title: Novel plasma exosome biomarkers for prostate cancer progression in co-morbid metabolic disease

abstract: Comorbid Type-2 diabetes (T2D), a metabolic complication of obesity, associates with worse cancer outcomes for prostate, breast, head and neck, colorectal and several other solid tumors. However, the molecular mechanisms remain poorly understood. Exosomes as carriers of miRNAs in blood encode the metabolic status of the originating tissues and deliver their cargo to target tissues. We hypothesized that T2D plasma exosomes induce epithelial-mesenchymal transition (EMT) and immune checkpoints in prostate cancer cells. Here, we show that plasma exosomes from subjects with T2D induce EMT features in prostate cancer cells and upregulate the checkpoint genes CD274 and CD155. We prove that specific exosomal miRNAs abundant in T2D plasma (miR374a-5p, miR-93-5p, miR-424-5p) are delivered to tumor cells and regulate these target genes. We build on our previous reports showing BRD4 controls migration and dissemination of castration-resistant prostate cancer and transcription of key EMT genes, to show that T2D exosomes drive EMT and immune ligand expression through BRD4. The results suggest novel, non-invasive approaches to evaluate prostate cancer progression risk in patients with comorbid T2D.


title: Single-cell transcriptomics reveals varying degrees of epithelial-mesenchymal plasticity in lymph node metastasis from oral cavity squamous cell carcinoma

abstract: Oral cavity squamous cell carcinomas (OSCC) that spread to the regional lymph nodes are associated with a high degree of epithelial-mesenchymal plasticity (EMP). Here, RNA sequencing of 1,946 carcinoma and 2,175 stromal cells of an advanced metachronous OSCC lymph node metastasis revealed heterogeneity of the OSCC cells with respect to epithelial-mesenchymal transition (EMT) states, metabolic adaptations, and cell cycle. Seven cell clusters formed a branching trajectory with epithelial differentiation, partial EMT states and metabolic adaptations. Notably, partial EMT was associated with stress response, especially with HSPA upregulation, immune-modulation through CXCL14 and a higher fraction of proliferating cells, whereas epithelial differentiation correlated with higher cytokeratin and kallikrein expression. While EMP-associated transcription factors SNAI2 and ZEB1 were active in all cancer cells, TWIST1, SNAI1 and ZEB1 activity were more pronounced in the epithelial branch. Epithelial differentiating cells have less receptor-ligand interactions with stromal cells than partial EMT cells indicating a more independent regulation. Interestingly, cells in and close to the trunk of the trajectory adapt to hypoxic and hypoglycemic conditions expressing genes related to glycolytic and amino acid catabolism. Our work provides in-depth insights into phenotypic heterogeneity within an OSCC lymph node metastasis, specifically how EMP drives locoregional progression.

category: cancer biology


title: Cytocapsulae and cytocapsular tubes are golden targets for precise, effective and efficient cancer diagnosis and therapy in 307 kinds of liquid and solid cancers

abstract: Cancer is a leading cause of human lethality worldwide. A cancer cell is not only the cytoplasm and nucleus enclosed in the cell membrane. A malignant tumor is not only a mass of cancer cells. Cancer in a patient is not only isolated tumors distributed in tissues and organs. The comprehensive understanding of the complete structural compartments and their biological functions of cancer cells, malignant tumors and tumor systems in patients in vivo is an indispensable prerequisite for effective drug development and efficient clinical cancer pharmacotherapies. However, there remains an open question for a long time: what are the complete structural compartments of cancer cells, malignant tumors and tumor systems in the patient body? Here, we comprehensively and systematically investigated the complete structural compartments of cancer cells, malignant tumors and cytocapsular tube (CCT) network-tumor system (CNTS) of 307 types/subtypes of cancers in 33 kinds of tissues and organs by biochemistry and molecular biology assays with 9,811 clinical cancer tissue specimens from 9,637 cancer patients and >110,000 immunohistochemistry (IHC) fluorescence staining images. We discovered the complete structural compartments of cancer cells, malignant tumors and CNTSs in 307 kinds of cancers, elucidated mechanisms of cytocapsular growth and CCT elongation, and identified the comprehensive procedures of cancer evolution in patients. This study paves avenues for curing all kinds of cancers.


title: Peptide-based drug predictions for cancer therapy using deep learning

abstract:
BackgroundTherapeutic drugs used in cancer treatment have ineffectiveness and resistance to drug action problems. Anticancer peptides (ACPs) are selective and toxic to cancer cells and quickly produced. Thus, ACPs can be a satisfactory substitute for therapeutic drugs. We developed AI4ACP, a user-friendly web-server ACP predictor that can predict the anticancer property of query peptides, thus promoting the discovery of peptides with anticancer activity.

ResultOur results revealed that the performance of our ACP predictor trained using the new ACP collection was superior to that of the available high-performance ACP predictors.

ConclusionsAI4ACP is a user-friendly web-server ACP predictor that can be used to determine whether a query sequence is an ACP. This tool can be beneficial for drug development for cancer treatment. AI4ACP is freely accessible at https://axp.iis.sinica.edu.tw/AI4ACP/


title: Canonical BMP2/4 signaling degrades SOX2 in glioblastoma propagating cells.

abstract: The effect of Bone Morphogenetic Proteins (BMPs) on glioblastoma propagation cells (GPCs) is being debated [1-5]. We observed that exposure of GPCs to BMP2/4 initiates a rapid proteasomal degradation of the pluripotency factor SOX2 followed by the differentiation of GPCs into glial cells using 5 primary human glioblastoma lines tested. Enforced expression of SOX2 in GPCs antagonized BMP2/4-induced gliogenesis and reduction of proliferation. Both outcomes are consistent with the role of SOX2 in normal neurogenesis [6-8]. Using gene expression analysis, we observed that level of SOX2 in different glioblastoma lines tracks with the levels of oncogenes H/K/N-RAS and OLIG2. Our work provides support for BMP2/4-SOX2 axis in GPCs and points to the proteasome-regulated degradation of SOX2 that initiates glycogenic differentiation similar to that observed during normal development [6, 7]. Our work supports a potential for developing novel therapeutic strategies aimed at differentiation of GPC into non-tumorigenic glia.


title: Oncogenic protein condensates modulate cell signal perception and drug tolerance

abstract: Drug resistance remains a central challenge towards durable cancer therapy, including for cancers driven by the EML4-ALK oncogene. EML4-ALK and related fusion oncogenes form cytoplasmic protein condensates that transmit oncogenic signals through the Ras/Erk pathway. However, whether such condensates play a role in drug response is unclear. Here, we used optogenetics to find that condensates suppress signaling through endogenous RTKs including EGFR. Notably, ALK inhibition hypersensitized RTK signals, which are known to drive resistance. Suppression of RTKs occurred because condensates sequestered downstream adapter proteins that are required for RTK signal transmission. Strikingly, EGFR hypersensitization resulted in rapid and pulsatile Erk signal reactivation, which originated from neighboring apoptotic cells. Paracrine signals promoted survival during ALK inhibition, and blockade of paracrine signals suppressed drug tolerance. Our results uncover a regulatory role for RTK fusion condensates in cancer drug response and demonstrate the potential of optogenetics for uncovering functional biomarkers of cancer cells.


title: Oncogenic protein condensates suppress growth factor perception and modulate drug tolerance


title: Reliable and efficient parameter estimation using approximate continuum limit descriptions of stochastic models

abstract: Stochastic individual-based mathematical models are attractive for modelling biological phenomena because they naturally capture the stochasticity and variability that is often evident in biological data. Such models also allow us to track the motion of individuals within the population of interest. Unfortunately, capturing this microscopic detail means that simulation and parameter inference can become computationally expensive. One approach for overcoming this computational limitation is to coarse-grain the stochastic model to provide an approximate continuum model that can be solved using far less computational effort. However, coarse-grained continuum models can be biased or inaccurate, particularly for certain parameter regimes. In this work, we combine stochastic and continuum mathematical models in the context of lattice-based models of two-dimensional cell biology experiments by demonstrating how to simulate two commonly used experiments: cell proliferation assays and barrier assays. Our approach involves building a simple statistical model of the discrepancy between the expensive stochastic model and the associated computationally inexpensive coarse-grained continuum model. We form this statistical model based on a limited number of expensive stochastic model evaluations at design points sampled from a user-chosen distribution, corresponding to a computer experiment design problem. With straightforward design point selection schemes, we show that using the statistical model of the discrepancy in tandem with the computationally inexpensive continuum model allows us to carry out prediction and inference while correcting for biases and inaccuracies due to the continuum approximation. We demonstrate this approach by simulating a proliferation assay, where the continuum limit model is the well-known logistic ordinary differential equation, as well as a barrier assay where the continuum limit model is closely related to the well-known Fisher-KPP partial differential equation. We construct an approximate likelihood function for parameter inference, both with and without discrepancy correction terms. Using maximum likelihood estimation, we provide point estimates of the unknown parameters, and use the profile likelihood to characterise the uncertainty in these estimates and form approximate confidence intervals. For the range of inference problems considered, working with the continuum limit model alone leads to biased parameter estimation and confidence intervals with poor coverage. In contrast, incorporating correction terms arising from the statistical model of the model discrepancy allows us to recover the parameters accurately with minimal computational overhead. The main tradeoff is that the associated confidence intervals are typically broader, reflecting the additional uncertainty introduced by the approximation process. All algorithms required to replicate the results in this work are written in the open source Julia language and are available at GitHub.

category: biophysics


title: Novel neutrophil subsets associated with sepsis, vascular dysfunction and metabolic alterations identified using systems immunology

abstract: Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Despite continued efforts to understand the pathophysiology of sepsis, no effective therapies are currently available. While singular components of the aberrant immune response have been investigated, comprehensive studies linking different data layers are lacking. Using an integrated systems immunology approach, we evaluated neutrophil phenotypes and concomitant changes in cytokines and metabolites in sepsis patients. Our findings identify novel differentially expressed immature neutrophil subsets in sepsis patients. These and other subsets correlate with various proteins, metabolites, and lipids, including pentraxin-3, angiopoietin-2 and lysophosphatidylcholines, in sepsis patients. These results enabled the construction of a predictive model based on weighted multi-omics linear regression analysis for patient classification. These findings could help inform earlier patient stratification and treatment options, as well as facilitate future mechanistic studies targeting the trifecta of surface marker expression, cytokines, and metabolites.

