title: A diagnostic relationship between the RNA Integrity Number equivalent and Time Since Deposition of blood

abstract:
Determining the time since deposition (TSD) of bloodstains would provide forensic scientists with critical information regarding the timeline of the events involving bloodshed. The physicochemical changes occurring to biomolecules as a bloodstain degrades can be used to approximate the TSD of bloodstains. Our study aims to quantify the timewise degradation trends and temperature dependence found in total RNA from bloodstains without the use of amplification, expanding the scope of the RNA TSD research which has previously targeted mRNA molecules. Whole bovine blood was stored in plastic microcentrifuge tubes at 21{degrees}C or 4{degrees}C and tested over different timepoints spanning one week. Nine RNA metrics were visually assessed and quantified using linear and mixed models; the RNA Integrity Number equivalent (RINe) and the DV200 demonstrated strong negative trends over time and statistical independence. The RINe model fit was high (R2 = 0.60), and while including the biological replicate as a random effect increased the fit for all RNA metrics, no significant differences were found between biological replicates stored at the same temperature for the RINe and DV200 metrics. Importantly, this suggests that these standardized metrics can likely be directly compared between scenarios and individuals, with DV200 having an inflection point at [~]28 hrs. This study provides a novel approach for blood TSD estimates, producing metrics that are not affected by inter-individual variation and improving our understanding of the rapid degradation occurring in bloodstains.

HIGHLIGHTSO_LIAmplification-free analysis of total RNA in degrading bloodstains.
C_LIO_LIShort-term RNA degradation assessment using high-resolution size measurements.
C_LIO_LITotal RNA quality and quantity metrics were assessed across a one-week.
C_LIO_LITotal RNA quality metrics demonstrated the strongest timewise trends.
C_LIO_LIBiological replicates produced similar results for RNA quality metrics.
C_LI

category: genetics


title: RNA degradation of blood reveals a time diagnostic window in a controlled environment


title: Using total RNA quality metrics for time since deposition estimates in degrading bloodstains


title: Accurate detection of RNA stem-loops in structurome data reveals widespread association with protein binding sites

abstract: RNA molecules are known to fold into specific structures which often play a central role in their functions and regulation. In silico folding of RNA transcripts, especially when assisted with structure profiling (SP) data, is capable of accurately elucidating relevant structural conformations. However, such methods scale poorly to the swaths of SP data generated by transcriptome-wide experiments, which are becoming more commonplace and advancing our understanding of RNA structure and its regulation at global and local levels. This has created a need for tools capable of rapidly deriving structural assessments from SP data in a scalable manner. One such tool we previously introduced that aims to process such data is patteRNA, a statistical learning algorithm capable of rapidly mining big SP datasets for structural elements. Here, we present a reformulation of patteRNAs pattern recognition scheme that sees significantly improved precision without major compromises to computational overhead. Specifically, we developed a data-driven logistic classifier which interprets patteRNAs statistical characterizations of SP data in addition to local sequence properties as measured with a nearest neighbor thermodynamic model. Application of the classifier to human structurome data reveals a marked association between detected stem-loops and RNA binding protein (RBP) footprints. The results of our application demonstrate that upwards of 30% of RBP footprints occur within loops of stable stem-loop elements. Overall, our work arrives at a rapid and accurate method for automatically detecting families of RNA structure motifs and demonstrates the functional relevance of identifying them transcriptome-wide.

category: genomics


title: Structural basis of the P4B ATPase lipid flippase activity

abstract: P4 ATPases are lipid flippases that are phylogenetically grouped into P4A, P4B and P4C clades. The P4A ATPases are heterodimers composed of a catalytic -subunit and accessory {beta}-subunit, and the structures of several heterodimeric flippases have been reported. The S. cerevisiae Neo1 and its orthologs represent the P4B ATPases, which function as monomeric flippases without a {beta}-subunit. It has been unclear whether monomeric flippases retain the architecture and transport mechanism of the dimeric flippases. Here we report the first structure of a P4B ATPase, Neo1, in its E1-ATP, E2P-transition, and E2P states. The structure reveals a conserved architecture as well as highly similar functional intermediate states relative to dimeric flippases. Consistently, structure-guided mutagenesis of residues in the proposed substrate translocation path disrupted Neo1s ability to establish membrane asymmetry. These observations indicate that evolutionarily distant P4 ATPases use a structurally conserved mechanism for substrate transport.

