact of parcellation and resolution on null model performance. Altogether, our findings highlight the need for continued development of statistically-rigorous methods for comparing brain maps. The present report provides a harmonised framework for benchmarking and comparing future advancements.