category: immunology


title: Maternal Wnt11b regulates cortical rotation during Xenopus axis formation: analysis of maternal-effect wnt11b mutants

abstract: Asymmetric signalling centres in the early embryo are essential for axis formation in vertebrates. These regions, namely the dorsal morula, yolk syncytial layer, and distal hypoblast/anterior visceral endoderm (in amphibians, teleosts and mammals, respectively), require the localised stabilisation of nuclear Beta-catenin (Ctnnb1), implying that localised Wnt/Beta-catenin signalling activity is critical in their establishment. However, it is becoming increasingly apparent that the stabilisation of Beta-catenin in this context may be initiated independently of secreted Wnt growth factor activity. In Xenopus, dorsal Beta-catenin stabilisation is initiated by a requisite microtubule-mediated symmetry-breaking event in the fertilised egg: "cortical rotation". Vegetally-localised wnt11b mRNA has been implicated upstream of Beta-catenin in this context, as has the dorsal enrichment of Wnt ligand-independent activators of Beta-catenin, but the extent that each of these processes contribute to axis formation in this paradigm remains unclear. Here we describe a maternal effect mutation in Xenopus laevis wnt11b.L, generated by CRISPR mutagenesis. We demonstrate a maternal requirement for timely and complete gastrulation morphogenesis and a zygotic requirement for proper left-right asymmetry. We also show that a subset of maternal wnt11b mutants have axis and dorsal gene expression defects, but that Wnt11b likely does not act through the Wnt coreceptor Lrp6 or through Dishevelled, which we additionally show (using exogenous constructs) do not exhibit patterns of activity consistent with roles in early Beta-catenin stabilisation. Instead, we find that microtubule assembly and cortical rotation are reduced in wnt11b mutant eggs, leading to less organised and directed vegetal microtubule arrays. In conclusion, we propose that Wnt11b signals to the cytoskeleton in the egg or early zygote to enable robust cortical rotation, and thus acts in the distribution of putative dorsal determinants rather than as a component or effector of the determinants themselves.

category: developmental biology


title: Gal1 repression memory in budding yeast

abstract: Cells must continuously adapt to changing environments and, thus, have evolved mechanisms allowing them to respond to repeated stimuli. For example, faster gene induction upon a repeated stimulus aids adaptation - a process known as reinduction memory. However, whether such a memory exists for gene repression is unclear. Here, we studied gene repression across repeated carbon source shifts in over 2,500 single Saccharomyces cerevisiae cells. By monitoring the expression of a carbon source-responsive gene, galactokinase 1 (Gal1), and mathematical modeling, we discovered repression memory at the population and single-cell level. Using a repressor model to estimate single-cell repression parameters, we show that repression memory is due to a shortened repression delay, the estimated time gap between carbon source shift and Gal1 expression termination, upon the repeated carbon source shift. Additionally, we show that cells lacking Elp6 display a gain-of-repression-memory phenotype characterized by a stronger decrease in repression delay between two consecutive carbon source shifts. Collectively, our study provides the first quantitative description of repression memory in single cells.

category: systems biology


title: Monitoring rapid evolution of plant populations at scale with Pool-Sequencing

abstract: The change in allele frequencies within a population over time represents a fundamental process of evolution. By monitoring allele frequencies, we can analyze the effects of natural selection and genetic drift on populations. To efficiently track time-resolved genetic change, large experimental or wild populations can be sequenced as pools of individuals sampled over time using high-throughput genome sequencing (called the Evolve & Resequence approach, E&R). Here, we present a set of experiments using hundreds of natural genotypes of the model plant Arabidopsis thaliana to showcase the power of this approach to study rapid evolution at large scale. First, we validate that sequencing DNA directly extracted from pools of flowers from multiple plants -- organs that are relatively consistent in size and easy to sample -- produces comparable results to other, more expensive state-of-the-art approaches such as sampling and sequencing of individual leaves. Sequencing pools of flowers from 25-50 individuals at ~40X coverage recovers genome-wide frequencies in diverse populations with accuracy r>0.95. Secondly, to enable analyses of evolutionary adaptation using E&R approaches of plants in highly replicated environments, we provide open source tools that streamline sequencing data curation and calculate various population genetic statistics two orders of magnitude faster than current software. To directly demonstrate the usefulness of our method, we conducted a two-year outdoor evolution experiment with A. thaliana to show signals of rapid evolution in multiple genomic regions. We demonstrate how these laboratory and computational Pool-seq-based methods can be scaled to study hundreds of populations across many climates.

category: evolutionary biology


title: Genomic signatures of host-specific selection in a parasitic plant

abstract:
PremiseParasitic plants and their hosts are emerging model systems for studying genetic variation in species interactions across environments. The parasitic plant Striga hermonthica (witchweed) attacks a range of cereal crop hosts in Africa. Striga hermonthica exhibits substantial genetic variation in host preference and in specificity versus generalism. Some of this variation is locally adapted, but the genetic basis of specialization on certain hosts is unknown.

MethodsWe present an alignment-free analysis of population diversity in S. hermonthica using whole genome sequencing (WGS) data for 68 individuals from western Kenya. We validate our reference-free approach with germination experiments and a de novo assembled draft genome.

ResultsK-mer based analyses reveal high genome-wide diversity within a single field, similar to values between individuals collected 100 km apart or farther. Analysis of host-associated k-mers implicated genes involved in development of the parasite haustorium (a specialized structure used to establish vascular connections with host roots) and a potential role of chemocyanins in molecular host-parasitic plant interactions. Conversely, no phenotypic or genomic evidence was observed suggesting host-specific selection on parasite response to strigolactones, hormones exuded by host roots and required for parasite germination.

ConclusionsThis study demonstrates the utility of WGS for plant species with large, complex genomes and no available reference. Contrasting with theory emphasizing the role of early recognition loci for genotype specificity, our findings support host-specific selection on later interaction stages, suggesting recurring host-specific selection each generation alternating with homogenizing gene flow.


title: GWAShub: A Web-based Resource to Democratize Genome-Wide Association Studies in Crop Plants

abstract: Genome-wide association study (GWAS) is a popular approach for linking natural genetic variation with phenotype variation and thus is central to crop quantitative genetics. The ever-increasing wealth of publicly available genomic sequence information for crop plants presents an unprecedented opportunity for utilizing GWAS for the identification of genes governing a plethora of agronomic traits. However, the lack of technical expertise and computational infrastructure is still hindering the ability of plant breeders to conduct GWAS in a self-reliant manner. Here, we present a GWAShub web server that provides a user-friendly interface for performing comprehensive GWAS and post-GWAS in crop plants utilizing publicly available genomic sequence variation data, comprehensive annotation data and diverse computational tools. The utility of GWAS-hub was further demonstrated by conducting large-scale GWAS for flowering/maturity time traits in chickpea. This analysis identified three different flowering/maturity time associated genes, all encoding different histone methyltransferases. Thus, epigenetic regulation is identified as vital mechanism regulating flowering time and maturity duration in chickpea. Finally, we hope GWAShub (www.gwashub.com) will enable resource-scarce researchers to join the GWAS revolution fueled by advancements in next-generation sequencing and computational genomics

category: bioinformatics


title: De novo stem cell establishment in meristems requires repression of organ boundary cell fate

abstract: Stem cells play important roles in animal and plant biology as they sustain morphogenesis and tissue replenishment following aging or injuries. In plants, stem cells are embedded in multicellular structures called meristems and the formation of new meristems is essential for the plastic expansion of the highly branched shoot and root systems. In particular, axillary meristems that produce lateral shoots arise from the division of boundary domain cells at the leaf base. The CUP-SHAPED COTYLEDON (CUC) genes are major determinants of the boundary domain and are required for axillary meristem initiation. However, how axillary meristems get structured and how stem cells become established de novo remains elusive. Here, we show that two NGATHA-LIKE transcription factors, DPA4 and SOD7, redundantly repress CUC expression in the initiating axillary meristem. Ectopic boundary fate leads to abnormal growth and organisation of the axillary meristem and prevents de novo stem cell establishment. Floral meristems of the dpa4 sod7 double mutant show a similar delay in stem cell de novo establishment. Altogether, while boundary fate is required for the initiation of axillary meristems, our work reveals how it is later repressed to allow proper meristem establishment and de novo stem cell niche formation.

category: plant biology


title: ABA signaling prevents phosphodegradation of the Arabidopsis SR45 splicing factor to negatively autoregulate inhibition of early seedling development

abstract:
Alternative splicing is a key posttranscriptional mechanism to expand the coding capacity of eukaryotic genomes. Although the functional relevance of this process remains poorly understood in plant systems, major modulators of alternative splicing called serine/arginine-rich (SR) proteins have been implicated in plant stress responses mediated by the abscisic acid (ABA) hormone. Loss of function of the Arabidopsis thaliana SR-like protein SR45, a bona fide splicing factor, has been shown to cause plant hypersensitivity to environmental cues and activation of the ABA pathway. Also, consistent with both animal and plant SR proteins being extensively and reversibly phosphorylated at their C-termini, ABA-induced changes in the phosphorylation status of SR45 have been reported.