category: biochemistry


title: A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb

abstract: The protein-protein interaction between the KIX motif of the transcriptional coactivator CBP/p300 and the transcriptional activator Myb is a high value target due to its established role in certain acute myeloid leukemias (AML) and potential contributions to other cancers. However, the CBP/p300 KIX domain has multiple binding sites, several structural homologues, many binding partners, and substantial conformational plasticity, making it challenging to specifically target using small molecule inhibitors. Here, we report a picomolar dual-site inhibitor (MybLL-tide) of the Myb-CBP/p300 KIX interaction. MybLL-tide has higher affinity for CBP/p300 KIX than any previously reported compounds while also possessing 16,000-fold selectivity for the CBP/p300 KIX domain over other coactivator domains. MybLL-tide blocks the association of CBP and p300 with Myb in the context of the proteome leading to inhibition of key Myb*KIX-dependent genes in AML cells. These results show that MybLL-tide is an effective, modifiable tool to selectively target the KIX domain and assess transcriptional effects in AML cells and potentially other cancers featuring aberrant Myb behavior. Additionally, the dual-site design has applicability to the other challenging coactivators that bear multiple binding surfaces


title: Selection of Sites for Field Trials of Genetically Engineered Mosquitoes with Gene Drive.

abstract: Novel malaria control strategies using genetically engineered mosquitoes (GEMs) are on the horizon. Population modification is one approach wherein mosquitoes are engineered with genes rendering them refractory to the malaria parasite coupled with a low-threshold, Cas9-based gene drive. When released into a wild vector population, GEMs preferentially transmit these beneficial genes to their offspring, ultimately modifying a vector population into a non-vector one. Deploying this technology awaits evaluation including ecologically contained field trials. Here, we consider a process for site selection, the first critical step in designing a trial. Our goal is to identify a site that maximizes prospects for success, minimizes risk, and serves as a fair, valid, and convincing test of efficacy and impacts of a GEM product intended for large-scale deployment in Africa. We base site selection on geographical, geological, and biological, rather than social or legal, criteria. We recognize the latter as critically important but not preeminent. We propose physical islands as being the best candidates for a GEM field trial and present an evaluation of 22 African islands. We consider geographic and genetic isolation, biological complexity, island size, topography, and identify two island groups that satisfy key criteria for ideal GEM field trial sites.

category: bioengineering


title: Mechanistic Insights on ATP's role as Hydrotrope

abstract: Hydrotropes are small amphiphilic molecules which help in solubilizing hydrophobic entities in aqueous medium. Recent experimental investigation has provided convincing evidences that, adenosine triphosphate (ATP), besides being an energy currency of cell, also can act as hydrotrope to inhibit the formation of protein condensates. In this work, we have designed computer simulations of prototypical macromolecules in aqueous ATP solution to dissect the molecular mechanism underlying ATPs newly discovered role as a hydrotrope. The simulation demonstrates that ATP can unfold a single-chain of hydrophobic macromolecule as well as can disrupt the aggregation process of a hydrophobic assembly. Moreover, the introduction of charges in the macromolecule is found to reinforce ATPs disaggregation effects in a synergistic fashion, a behaviour reminiscent of recent experimental observation of pronounced hydrotropic action of ATP in intrinsically disordered proteins. A molecular analysis indicates that this new-found ability of ATP are ingrained in its propensity of preferential binding to the polymer surface, which gets fortified in presence of charges. The investigation also renders evidence that the key to the ATPs superior hydrotropic role over chemical hydrotrope (Sodium xylene sulfonate, NaXS) may lie in its inherent self-aggregation propensity. Overall, via employing a bottom-up approach the current investigation provides fresh mechanistic insights into the dual solubilizing and denaturing abilities of ATP.

category: biophysics


title: Can active hydrodynamic fluctuations affect barrier crossing during enzymatic catalysis?

abstract: The cellular milieu is teeming with biochemical nano-machines whose activity is a strong source of correlated non-thermal fluctuations termed active noise. Essential elements of this circuitry are enzymes, catalysts that speed up the rate of metabolic reactions by orders of magnitude, thereby making life possible. Here, we examine the possibility that active noise in the cell, or in vitro, affects enzymatic catalytic rate by accelerating or decelerating the crossing rate of energy barriers during the reaction. Considering hydrodynamic perturbations induced by biochemical activity as a source of active noise, we evaluate their impact on the enzymatic cycle using a combination of analytic and numerical methods. Our estimates show that the fast component of the active noise spectrum enhances the rate of enzymes, while reactions remain practically unaffected by the slow noise spectrum. Revisiting the physics of barrier crossing under the influence of active hydrodynamic fluctuations suggests that the biochemical activity of macromolecules such as enzymes is coupled to active noise. Thus, we propose that enzymatic catalysis is a collective, many-body process in which enzymes may affect each others activity via long-range hydrodynamic interaction, with potential impact on biochemical networks in living and artificial systems alike.


title: Acceleration of enzymatic catalysis by active hydrodynamic fluctuations


title: Using 3D geometric morphometrics to aid taxonomic and ecological understanding of a recent speciation event within a small Australian marsupial (genus Antechinus)

abstract: Taxonomic distinction of species forms the foundation of biodiversity assessments and conservation priorities. However, traditional morphological and/or genetics-based taxonomic assessments frequently miss the opportunity of elaborating on the ecological and functional context of species diversification. Here, we used 3D geometric morphometrics of the cranium to improve taxonomic differentiation and add eco-morphological characterisation of a young cryptic divergence within the marsupial carnivorous genus Antechinus. Specifically, we used 168 museum specimens to characterise the recently proposed clades A. stuartii "south", A. stuartii "north" and A. subtropicus. Beyond slight differences attributable to overall size (and therefore not necessarily diagnostic), we also found clear allometry-independent shape variation. This allowed us to define new, easily measured diagnostic traits in the palate, which differentiate the three clades. Contrary to previous suggestions, we found no support for a latitudinal gradient as causing the differentiation between the clades. However, skull shape co-varied with temperature and precipitation seasonality, suggesting that the clades may be adapted to environmental variables that are likely to be impacted by climate change. Our study demonstrates the use of 3D geometric morphometrics to improve taxonomic diagnosis of cryptic mammalian species, while providing perspectives on the adaptive origins and potential future threats of mammalian diversity.

category: zoology


title: Fragmentation of macrophages during isolation confounds analysis of single cell preparations from mouse hematopoietic tissues

abstract: Mouse hematopoietic tissues contain abundant and heterogeneous populations of tissue-resident macrophages attributed trophic functions in control of immunity, hematopoiesis and bone homeostasis. A systematic strategy to characterise macrophage subsets in mouse bone marrow (BM), spleen and lymph node, unexpectedly revealed macrophage surface marker staining typically emanated from membrane-bound subcellular remnants associated with unrelated cell types. Remnant-restricted macrophage-specific membrane markers, cytoplasmic fluorescent reporters and mRNA were all detected in non-macrophage cell populations including isolated stem and progenitor cells. The profile of macrophage remnant association reflects adhesive interactions between macrophages and other cell types in vivo. Applying this knowledge, reduced macrophage remnant attachment to BM granulocytes in Siglec1 deficient mice was associated with compromised emergency granulocytosis, revealing a function for Siglec1-dependent granulocyte-macrophage interactions. Analysis of published RNA-seq data for purified macrophage and non-macrophage populations indicates that macrophage fragmentation is a general phenomenon that confounds bulk and single cell analysis of disaggregated tissues.

category: immunology


title: Unraveling the critical growth factors for stable cultivation of (nano-sized) Micrarchaeota

abstract: Micrarchaeota are members of the archaeal DPANN superphylum. These so far poorly characterized archaea have been found to have reduced genomes and likely depend on interactions with host organisms for growth and survival. Here we report on the enrichment of the first stable co-culture of a member of the Micrarchaeota together with its host, as well as the isolation of the latter. Electron microscopic analysis suggest that growth is dependent on the physical interaction of the two organisms within a biofilm. The interaction seems to be ensured by the necessity to grow in form of a biofilm. Furthermore, transcriptomic analyses indicate a shift towards biofilm formation of the host as a result of co-cultivation. Finally, genomic, metabolomic, extracellular polymeric substance (EPSs) and lipid content analyses reveal that the Micrarchaeon symbiont relies on the acquisition of metabolites from its host and thereby provide first insights into the basis of symbiont-host interactions.