Here, we show that SR45 overexpression reduces Arabidopsis sensitivity to ABA during early seedling development. Moreover, exposure to ABA dephosphorylates SR45 at multiple amino acid residues and leads to accumulation of the protein via reduction of SR45 ubiquitination and proteasomal degradation. Using phosphomutant and phosphomimetic transgenic Arabidopsis lines, we demonstrate the functional relevance of ABA-mediated dephosphorylation of a single SR45 residue, T264, in antagonizing SR45 ubiquitination and degradation to promote its function as a repressor of seedling ABA sensitivity. Taken together, our results reveal a mechanism in which ABA signaling negatively autoregulates during early plant development via posttranslational control of the SR45 splicing factor.


title: Modulation of stress-related behaviour by hypothalamic engagement of preproglucagon neurons in the nucleus of the solitary tract

abstract: Stress-induced behaviours are driven by complex neural circuits and some neuronal populations concurrently modulate diverse behavioural and physiological responses to stress. Glucagon-like peptide-1 (GLP1)-producing preproglucagon (PPG) neurons within the lower brainstem caudal nucleus of the solitary tract (cNTS) are particularly sensitive to stressful stimuli and are implicated in multiple physiological and behavioural responses to interoceptive and psychogenic threats. However, the afferent inputs driving stress-induced activation of PPG neurons are largely unknown, and the role of PPG neurons in anxiety-like behaviour is controversial. Through chemogenetic manipulations we reveal that cNTS PPG neurons have the ability to moderately increase anxiety-like behaviours in mice in a sex-dependent manner. Using an intersectional approach, we show that a corticotropin-releasing hormone (CRH)-rich input from the paraventricular nucleus of the hypothalamus (PVN) drives activation of both the cNTS as a whole and PPG neurons in particular in response to acute stress. Finally, we demonstrate that NTS-projecting PVN neurons are necessary for the ability of acute stress to suppress food intake. Our findings reveal sex differences in behavioural responses to PPG neural activation and highlight a hypothalamic-brainstem pathway in stress-induced hypophagia.

category: neuroscience


title: Graph theoretical analysis reveals the adaptive role of the left ventral occipito-temporal cortex in the brain networks during speech processing

abstract: The left ventral occipito-temporal cortex (left-vOT) plays a key role in reading. Several studies have also reported its activation during speech processing, suggesting that it may play a role beyond written word recognition. Here, we adopt a graph theoretical analysis to investigate the functional role of this area in the whole-brain network while participants processed spoken sentences in different tasks. We find that its role and interactions with other areas changes in an adaptive manner. In a low-level speech perception task, the left-vOT is part of the visual network and acts as a connector that supports the communication with other cognitive systems. When speech comprehension is required, the area becomes a connector within the sensorimotor-auditory network typically recruited during speech processing. However, when comprehension is compromised due to degradation of speech input, the area disengages from the sensorimotor-auditory network. It becomes part of the visual network again and turns from connector into a simple peripheral node. These varying connectivity patterns are coherent with the Interactive Account considering the left-vOT as a convergent zone with multiple functions and interaction patterns that depend on task demands and the nature of sensory input.


title: Neural mechanism of acute stress management by trace aminergic signalling in the lateral habenula

abstract: Stress management is a prerequisite for the survival of vertebrates because chronic stress may cause depression and is known to negatively modulate the dopaminergic reward system1. Enhanced excitability of neurons in the lateral habenula (LHb) induced by chronic stress is essential for silencing dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neurons in the rostromedial tegmental nucleus (RMTg)2-10. However, the effect of acute stress on the LHb-RMTg-VTA pathway is unknown11-14. Here, we show that both aromatic L-amino acid decarboxylase (AADC)-expressing neurons (D-neurons)15 in the LHb and dopaminergic neurons in the VTA are activated by acute stress, whereas GABAergic neurons in the RMTg are not. Selective stimulation of LHb D-neurons and AADC knockdown of these neurons reverse-regulate the RMTg-VTA pathway. Circuit tracing and electrophysiology data demonstrate that trace aminergic signalling by LHb D-neurons directly suppresses RMTg GABAergic neurons. Furthermore, local activation of trace amine-associated receptor 1 (TAAR1; a trace amine receptor) in the RMTg is sufficient to rescue the despair-like behaviour produced by the loss of AADC expression. Our results identify a novel efferent pathway from the LHb to the RMTg whereby trace aminergic signalling allows the brain to manage acute stress by preventing VTA dopaminergic neuron hypoactivity. The TAAR1-mediated trace aminergic signalling in the LHb-RMTg pathway may hold promise as a therapeutic target for stress-mediated psychological diseases.


title: mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits comparable B cell expansion, neutralizing antibodies and protection against Omicron

abstract: SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to antibody neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-specific vaccines would enhance immunity and protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing antibody titers against D614G were 4760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (pre-boost), respectively, and 320 and 110 for Omicron. Two weeks after boost, titers against D614G and Omicron increased to 5360 and 2980, respectively, for mRNA-1273 and 2670 and 1930 for mRNA-Omicron. Following either boost, 70-80% of spike-specific B cells were cross-reactive against both WA1 and Omicron. Significant and equivalent control of virus replication in lower airways was observed following either boost. Therefore, an Omicron boost may not provide greater immunity or protection compared to a boost with the current mRNA-1273 vaccine.


title: Extinction Risk of Sonoran Desert Annuals Following Potential Changes in Precipitation Regimes

abstract: Rapid environmental change can affect both the mean and variability in environmental conditions. Natural selection tends to favour those organisms that best respond to such changes. Here, we consider delayed germination as bet hedging strategies for 10 Sonoran Desert annuals. We use a germination model parameterized with long-term demographic and climate data to explore potential effects of changes in the mean and variance in precipitation on the evolution of germination strategies, as well as the risk of extinction. We then explored the potential for evolutionary rescue in response to these changes. As expected, results indicate that as rainfall declines, or uncertainty in rainfall increases, all species have higher extinction risk (the former being more detrimental). These shifts also increased the benefit of delayed germination. Results also indicate that evolutionary rescue can often occur for small shifts, especially for more variable rainfall regimes, but would not likely save populations experiencing larger environmental changes. Finally, we identified life history traits and functional responses to precipitation that were most strongly correlated to the ability to cope with changes in rainfall and with potential for evolutionary rescue: dormant seed survivorship and, to a smaller degree, chance of reproduction and seed yield sensitivity to precipitation.

category: ecology


title: Superstitious learning of abstract order from random reinforcement

abstract: Survival depends on identifying learnable features of the environment that predict reward, and avoiding others that are random and unlearnable. However, humans and other animals often infer spurious associations among unrelated events, raising the question of how well they can distinguish learnable patterns from unlearnable events. Here, we tasked monkeys with discovering the serial order of two pictorial sets: a "learnable" set in which the stimuli were implicitly ordered and monkeys were rewarded for choosing the higher-rank stimulus and an "unlearnable" set in which stimuli were unordered and feedback was random regardless of the choice. We replicated prior results that monkeys reliably learned the implicit order of the learnable set. Surprisingly, the monkeys behaved as though some ordering also existed in the unlearnable set, showing consistent choice preference that transferred to novel untrained pairs in this set, even under a preference-discouraging reward schedule that gave rewards more frequently to the stimulus that was selected less often. In simulations, a model-free RL algorithm (Q-learning) displayed a degree of consistent ordering among the unlearnable set but, unlike the monkeys, failed to do so under the preference, discouraging reward schedule. Our results suggest that monkeys infer abstract structures from objectively random events using heuristics that extend beyond stimulus-outcome conditional learning to more cognitive model-based learning mechanisms.

category: animal behavior and cognition


title: Affective arousal explains infant gaze following under various social context

abstract: Gaze following is fundamental to human sociocognitive development, such as language and cultural learning. Previous studies have revealed that infant gaze following is not a reflexive orienting to adults eye movement. Instead, infants adaptively modulate gaze following behaviour depending on social contexts. However, the neurophysiological mechanisms underlying contextual modulation of gaze following remain unclear. We tested whether contextual modulation of infant gaze following is mediated by the infants heart rate, which is hypothesised to indicate the calculation of action value. Forty-one 6- to 9-month-old infants participated in this study. Infants observed either a reliable face, which gazed toward the location of an object, or an unreliable face, which gazed away from the location of an object. Then, the infants watched a video of the same model making eye contact or not showing any ostensive signals, before shifting her gaze toward one of two objects. We revealed that reliability and eye contact independently increased heart rates, which then fully mediate the effect of these social cues on the frequency of infant gaze following. Results suggest that each social cue independently enhances physiological arousal which then accumulatively predicts the likelihood of infant gaze following behaviour.


title: Primary human macrophages exhibit a modest inflammatory response early in SARS-CoV-2 infection

abstract: Involvement of macrophages in the SARS-CoV-2-associated cytokine storm, the excessive secretion of inflammatory/anti-viral factors leading to the acute respiratory distress syndrome (ARDS) in COVID-19 patients, is unclear. In this study, we sought to characterize the interplay between the virus and primary human monocyte-derived macrophages (MDM). MDM were stimulated with recombinant IFN- and/or infected with either live or UV-inactivated SARS-CoV-2 or with two reassortant influenza viruses containing external genes from the H1N1 PR8 strain and heterologous internal genes from a highly pathogenic avian H5N1 or a low pathogenic human seasonal H1N1 strain. Virus replication was monitored by qRT-PCR for the E viral gene for SARS-CoV-2 or M gene for influenza and TCID50 or plaque assay, and cytokine levels were assessed semiquantitatively with qRT-PCR and a proteome cytokine array. We report that MDM are not susceptible to SARS-CoV-2 whereas both influenza viruses replicated in MDM, albeit abortively. We observed a modest cytokine response in SARS-CoV-2 infected MDM with notable absence of IFN-{beta} induction, which was instead strongly induced by the influenza viruses. Pre-treatment of MDM with IFN- enhanced proinflammatory cytokine expression upon infection. Together, the findings concur that the hyperinflammation observed in SARS-CoV-2 infection is not driven by macrophages.

category: microbiology


title: Plasma ST6Gal1 is Dispensable for IgG Sialylation

abstract: The glycosylation of IgG has attracted increased attention due to the impact of N-glycan modifications at N297 on IgG function, acting primarily through modulation of Fc domain conformation and Fc{gamma} receptor binding affinities and signaling. However, the mechanisms regulating IgG glycosylation and especially 2,6-sialylation of its N-glycan remain poorly understood. We observed previously that IgG is normally sialylated in mice with B cells lacking the sialyltransferase ST6Gal1. This supported the hypothesis that IgG may be sialylated outside of B cells, perhaps through the action of hepatocyte-released plasma ST6Gal1. Here we demonstrate that this model is incorrect. Animals lacking hepatocyte expressed ST6Gal1 retain normal IgG 2,6-sialylation, despite the lack of detectable ST6Gal1 in plasma. Moreover, we confirmed that B cells were not a redundant source of IgG sialylation. Thus, while 2,6-sialylation is lacking in IgG from mice with germline ablation of ST6Gal1, IgG 2,6-sialylation is normal in mice lacking ST6Gal1 in either hepatocytes or B cells. These results indicate that IgG 2,6-sialylation arises after release from a B cell, but is not dependent on plasma-localized ST6Gal1 activity.


title: Bergerac Strains of C. elegans Revisited: Expansion of Tc1 elements Impose a Significant Genomic and Fitness Cost

abstract: The DNA transposon Tc1 was the first transposable element (TE) to be characterized in Caenorhabditis elegans and to date, remains the best-studied TE in Caenorhabditis worms. While Tc1 copy-number is regulated at approximately 30 copies in the laboratory N2/Bristol and the vast majority of C. elegans strains, the Bergerac strain and its derivatives have experienced a marked Tc1 proliferation. Given the historical importance of the Bergerac strain in the development of the C. elegans model, we implemented a modern genomic analysis of three Bergerac strains (CB4851, RW6999, and RW7000) in conjunction with multiple phenotypic assays to better elucidate the (i) genomic distribution of Tc1, and (ii) phenotypic consequences of TE deregulation for the host organism. The median estimates of Tc1 copy-number in the Bergerac strains ranged from 451 to 748, which is both (i) greater than previously estimated, and (ii) likely to be an underestimate of the actual copy-numbers since coverage-based estimates and ddPCR results both suggest higher Tc1 numbers. All three Bergerac strains had significantly reduced trait means compared to the N2 control for each of four fitness-related traits, with specific traits displaying significant differences between Bergerac strains. Tc1 proliferation was genome-wide, specific to Tc1, and particularly high on chromosomes V and X. There were fewer Tc1 insertions in highly expressed chromatin environments than expected by chance. Furthermore, Tc1 integration motifs were also less frequent in exon than non-coding sequences. The source of the proliferation of Tc1 in the Bergerac strains is specific to Tc1 and independent of other TEs. The Bergerac strains contain none of the alleles that have previously been found to derepress TE activity in C. elegans. However, the Bergerac strains had several Tc1 insertions near or within highly germline-transcribed genes which could account for the recent germline proliferation.


title: Single-Cell Transcriptome Analysis Identifies Novel Biomarkers Involved in Major Liver Cancer Subtypes

abstract: Liver cancers including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are leading cause of death worldwide. Single-cell transcriptomics studies have vast potential in advancing our understanding of cancers by defining the cellular composition of different solid tumor types. We peformed an integrated analysis using single-cell RNA sequencing (scRNA-seq) data from cancerous and healthy liver tissues in order to identify the molecular progression and intercellular heterogeneity across cell types in the liver cancer. Moreover, we performed a subtype specific analyses, separately for HCC and ICC, to identify any molecular drivers uniquely associated with these liver cancers. The scRNA-seq dataset comprising 5 healthy controls and 19 liver cancer patients were collected from Human Cell Atlas and Gene Expression Omnibus (GEO), respectively. Our analyses confirmed upregulation of four previously known malignant cell marker genes, namely, EPCAM, KRT19, KRT7 and S100P in the cancerous liver cells. Of these, KRT7 gene has been reported to be associated with ovarian cancer in the past studies. Noteworthy, four marker genes specific to the G1/S (MCM5 and PCNA) and G2/M phases (HMGB2 and CKS2) of the cell cycle were upregulated in the cancerous liver cells. This indicates that these four marker genes are actively dividing in these two phases in cancerous cells as compared to normal liver cells. Our differential expression analysis identified 2 upregulated genes (ATF3 and S100A11) and 2 downregulated genes (FCN3 and FGB) in the liver cancer. Our subtype based differential expression analysis identified 4 genes (HSPA6, LMNA, ATP1B1 and DCXR) specific to HCC and 3 genes (HSPB1, APOC3 and APOA1) specific to ICC. CD4+ T-cell, Hepatocyte, neutrophil, mesenchymal cells and liver bud hepatic cells are the predominant cell-types in liver cells. Our scRNA-seq study revealed the mesenchymal cells as potential malignant cell types in liver cancers. Our work suggests future research on developing liver cancer subtypes therapies could target these cell types and associated molecular markers.

category: genomics


title: An interpretable and versatile machine learning approach for oocyte phenotyping

abstract: Meiotic maturation is a crucial step of oocyte development allowing its potential fertilization and embryo development. Elucidating this process is important both for fundamental research and assisted reproductive technology. However, only few computational tools, based on non-invasive measurements, are currently available to characterize oocyte meiotic maturation. Here, we develop a computational framework to phenotype oocytes based on images or movies acquired exclusively in transmitted light. We first trained neural networks to segment the contours of oocytes and their zona pellucida using a diverse cohort of both mouse and human oocytes. We then defined a comprehensive set of morphological features to describe a single oocyte. We have implemented these steps in a versatile and user-friendly open source Fiji plugin available to the mouse and human oocyte community. Then, we present a machine learning pipeline based on selected features to automatically recognize oocyte populations and determine their morphological differences. Its first application is a novel approach to screen oocyte strains and automatically identify their morphological characteristics. We demonstrate its potential by phenotyping a well characterized genetically modified mouse oocyte strain. Its second application is to predict and characterize the maturation potential of oocytes. Importantly, we identify two new features to assess mouse oocyte maturation potential, consisting in the texture of the zona pellucida and the cytoplasmic particles size. Eventually, we tested whether these mouse oocyte quality features were applicable to human oocytes developmental potential.


title: Comprehensive analysis of next-generation sequencing data in COVID-19 and its secondary complications

abstract: The ongoing pandemic of coronavirus disease 2019 (COVID-19) has made a serious public health threat globally. To discover key molecular changes in COVID-19 and its secondary complications, we analyzed next-generation sequencing (NGS) data of COVID-19. NGS data (GSE163151) was screened and downloaded from the Gene Expression Omnibus database (GEO). Differentially expressed genes (DEGs) were identified in the present study, using DESeq2 package in R programming software. Gene ontology (GO) and pathway enrichment analysis were performed, and the protein-protein interaction (PPI) network, module analysis, miRNA-hub gene regulatory network and TF-hub gene regulatory network were established. Subsequently, receiver operating characteristic curve (ROC) analysis was used to validate the diagonostics valuesof the hub genes. Firstly, 954 DEGs (477 up regulated and 477 down regulated) were identified from the four NGS dataset. GO enrichment analysis revealed enrichment of DEGs in genes related to the immune system process and multicellular organismal process, and REACTOME pathway enrichment analysis showed enrichment of DEGs in the immune system and formation of the cornified envelope. Hub genes were identified from the PPI network, module analysis, miRNA-hub gene regulatory network and TF-hub gene regulatory network. Furthermore, the ROC analysis indicate that COVID-19 and its secondary complications with following hub genes, namely, RPL10, FYN, FLNA, EEF1A1, UBA52, BMI1, ACTN2, CRMP1, TRIM42 and PTCH1, had good diagnostics values. This study identified several genes associated with COVID-19 and its secondary complications, which improves our knowledge of the disease mechanism.


title: Deepwater Horizon crude oil reduces aerobic capacity of birds

abstract:
Crude oil spills can have catastrophic effects on marine and inland ecosystems, yet it is difficult to accurately quantify the extent of ecological damage caused by oil spills. For instance, avian population damage assessments conducted after large oil spills (e.g., Deepwater Horizon spill) often focus on the number of visibly oiled birds. However, birds without visible oiling can exhibit hematological damage from oil ingestion. If such hematological responses limit oxygen deliver to tissues and impair aerobic performance, then energy-mediated effects from oil ingestion may ultimately affect endpoints of demographic significance (e.g., survival and reproduction). We investigated whether oil ingestion affects aerobic performance in birds by orally dosing zebra finches (Taeniopygia guttata) with 2 or 6 mL/kg of weathered MC252 crude oil for 28 days. After 14 and 28 days of dosing, we measured hematological indices (oxidative damage, packed cell volume [PCV], hemoglobin, reticulocytes), maximum metabolic rate (MMR), resting metabolic rate (RMR), and short-distance flight performance. Finches exposed to oil exhibited lower hemoglobin and PCV, higher reticulocyte counts, and greater oxidative damage. Shifts in these hematological indices appeared to alter organismal energetics, resulting in reduced MMR, RMR, and aerobic scope. Short-distance burst-flight was not negatively impacted by oil ingestion. Collectively, these results suggest oil ingestion impairs metabolic performance, which may negatively impact a birds ability to perform sustained energetically expensive activities (e.g., migration).