category: microbiology


title: Genetic determinants of endophytism in the Arabidopsis root mycobiome

abstract: Roots of Arabidopsis thaliana do not engage in symbiotic associations with mycorrhizal fungi but host taxonomically diverse fungal communities that influence health and disease states. We sequenced the genomes of 41 fungal isolates representative of the A. thaliana root mycobiota for comparative analysis with 79 other plant-associated fungi. We report that root mycobiota members evolved from ancestors with diverse lifestyles and retained large repertoires of plant cell wall-degrading enzymes (PCWDEs) and effector-like small secreted proteins. We identified a set of 84 gene families predicting best endophytism, including families encoding PCWDEs acting on xylan (GH10) and cellulose (AA9). These genes also belong to a core transcriptional response induced by phylogenetically-distant mycobiota members in A. thaliana roots. Recolonization experiments with individual fungi indicated that strains with detrimental effects in mono-association with the host not only colonize roots more aggressively than those with beneficial activities but also dominate in natural root samples. We identified and validated the pectin degrading enzyme family PL1_7 as a key component linking aggressiveness of endophytic colonization to plant health.


title: ROMO1 is essential for glucose coupling in the pancreatic beta cell of male mice

abstract: Reactive oxygen species modulator 1 (ROMO1) is a highly conserved inner mitochondrial membrane protein that senses ROS and regulates mitochondrial dynamics 1. ROMO1 is required for mitochondrial fusion in vitro, and silencing ROMO1 increases sensitivity to cell death stimuli. How ROMO1 promotes mitochondrial fusion and its physiological role remain unclear. Here we show that ROMO1 is essential for embryonic development, as ROMO1-null mice die before embryonic day 8.5, earlier than GTPases OPA1 or MFN1/2 that catalyze mitochondrial membrane fusion. Knockout of ROMO1 in adult pancreatic {beta} cells results in impaired glucose homeostasis in male mice due to an insulin secretion defect resulting from impaired glucose sensing. Mitochondria in ROMO1 {beta} cell KO cells were swollen and fragmented, consistent with a role for ROMO1 in mitochondrial fusion in vivo. While basal respiration was normal in ROMO1{beta} cell KO islets, spare respiratory capacity was lost. Taken together, our data indicate that ROMO1 is required for nutrient coupling in the {beta} cell and point to a critical role for spare respiratory capacity in the maintenance of euglycemia in males.

category: cell biology


title: Ability of known colorectal cancer susceptibility SNPs to predict colorectal cancer risk: A cohort study within the UK Biobank

abstract: Colorectal cancer risk stratification is crucial to improve screening and risk-reducing recommendations, and consequently do better than a one-size-fits-all screening regimen. Current screening guidelines in the UK, USA and Australia focus solely on family history and age for risk prediction, even though the vast majority of the population do not have any family history. We investigated adding a polygenic risk score based on 45 single-nucleotide polymorphisms to a family history model (combined model) to quantify how it improves the stratification and discriminatory performance of 10-year risk and full lifetime risk using a prospective population-based cohort within the UK Biobank. For both 10-year and full lifetime risk, the combined model had a wider risk distribution compared with family history alone, resulting in improved risk stratification of nearly 2-fold between the top and bottom risk quintiles of the full lifetime risk model. Importantly, the combined model can identify people (n=72,019) who do not have family history of colorectal cancer but have a predicted risk that is equivalent to having at least one affected first-degree relative (n=44,950). We also confirmed previous findings by showing that the combined full lifetime risk model significantly improves discriminatory accuracy compared with a simple family history model 0.673 (95% CI 0.664-0.682 versus 0.666 (95% CI 0.657-0.675), p=0.0065. Therefore, a combined polygenic risk score and first-degree family history model could be used to improve risk stratified population screening programs.