SignificanceThe 2010 Deepwater Horizon oil spill released an unprecedented volume of crude oil (MC252) into the northern Gulf of Mexico and contaminated 2100 km of shoreline habitat that serves as critical breeding grounds and migratory stop-over sites for birds. Here we describe the impact of oil ingestion on the aerobic capacity of zebra finches, a model songbird. Oil ingestion reduced maximum metabolic rate and aerobic scope, which may be caused in part by hematological damage. These data suggest oil ingestion limits the ability of birds to perform essential energetically demanding activities (e.g., migration, nest incubation), thus quantification of avian injury based on external oiling alone may underestimate the true impact of oil spills on avian populations.

category: pharmacology and toxicology


title: Rabbit hindlimb kinematics and ground contact pressure during the stance phase of hopping gait

abstract: Though the rabbit is a common animal model in musculoskeletal research, there is very limited data reported on healthy rabbit biomechanics. Our objective was to quantify the normative hindlimb biomechanics of six New Zealand White rabbits (3 male, 3 female) during the stance phase of hopping gait. We measured biomechanics by synchronously recording sagittal plane motion and ground contact pressure using a video camera and pressure mat, respectively. Both foot angle (i.e., angle between foot and ground) and ankle angle curves were unimodal. The peak ankle dorsiflexion angle was 65.9{degrees}{+/-}12.7{degrees} and occurred at 39% stance, while the peak ankle plantarflexion angle was 136.9{degrees}{+/-}7.8{degrees} at toe-off. Minimum and maximum foot angles were 16.6{degrees}{+/-}6.4{degrees} at 12% stance and 125.4{degrees}{+/-}4.0{degrees} at toe-off, respectively. During stance, the knee joint center gradually progressed 4.7 cm downward and 18.1 cm forward, on average. The maximum vertical ground reaction force and contact area, both averaged across rabbits, were 42.5 {+/-} 11.4 %BW and 7.5 {+/-} 1.8 cm2, respectively. Our study confirmed that rabbits exhibit a plantigrade gait pattern, similar to humans. Future studies can reference our data to quantify the extent to which orthopedic interventions affect rabbit biomechanics.


title: Artificial soils reveal individual factor controls on microbial processes

abstract:
Soil matrix properties influence microbial behaviors that underlie nutrient cycling, greenhouse gas production, and soil formation. However, the dynamic and heterogeneous nature of soils makes it challenging to untangle the effects of different matrix properties on microbial behaviors. To address this challenge, we developed a tunable artificial soil recipe and used these materials to study the abiotic mechanisms driving soil microbial growth and communication. When we used standardized matrices with varying textures to culture gas-reporting biosensors, we found that Gram-negative bacteria grew best in synthetic silt soils, remaining active over a wide range of soil matric potentials, while Gram-positive bacteria preferred sandy soils, sporulating at a low water potentials. Soil texture, mineralogy, and alkalinity all attenuated the bioavailability of an acyl-homoserine lactone (AHL) signaling molecule that controls community-level microbial behaviors. Texture controlled the timing of AHL sensing, while AHL bioavailability was decreased [~]105-fold by mineralogy and [~]103-fold by alkalinity. Finally, we built artificial soils with a range of complexities that converge on the properties of one Mollisol. As artificial soil complexity increased to more closely resemble the Mollisol, microbial behaviors approached those occurring in the natural soil, with the notable exception of organic matter. Properties that behaved additively were soil texture, pH, and mineralogy, while organic matter did not, suggesting that its soil behavior is an emergent property.

IMPORTANCEUnderstanding environmental controls on soil microbes is difficult because many abiotic parameters vary simultaneously and uncontrollably when different natural soils are compared, preventing mechanistic determination of any individual soil parameters effect on microbial behaviors. We describe how soil texture, mineralogy, pH, and organic matter content can be varied individually within artificial soils to study their effects on soil microbes. Using microbial biosensors that report by producing a rare indicator gas, we identify soil properties that control microbial growth and attenuate the bioavailability of a diffusible chemical used to control community-level behaviors. We find that artificial soils differentially affect signal bioavailability and the growth of Gram-negative and Gram-positive microbes. We show that some soil properties have additive effects on signal bioavailability, while others exhibit emergent properties. These artificial soils are useful for studying the mechanisms that underlie soil controls on microbial fitness, signaling, and gene transfer.


title: Within-individual consistency and between-individual variation in the shapes of eggs laid by tree swallows (Tachycineta bicolor)

abstract: Bird eggs come in a wide variety of shapes and recent large-scale studies across species have renewed interest in understanding the factors that generate and maintain this diversity. However, these advances largely overlook the fact that egg shape also varies dramatically within species: between populations, between individuals, and between eggs produced by the same individual. We measured the shape and size of 1382 eggs produced by 205 tree swallows (Tachycineta bicolor) in 259 nests with many females having eggs measured in two or three years. We found that intra-specific variation in the asymmetry and ellipticity of tree swallow eggs spanned the range of typical egg shapes from 69% of species reported in a recent comparative study. Variation in shape and size was largely explained by individual identity, as the repeatability of egg shape and size was remarkably high both for eggs produced within a clutch and for clutches produced in successive years. All characteristics of mother and daughter eggs were positively correlated, although with a sample size of only 15 pairs these relationships were not significant. Female mass and structural size were correlated with the size of eggs produced, but not with their shape. Older females produced eggs that were larger, more asymmetrical, and less elliptical; this pattern was driven by a combination of both longitudinal changes in egg characteristics as females aged and by differential overwinter survival of females with particular egg characteristics. We found no evidence that any aspect of shape or size that we measured was related to nestling measurements or fate. Finally, we found that the patterns of covariation in aspects of egg size and shape between-individuals differed from that observed within-individuals, suggesting that the mechanisms driving egg shape variation might differ across these levels. A complete understanding of avian egg shapes will need to incorporate variation at multiple scales and we discuss the interpretation of our results in light of recent large-scale comparative studies that focus only on mean species egg shapes.

category: zoology


title: Movement characteristics impact decision-making and vice versa

abstract: Previous studies suggest that humans are capable of coregulating the speed of decisions and movements if promoted by task incentives. It is unclear however whether such behavior is inherent to the process of translating decisional information into movements, beyond posing a valid strategy in some task contexts. Therefore, in a behavioral online study we imposed time constraints to either decision or movement -phases of a sensorimotor task, ensuring that coregulating decisions and movements was not promoted by task incentives. We found that participants indeed moved faster when fast decisions were promoted and decided faster when subsequent movements had to be executed swiftly. Furthermore, inflicting faster movements seems to alter decision-making in a similar fashion as conditions promoting faster decisions: In both fast-decision and fast-movement blocks, decisions relied more strongly on information presented shortly rather than long before movement onset. Taken together, these findings suggest that decisions not only impact movement characteristics, but that properties of movement impact the time and manner with which decisions are made. We interpret these behavioral results in the context of embodied decision-making, whereby shared neural mechanisms may not only enable faster movements but also assist in making decisions in less time.


title: Deep Immunophenotyping Reveals Endometriosis is Marked by Dysregulation of the Mononuclear Phagocytic System in Endometrium and Peripheral Blood

abstract:
BackgroundEndometriosis is a chronic, estrogen-dependent disorder where inflammation contributes to disease-associated symptoms of pelvic pain and infertility. Immune dysfunction includes insufficient immune lesion clearance, a pro-inflammatory endometrial environment, and systemic inflammation. Comprehensive understanding of endometriosis immune pathophysiology in different hormonal milieu and disease severity has been hampered by limited direct characterization of immune populations in endometrium, blood, and lesions. Simultaneous deep phenotyping at single cell resolution of complex tissues has transformed our understanding of the immune system and its role in many diseases. Herein, we report mass cytometry and high dimensional analyses to study immune cell phenotypes, abundance, activation states, and functions in endometrium and blood of women with and without endometriosis in different cycle phases and disease stages.

MethodsA case-control study was designed. Endometrial biopsies and blood (n=60 total) were obtained from women with (n=20, n=17, respectively) and without (n=14, n=9) endometriosis in the proliferative and secretory cycle phases of the menstrual cycle. Two mass cytometry panels were designed; one broad panel and one specific for mononuclear phagocytic cells (MPC), and all samples were multiplexed to characterize both endometrium and blood immune composition at unprecedented resolution. We combined supervised and unsupervised analyses to finely define the immune cell subsets with an emphasis on MPC. Then, association between cell types, protein expression, disease status, and cycle phase were performed.

ResultsThe broad panel highlighted a significant modification of MPC in endometriosis; thus, they were studied in detail with an MPC-focused panel. Endometrial CD91+ macrophages overexpressed SIRP (phagocytosis inhibitor) and CD64 (associated with inflammation) in endometriosis, and they were more abundant in mild versus severe disease. In blood, classical and intermediate monocytes were less abundant in endometriosis, whereas plasmacytoid dendritic cells and non-classical monocytes were more abundant. Non-classical monocytes were higher in severe versus mild disease.

ConclusionsA greater inflammatory phenotype and decreased phagocytic capacity of endometrial macrophages in endometriosis are consistent with defective clearance of endometrial cells shed during menses and in tissue homeostasis, with implications in endometriosis pathogenesis and pathophysiology. Different proportions of monocytes and plasmacytoid dendritic cells in blood from endometriosis suggest systemically aberrant functionality of the myeloid system opening new venues for the study of biomarkers and therapies for endometriosis.


title: An in vitro model of fibrosis using crosslinked native extracellular matrix-derived hydrogels to modulate biomechanics without changing composition

abstract: Extracellular matrix (ECM) is a dynamic network of proteins, proteoglycans and glycosaminoglycans, providing structure to the tissue and biochemical and biomechanical instructions to the resident cells. In fibrosis, the composition and the organization of the ECM are altered, and these changes influence cellular behaviour. Biochemical (i. e. protein composition) and biomechanical changes in ECM take place simultaneously in vivo. Investigating these changes individually in vitro to examine their (patho)physiological effects has been difficult. In this study, we generated an in vitro model to reflect the altered mechanics of a fibrotic microenvironment through applying fibre crosslinking via ruthenium/sodium persulfate crosslinking on native lung ECM-derived hydrogels. Crosslinking of the hydrogels without changing the biochemical composition of the ECM resulted in increased stiffness and decreased viscoelastic stress relaxation. The altered stress relaxation behaviour was explained using a generalized Maxwell model. Fibre analysis of the hydrogels showed that crosslinked hydrogels had a higher percentage of matrix with a high density and a shorter average fibre length. Fibroblasts seeded on ruthenium-crosslinked lung ECM-derived hydrogels showed myofibroblastic differentiation with a loss of spindle-like morphology together with greater -smooth muscle actin (-SMA) expression, increased nuclear area and circularity without any decrease in the viability, compared with the fibroblasts seeded on the native lung-derived ECM hydrogels. In summary, ruthenium crosslinking of native ECM-derived hydrogels provides an exciting opportunity to alter the biomechanical properties of the ECM-derived hydrogels while maintaining the protein composition of the ECM to study the influence of mechanics during fibrotic lung diseases.

category: pathology


title: Macrophages and glia are the dominant P2X7-expressing cell types in the gut nervous system - no evidence for a role of neuronal P2X7 receptors in colitis

abstract: SummaryBlockade or deletion of the pro-inflammatory P2X7 receptor channel has been shown to reduce tissue damage and symptoms in models of inflammatory bowel disease (IBD) and P2X7 receptors on enteric neurons were suggested to mediate neuronal death and associated motility changes. Here we used P2X7-specific antibodies and nanobodies as well as a BAC transgenic P2X7-EGFP reporter mouse model and P2rx7-/- controls to perform a detailed analysis of cell type-specific P2X7 expression and possible overexpression effects in the enteric nervous system. In contrast to previous studies, we did not detect P2X7 in neurons but found dominant expression in glia and macrophages which closely interact with the neurons. P2X7 overexpression per se did not induce significant pathological effects. Our data indicate that macrophages and/or glia account for P2X7-mediated neuronal damage in IBD and provide a refined basis for the exploration of P2X7-based therapeutic strategies.

category: physiology


title: Heroin Self-Administration Induces Altered Dopamine Terminal Dynamics in the Nucleus Accumbens

abstract: Administration of heroin results in the engagement of multiple brain regions and the rewarding and addictive effects are mediated, at least partially, through activation of the mesolimbic dopamine system. However, less is known about dopamine system function following chronic exposure to heroin. Withdrawal from chronic heroin exposure is likely to drive a state of low dopamine in the nucleus accumbens (NAc), as previously observed during withdrawal from other drug classes. Thus, we aimed to investigate alterations in NAc dopamine terminal function following chronic heroin self-administration to identify a mechanism for dopaminergic adaptations. Adult male Long Evans rats were trained to self-administer heroin (0.05 mg/kg/inf, IV) and then placed on a long access (FR1, 6-hrs, unlimited inf, 0.05 mg/kg/inf) protocol to induce escalation of intake. After one day of withdrawal, male rats exhibited lower basal extracellular levels of dopamine as well as reduced dopaminergic responses to a heroin challenge (0.1 mg/kg/inf, IV). Following heroin self-administration, rats had decreased basal extracellular levels of dopamine and blunted dopamine response following a heroin challenge (0.1 mg/kg/inf, IV) in the NAc compared to saline controls. FSCV revealed that heroin-exposed rats have reduced stimulated dopamine release during tonic-like, single-pulse stimulations but increased phasic-like dopamine release during multi-pulse stimulation trains (5 pulses, 5-100Hz) in addition to an altered dynamic range of release stimulation intensities when compared to controls. Further, we found that presynaptic D3 autoreceptor and kappa-opioid receptor activity was increased following heroin self-administration. These results reveal a marked low dopamine state following heroin-exposure and suggest the combination of altered dopamine release dynamics may contribute to increased heroin seeking.


title: Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice

abstract:
The innate immune system can protect against certain aspects of neurodegenerative diseases, but also contribute to disease progression. Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the defense against viral pathogens, activating type I interferon and NF-kB/inflammasome signaling. In order to specifically test the relevance of this pathway for the degeneration of dopaminergic neurons in Parkinsons disease, we studied a mouse model with heterozygous expression of the constitutively active STING variant N153S.

In adult mice expressing N153S STING, the number of dopaminergic neurons was smaller than in controls, as was the density of dopaminergic axon terminals and the concentration of dopamine in the striatum. We also observed alpha-synuclein pathology and a lower density of synaptic puncta. Neuroinflammation was quantified by staining astroglia and microglia, by measuring mRNAs, proteins and nuclear translocation of transcription factors. Neuroinflammatory markers were already elevated in juvenile mice, thus preceding the degeneration of dopaminergic neurons. Inflammation and neurodegeneration were blunted in mice deficient for signaling by type I interferons or inflammasomes, but not suppressed completely.

Collectively, these findings demonstrate that chronic activation of the STING innate immunity pathway is sufficient to cause degeneration of dopaminergic neurons. This pathway could be targeted therapeutically.


title: Melanism in a wild sifaka population: Darker where cold and fragmented

abstract: Pigmentation is one of the most striking examples of diversity in the natural world. Mainly, pelage (hair/fur) pigmentation provides a substrate for selection (i.e., crypsis, signaling, thermoregulation) and is capable of rapid change. Thus, this trait may be the one potential early signal of adaptation (or maladaptation) in wild primate populations. However, most of our hypotheses on the forces responsible for primate pelage pigmentation are based solely on macro-evolutionary studies. Here, we characterize pelage color and pattern variation within a population of wild primates, diademed sifakas (Propithecus diadema), exhibiting striking diversity in coloration (melanic to tri-colored). Our approach jointly assesses climate and pelage variation across the region. We score pelage using a semi-quantitative methodology. We then test if pelage variation is associated with climatic or demographic factors (i.e., sex-class, age-class) across the Tsinjoarivo forest, Madagascar. We find darker bodies and less complex faces occur in colder and more fragmented forests. We explore three hypotheses that may explain this phenotypic pattern: isolation by distance, an environmental gradient, or unique local adaptation. Importantly, each scenario signals the need for enhanced conservation of diademed sifakas in the Tsinjoarivo forest. More studies on primate pigmentation in wild populations will be needed to contextualize if this pattern is exceptional or typical. It is likely that in other primate populations pigmentation may also foretell of adaptation or environmental mismatch.


title: Residual DNA in enzymes may pose a challenge for DIY RNA sequencing protocols: how to deal

abstract: High-throughput RNA sequencing (RNA-seq) is widely employed for gene expression profiling. This report on do-it-yourself RNA-Seq library preparation pitfalls, highlighting their correct identification and successful overcoming, may be helpful to research groups commencing a DIY RNA-Seq workflow and facing similar problems.


title: Using the Dynamic Forward Scattering Signal for Optical Coherence Tomography based Blood Flow Quantification

abstract: To our knowledge, all existing optical coherence tomography approaches for quantifying blood flow, whether Doppler-based or decorrelation-based, analyze light that is back-scattered by moving red blood cells (RBCs). This work investigates the potential advantages of basing these measurements on light that is forward-scattered by RBCs, i.e., by looking at the signals back-scattered from below the vessel. We show experimentally that this results in a flowmetry measure that is insensitive to vessel orientation for vessels that are approximately orthogonal to the imaging beam. We further provide proof-of-principle demonstrations that DFS can be used to measure flow in human retinal and choroidal vessels.

category: bioengineering


title: Systematic lncRNA mapping to genome-wide co-essential pathways uncovers cancer dependency on uncharacterized lncRNAs

abstract: Quantification of gene dependency across hundreds of cell lines using genome-scale CRISPR screens have revealed co-essential pathways/modules and critical functions of uncharacterized genes. In contrast to protein-coding genes, robust CRISPR-based loss-of-function screens are lacking for long non-coding RNAs (lncRNAs), which are key regulators of many cellular process, leaving many essential lncRNAs unidentified and uninvestigated. Integrating copy- number, epigenetic, and transcriptomic data of >800 cancer cell lines with CRISPR-derived co-essential pathways, our method recapitulates known essential lncRNAs and predicts proliferation/growth dependency of 289 poorly characterized lncRNAs. Analyzing lncRNA dependencies across ten cancer types and their expression alteration by diverse growth- inhibitors across cell types, we prioritize 30 high-confidence pan-cancer proliferation/growth- regulating lncRNAs. Further evaluating two previously uncharacterized top proliferation-suppressive lncRNAs (PSLR-1, PSLR-2) showed they are transcriptionally regulated by p53, induced by multiple cancer treatments, and significantly correlate to increased cancer patient survival. These lncRNAs modulate G2 cell cycle-regulating genes within the FOXM1 transcriptional network, inducing a G2 arrest and inhibiting proliferation and colony formation. Collectively, our results serve as a powerful resource for exploring lncRNA-mediated regulation of cellular fitness in cancer, circumventing current limitations in lncRNA research.


title: ORFanID: A Web-Based Search Engine for the Discovery and Identification of Orphan and Taxonomically Restricted Genes

abstract:
With the multiplicity of genomes sequenced today, it has been shown that significant percentages of genes in any given taxon do not possess orthologous sequences in other taxa. These sequences are typically designated as orphans/ORFans when found as singletons in one species only or taxonomically restricted genes (TRGs) when found at higher taxonomic ranks. Therefore, quantitative and collective studies of these genes are necessary for understanding their biological origins. Currently, orphan gene identifying software is limited, and those previously available are either not functional, are limited in their database search range, or are too complex algorithmically. Thus, an interested researcher studying orphan genes must harvest their data from many disparate sources. ORFanID is a graphical web-based search engine that efficiently finds orphan genes and TRGs at all taxonomic levels, from DNA or amino acid sequences in the entire NCBI database cluster and other large bioinformatics repositories. To our knowledge, this is the first program that allows the identification of orphan genes using both nucleotide and protein sequences in any species of interest.

ORFanID identifies genes unique to any taxonomic rank, from species to a domain, using standard NCBI systematic classifiers. The software allows for user control of the NCBI database search parameters. The results of the search are provided in a spreadsheet as well as a graphical display. All the tables in the software are sortable by column, and results can be easily filtered with fuzzy search functionality. In addition, the visual presentation is expandable and collapsible by taxonomy.


title: Accurate and robust inference of genetic ancestry from cancer-derived molecular data across genomic platforms

abstract: Genetic ancestry-oriented cancer research requires the ability to perform accurate and robust ancestry inference from existing cancer-derived data, including whole exomes, transcriptomes and targeted gene panels, very often in the absence of matching cancer-free genomic data. In order to optimize and assess the performance of the ancestry inference for any given input cancer-derived molecular profile, we develop a data synthesis framework. In its core procedure, the ancestral background of the profiled patient is replaced with one of any number of individuals with known ancestry. Data synthesis is applicable to multiple profiling platforms and makes it possible to assess the performance of inference separately for each continental-level ancestry. This ability extends to all ancestries, including those without statistically sufficient representation in the existing cancer data. We further show that our inference procedure is accurate and robust in a wide range of sequencing depths. Testing our approach for three representative cancer types, and across three molecular profiling modalities, we demonstrate that global, continental-level ancestry of the patient can be inferred with high accuracy, as quantified by its agreement with the golden standard of the ancestry derived from matching cancer-free molecular data. Our study demonstrates that vast amounts of existing cancer-derived molecular data potentially are amenable to ancestry-oriented studies of the disease, without recourse to matching cancer-free genomes or patients self-identification by ancestry.


title: Characterization of the adult zebrafish electrocardiogram

abstract:
BackgroundThe use of zebrafish to explore cardiac physiology has been widely adopted within the scientific community. Whether this animal model can be used to determine drug cardiac toxicity via electrocardiogram (ECG) analysis, is still an ongoing question. Several reports indicate that the recording configuration severely affects the ECG waveforms and its derived-parameters, emphasizing the need for improved characterization.

MethodsECGs were recorded from adult zebrafish hearts in 3 different configurations (unexposed heart, exposed heart and extracted heart) to identify the most reliable method to explore ECG recordings at baseline and in response to commonly used clinical therapies.

ResultsWe found that the exposed heart configuration provided the most reliable and reproducible ECG recordings of waveforms and intervals. We were unable to determine T-wave morphology in unexposed hearts. In extracted hearts, ECG intervals were lengthened and P-waves were unstable. However, in the exposed heart configuration, we were able to reliably record ECGs and subsequently establish the QT-RR relationship (Holzgrefe correction) in response to changes in heart rate.

ConclusionsThe exposed heart configuration appears to be the most reliable technique to record ECGs in adult zebrafish. In this configuration, the QT-RR relationship, an important parameter in cardiac toxicity evaluation, can be determined using the Holzgrefe correction.


title: An integrative approach: using transcriptomic data and network analysis of transcriptional reprogramming in tomato response to PSTVd variants

abstract: Viroids are minimal pathogens of angiosperms, consisting of non-coding RNAs that cause severe diseases in agronomic crops. Symptoms associated with viroid infection are linked to developmental alterations due to genetic regulation. To understand the global molecular mechanisms of host response, we implemented an omics approach to identify master transcription regulators (MTRs) and their differentially expressed targets in tomato infected with mild and severe variants of PSTVd. Our approach integrates root and leaf transcriptomic data, gene regulatory network analysis, and identification of affected biological processes. Overall, our results reveal that specific bHLH, MYB, and ERF transcription factors regulate genes involved in molecular mechanisms underlying critical signaling pathways. Functional enrichment of regulons shows that bHLH-MTRs are linked to metabolism and plant defense, while MYB-MTRs are involved in signaling regulation and hormone-related processes. Strikingly, a member of the bHLH-TF family have a potential specific role as a microprotein involved in the post-translational regulation of hormone signaling events. For the severe variant, ERF-MTRs are characteristic, while ZNF-TF, tf3a-TF, BZIP-TFs, and NAC-TF act as unique MTRs. Altogether, our results lay a foundation for further research on the PSTVd and host genome interaction, providing evidence for identifying potential key genes that influence symptom development in tomato plants.


title: Musical expertise shapes visual-melodic memory integration

abstract: Music can act as a powerful mnemonic device that can elicit vivid episodic memories. However, how musical information is integrated with non-musical information is largely unknown. Here, we investigated whether and how musical expertise modulates binding of melodies and visual information into integrated memory representations. We reasoned that the significant mnemonic demands of musicianship might alter the underlying integration process and reveal mechanisms by which music promotes retrieval of non-musical memories. Professional musicians and musical laypersons learned overlapping pairs of everyday objects and melodies (AB- and BC-pairs, object-melody and melody-object pairs). Participants were then tested for memory of studied pairs (direct trials) and for inferential AC-decisions (indirect trials). Although musicians showed a higher overall performance than non-musicians, both groups performed well above chance level in both trial types. Non-musicians reacted faster in indirect compared to direct trials, whereas the reverse pattern was found in musicians. Differential correlations of trial type performance between groups further suggested that non-musicians efficiently formed integrated ABC-triplets already during the encoding phase of the task, while musicians separately memorized AB- and BC-pairs and recombined them at retrieval for AC-decisions. Our results suggest that integrative encoding is a default mechanism for integration of musical and non-musical stimuli that works with great efficacy even in musically untrained subjects and may contribute to the everyday experience of music-evoked episodic memories. By contrast, recombination at retrieval seems to be an advanced strategy for memory integration that critically depends on an expert ability to maintain and discriminate musical stimuli across extended memory delays.


title: Gamma Oscillations and Emotional Memory

abstract: Increased visual gamma band activity is known to relate to memory and encoding in cognitive tasks and has been shown to be present during arousing compared to neutral stimulus processing. Here, we set out to investigate whether gamma activity is stronger for later remembered compared to later forgotten emotional pictures. Thirty-two healthy participants underwent a passive viewing task in which they viewed 208 (104 arousing (52 pleasant and 52 unpleasant) and 104 neutral) pictures from the International Affective Picture System (IAPS) database while we simultaneously recorded their electroencephalogram (EEG). Immediately after, they performed a recognition task including the 208 target pictures they saw before and 104 new pictures (52 arousing (26 pleasant and 26 unpleasant) and 52 neutral) as lures. We found that arousing pictures (unpleasant ones in particular) were better remembered compared to neutral pictures. Importantly, gamma activity was enhanced for remembered compared to forgotten pictures and this effect was stronger for arousing pictures. We conclude that previous findings regarding enhanced gamma as a signature of subsequent memory generalizes to emotional memory. Our findings therefore shed new light on the role of visual gamma band activity in arousal and memory formation.


title: Poor matching of action codes challenges 'mirroring' in macaque F5 mirror neurons

abstract: The discharge of F5 mirror neurons of a monkey observing another individual performing an action has been interpreted as a motor representation, stimulated by sensory input, ultimately serving action understanding. This hypothesis requires mirror neurons to exhibit an action tuning that is matched between action observation and execution. However, the evidence for this is insufficient, mainly because previous work has suffered from a limited exploration of action space tuning and an object vs. action vision confound. To overcome these limitations, we conducted an experiment in which identical objects had to be manipulated in three different ways in order to serve distinct action goals. We show that the population of F5 mirror neurons can dissociate the three actions almost perfectly, during both observation and execution. However, the population code for action execution was only poorly matched to the code for observation. Just a few neurons exhibited only matched codes, yet, always confined to short, varying segments of the overall action. These findings challenge the hypothesis that an observer understands the actions of others by the activation of motor representations of the observed actions. Rather they support the alternative notion that F5 might use information on observed actions to select behavioral responses.


title: A novel hidden Markov approach to studying dynamic functional connectivity states in human neuroimaging

abstract:
IntroductionHidden Markov models are a popular choice to extract and examine recurring patterns of activity or functional connectivity in neuroimaging data, both in terms of spatial patterns and their temporal progression. Although many diverse hidden Markov models have been applied to neuroimaging data, most have defined states based on activity levels (intensity-based states) rather than patterns of functional connectivity between brain areas (connectivity-based states), which is problematic if we want to understand connectivity dynamics: intensity-based states are unlikely to provide useful information about dynamic connectivity patterns.

MethodsWe addressed this problem by introducing a new hidden Markov model that defines states based on full functional connectivity profiles among brain regions. We empirically explored the behavior of this new model in comparison to existing approaches based on intensity-based or summed functional connectivity states using the HCP unrelated 100 functional magnetic resonance imaging "resting state" dataset.

ResultsOur  full functional connectivity model discovered connectivity states with more distinguishable patterns than previous approaches, and recovered simulated connectivity-based states more faithfully.

DiscussionThus, if our goal is to extract and interpret connectivity states in neuroimaging data, our new model outperforms previous methods which miss crucial information about the evolution of functional connectivity in the brain.

Impact statementHidden Markov models can be used to investigate brain states noninvasively. Previous models "recover" connectivity from intensity-based hidden states, or from connectivity  summed across nodes. Here we introduce a novel connectivity-based hidden Markov model and show how it can reveal true connectivity hidden states under minimal assumptions.


title: A novel rhesus macaque model of Huntington's disease recapitulates key neuropathological changes along with progressive motor and cognitive decline

abstract: We created a new nonhuman primate model of the genetic neurodegenerative disorder, Huntingtons disease (HD), by injecting a mixture of recombinant adeno-associated viral vectors, serotypes AAV2 and AAV2.retro, each expressing a fragment of human mutant HTT (mHTT) into the caudate and putamen of adult rhesus macaques. This novel modeling strategy results in robust expression of mutant huntingtin protein (mHTT) in the injected brain regions, as well as dozens of other cortical and subcortical brain regions that are also affected in human HD patients. We queried the disruption of cortico-basal ganglia circuitry for 20-months post-surgery using a variety of behavioral and imaging readouts. Compared to controls, mHTT-treated macaques developed progressive working memory decline and motor impairment. Multimodal imaging revealed circuit-wide white and gray matter degenerative processes in several key brain regions affected in HD. This novel model will aid in the development of disease biomarkers and therapeutic strategies for this devastating disorder.


title: The outer-hair-cell RC time constant: A feature, not a bug, of the mammalian cochlea

abstract: The cochlea of the mammalian inner ear includes an active, hydromechanical amplifier thought to arise via the piezoelectric action of the outer hair cells (OHCs). A classic problem of cochlear biophysics is that the long resistance-capacitance (RC) time constant of the hair-cell membrane produces an effective cut-off frequency much lower than that of most audible sounds. The long RC time constant implies that the OHC receptor potential--and hence its electromotile response--decreases by several orders of magnitude over the frequency range of hearing. This "RC problem" is often invoked to question the role of cycle-by-cycle OHC-based amplification in mammalian hearing. Here, we use published data and simple physical reasoning to show that the RC problem is, in practice, a relatively minor physical issue whose importance has been unduly magnified by viewing it through the wrong lens. Indeed, our analysis indicates that the long RC time constant is actually beneficial for hearing, reducing noise and distortion while increasing the fidelity of cochlear amplification.


title: Sensory target detection at local and global time scales dissociates modality-specific and supramodal dynamics in the cortical hierarchy

abstract: How do cortical networks support the detection of irregular sensory events for different senses? Here we reconcile two views of cortical function according to which supramodal processing is either deferred to associative cortices in higher levels of a unimodal-to-supramodal cortical hierarchy or features across all cortical processing stages. In a series of hierarchical multisensory target detection studies using EEG, we applied a temporal cross-decoding approach to reveal the cortical dynamics elicited by rule-based global and feature-based local sensory deviations within and between the visual, somatosensory and auditory modality. We uncovered simple feature-based sensory deviations presented in temporal vicinity to a monotonous input stream triggered an MMN-like local negativity which decayed quickly and early in different sensory modalities. Conversely, complex rule-based targets tracked across time evoked a P3b-like global effect which generalised across a late time window. Ultimately, a series of temporal cross-modality decoding analyses demonstrated that global effects are maintained in supramodal networks whereas local effects propagate along modality-specific cortical networks and evolve into short-lived supramodal activity. Taken together, each sense implements a cortical hierarchy which orchestrates target detection responses operating on local and global time scales at successive processing stages. Converging evidence from different analyses and studies, we show that cortical organisation largely follows a gradient in which modality-specific processes dominate local responses and higher-order processes encode abstract supramodal information fed forward from modality-specific cortices. In conclusion, the cortex implements a hierarchy which hosts increasingly supramodal processes in each level rather than a strict hierarchy which delays supramodal function to associative cortices.


title: High resolution micro-CT imaging in mice stroke models: from 3D detailed infarct characterization to automatic area segmentation

abstract: Characterization of brain infarct lesion in rodent models of stroke is crucial to assess the outcome of stroke therapies and to study the disease pathophysiology. However, so far it has been mostly performed by: 1) histological methods, a time-consuming process that lead to significant flaws and tissue distortion; or 2) via MRI imaging, which is faster, yielding 3D information but at high costs. High-resolution micro-CT imaging became, in the last decade, a simple, fast, and cheaper solution, allowing 3D analysis of samples. Here, we describe that high-resolution micro-CT, either using iodine/OsO4 as contrast agents, can be successfully applied for fine quantification and localization of lesion size and edema volume in preclinical stroke models. We successfully correlated this new approach with the standard histological method TTC. In transient MCAO mouse stroke model, we were able to identify/quantify large lesioned areas (segmented in core and penumbra), up to degenerated finer striatal myelinated fibers in a transient ischemic attack (TIA) mouse model, at different timepoints post-ischemia, through manual and automatic segmentation approaches (deep learning). Furthermore, 3D reconstructions of the whole brain allow for brain atlas co-registration of the specific affected brain areas. Hence, the presented methodology, through iodine/OsO4 micro-CT imaging, constitutes a valuable advance in tools for precise and detailed assessment of stroke outcomes in preclinical animal studies.


title: Scratching bouts are modeled as Bernoulli trials until successful itch-extinguishing in mice

abstract: Itching and subsequent scratching behavior have been observed in many species, including humans. The behavior was evolved to remove skin parasites. Yet, scratching is performed without reliable indicators of whether a parasite is present. We addressed this apparent paradox by studying scratching in mice. Video recordings of ~5000 scratching bouts were collected in free-moving C57BL6/J mice. The statistical properties of their temporal sequence were analyzed. Inter-bout time intervals preceding over 50% of 5000 bouts were <10 s. We hypothesized that episodes of repetitive scratching corresponded to the duration of discrete events of itch sensation and comprised bouts separated by inter-bout intervals of <10 s. The distribution of itch episodes comprising n (n = 1, 2, 3, ...) scratching bouts was well-approximated by the geometric distribution with success probability = 0.5 in healthy mice and lower probability in dry skin mice. This suggests that scratching bouts are modeled by probabilistic Bernoulli trials, and their repetitive sequence in each episode continues until the itch is successfully extinguished. Accordingly, we can presume the presence of parasites from the repeat length of scratching bouts determined by the probability of successful itch-extinguishing. This may provide a promising stochastic model to assess itchy phenotypes.


title: No evidence that post-training D2R dopaminergic drug administration affects differential fear responding in rats

abstract: The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear. The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) in differential fear responding in male Wistar rats. In a series of five experiments, D2R dopaminergic drugs were injected systemically after differential cued fear conditioning. One day later, the differential expression of acquired fear was assessed. All five experiments involved the administration of the D2R agonist quinpirole at different doses or saline (n = 12, 16 or 44 rats/treatment condition). Additionally, one of the studies administered the D2R antagonist raclopride (n = 12 rats/treatment condition). We found no indications for an effect of quinpirole or raclopride on differential fear responding during a later drug-free test. In addition, there were no effects of treatment on baseline freezing levels (i.e., before tone onset) or freezing during the conditioned tones (CS+) at test. We did observe acute behavioral effects of both drugs on a locomotor activity test.


title: Human orbitofrontal cortex signals decision outcomes to sensory cortex during behavioural adaptations

abstract: The ability to respond adaptively to an ever-changing environment relies on the orbitofrontal cortex (OFC). The OFC sends neuroanatomical projections to the primary sensory cortex - yet the contribution of this top-down feedback projection to behavioural flexibility in humans is unknown. Inspired from recent rodent studies, we here combined a probabilistic Go/No-Go tactile reversal learning task with functional magnetic resonance imaging (fMRI) in human participants to investigate how OFC interacts with the primary somatosensory cortex (S1) to promote flexible decision-making. We show a distinct task-dependent engagement of S1 and lateral OFC: while the lateral OFC responds saliently and transiently to rule-switches, activity in S1 reflects initial task learning and persistent engagement after each rule-switch event. Unlike the contralateral S1, which represents the sensory input, activity in ipsilateral S1 mirrors the outcome value during re-learning. Importantly, the implementation of this outcome-selectivity in ipsilateral S1 is dependent on top-down  teaching signals from lateral OFC. Overall, as in mice, we show comparable physiological and computational signatures of how dynamic interactions between OFC and sensory cortex support flexible decision-making in humans.


title: Evidence for independent processing of shape by vision and touch

abstract: Although visual object recognition is well-studied and relatively well understood, much less is understood about how shapes are recognized by touch and how such haptic stimuli might be compared to visual shapes. One might expect that the processes of visual and haptic object recognition engage identical brain structures given the similarity of the problem and the advantages of avoiding redundant brain circuitry, but it has not yet been established the extent to which this is true. We recruited human participants to perform a one-back same-different visual and haptic shape comparison task both within (i.e., comparing two visual shapes or two haptic shapes) and across (i.e., comparing visual with haptic shapes) modalities. Participants saw or felt a shape and responded according to whether they thought the shape was the same or different from the previously felt or seen shape. We then used various shape metrics to predict performance based on the shape, orientation, and modality of the two stimuli which were being compared on each trial. We found that the fixed orientation of the shape stimuli was an important factor for predicting within-modal behavior, but the orientation of shapes compared across modality did not depend on knowing the presented orientation. We also found that the metrics which best predict shape comparison behavior heavily depended on the modality of the two shapes. We take these results as evidence that object recognition is not necessarily performed in a single, modality-agnostic region.


title: Genetic population structure across Brittany and the downstream Loire basin provides new insights on the demographic history of Western Europe

abstract: European genetic ancestry originates from three main ancestral populations - Western hunter-gatherers, early European farmers and Yamnaya Eurasian herders - whose edges geographically met in present-day France. Despite its central role to our understanding of how the ancestral populations interacted and gave rise to modern population structure, the population history of France has remained largely understudied. Here, we analysed 856 high-coverage whole-genome sequences along with genome-wide genotyping data of 3,234 present-day individuals from the northern half of France and merged them with publicly available present-day and ancient Europe-wide genotype datasets. We also analysed, for the first time, the whole-genome sequences of six medieval individuals (300-1100 CE) from Western France to gain insights into the genetic impact of what is commonly known as the Migration Period in Europe. We found extensive fine-scale population structure across Brittany and the downstream Loire basin, emphasizing the need for investigating local populations to better understand the distribution of rare and putatively deleterious variants across space. Overall, we observed an increased population differentiation between the northern and southern sides of the river Loire, which are characterised by different proportions of steppe vs. Neolithic-related ancestry. Samples from Western Brittany carry the largest levels of steppe ancestry and show high levels of allele sharing with individuals associated with the Bell Beaker complex, levels that are only comparable with those found in populations lying on the northwestern edges of Europe. Together, our results imply that present-day individuals from Western Brittany retain substantial legacy of the genetic changes that occurred in Northwestern Europe following the arrival of the Bell Beaker people c. 2500 BCE. Such genetic legacy may explain the sharing of disease-related alleles with other present-day populations from Western Britain and Ireland.

category: genetics


title: A Prism Vote Framework for Individualized Risk Prediction of Traits in Genome-wide Sequencing Data of Multiple Populations

abstract: Multi-population cohorts offer unprecedented opportunities for profiling disease risk in large samples, however, heterogeneous risk effects underlying complex traits across populations make integrative prediction challenging. In this study, we propose a novel Bayesian probability framework, the Prism Vote (PV), to construct risk predictions in heterogeneous genetic data. The PV views the trait of an individual as a composite risk from subpopulations, in which stratum-specific predictors can be formed in data of more homogeneous genetic structure. Since each individual is represented by a composition of subpopulation memberships, the framework enables individualized risk characterization. Simulations demonstrated that the PV framework applied with alternative prediction methods significantly improved prediction accuracy in mixed and admixed populations. The advantage of PV enlarges as the sample size, genetic heterogeneity, and population diversity increase. In two real genome-wide association data consists of multiple populations, we showed that the framework enhanced prediction accuracy of the linear mixed model by up to 12.1% in five-group cross validations. The proposed framework offers a new aspect to analyze individuals disease risk and improve accuracy for predicting complex traits in genome data.