title: No increased circular inference in autism or autistic traits

abstract:
Autism spectrum disorders have been proposed to arise from impairments in the probabilistic integration of prior knowledge with sensory inputs. Circular inference is one such possible impairment, in which excitation-to-inhibition imbalances in the cerebral cortex cause the reverberation and amplification of prior beliefs and sensory information. Recent empirical work has associated circular inference with the clinical dimensions of schizophrenia. Inhibition impairments have also been observed in autism, suggesting that signal reverberation might be present in that condition as well. In this study, we collected data from 21 participants with diagnosed autism spectrum disorders and 155 participants with a broad range of autistic traits in an online probabilistic decision-making task (the fisher task). We used previously established Bayesian models to investigate possible associations between autism or autistic traits and circular inference. No differences in prior or likelihood reverberation were found between autistic participants and those with no diagnosis. Similarly, there was no correlation between any of the circular inference model parameters and autistic traits across the whole sample. Furthermore, participants incorporated information from both priors and likelihoods in their decisions, with no relationship between their weights and psychiatric traits, contrary to what common theories for both autism and schizophrenia would suggest. These findings suggest that there is no increased signal reverberation in autism, despite the known presence of excitation-to-inhibition imbalances. They can be used to further contrast and refine the Bayesian theories of schizophrenia and autism, revealing a divergence in the computational mechanisms underlying the two conditions.

Author SummaryPerception results from the combination of our sensory inputs with our brains previous knowledge of the environment. This is usually described as a process of Bayesian inference or predictive coding and is thought to underly a multitude of cognitive modalities. Impairments in this process are thought to explain various psychiatric disorders, in particular autism and schizophrenia, for which similar Bayesian theories have been proposed despite important differences in their symptoms. Recently, a new model of Bayesian impairment in schizophrenia has been proposed and validated using behavioural experiments, called the "circular inference" model. In the current study, we used the same task and computational modelling to explore whether circular inference could also account for autism spectrum disorder. We find that participants with autistic traits or diagnoses of autism do not present increased levels of circularity. This is the first study to investigate circular inference in autism, and one of the very few to explore possible autism and schizophrenia impairments with the same task and identical analytical methods. Our findings indicate one potential way in which the explanations of the two conditions might differ.

category: pathology


title: Red blood cells protect oxygen transport with adrenergic sodium-proton exchangers in hypoxic and hypercapnic white seabass

abstract: White seabass (Atractoscion nobilis) are increasingly experiencing periods of low oxygen (O2; hypoxia) and high carbon dioxide (CO2, hypercapnia) due to climate change and eutrophication of the coastal waters of California. Hemoglobin (Hb) is the principal O2 carrier in the blood and in many teleost fishes Hb-O2 binding is compromised at low pH; however, the red blood cells (RBC) of some species regulate intracellular pH with adrenergically-stimulated sodium-proton-exchangers ({beta}-NHE). We hypothesized that RBC {beta}-NHEs in white seabass are an important mechanism that can protect the blood O2-carrying capacity during hypoxia and hypercapnia. We determined the O2-binding characteristics of white seabass blood, the response of RBCs to adrenergic stimulation, and quantified the protective effect of {beta}-NHE activity on Hb-O2 saturation. White seabass had typical teleost Hb characteristics, with a moderate O2 affinity (PO2 at half-saturation; P50 2.9 kPa) that was highly pH-sensitive (Bohr coefficient -0.92; Root effect 52%). The presence of RBC {beta}-NHEs was confirmed by functional, molecular and bioinformatic data and super-resolution imaging revealed, for the first time, the subcellular location of {beta}-NHE protein in vesicle-like structures and on the RBC membrane, and its translocation after adrenergic stimulation. The activation of RBC {beta}-NHEs increased Hb-O2 saturation by [~]8% in normoxia at 1 kPa PCO2, and by up to 20% in hypoxia. Our results confirm that RBC {beta}-NHE activity in white seabass has great potential to protect arterial O2 transport in environmentally relevant conditions of hypoxia and hypercapnia, but also reveal a potential vulnerability of fish to combinations of these stressors.

category: physiology


title: Quantifying the potential for red blood cell β-adrenergic sodium-proton exchangers to protect oxygen transport in hypoxic and hypercapnic white seabass


title: A modular approach for modeling the cell cycle based on functional response curves

abstract:
Modeling biochemical reactions by means of differential equations often results in systems with a large number of variables and parameters. As this might complicate the interpretation and generalization of the obtained results, it is often desirable to reduce the complexity of the model. One way to accomplish this is by replacing the detailed reaction mechanisms of certain modules in the model by a mathematical expression that qualitatively describes the dynamical behavior of these modules. Such an approach has been widely adopted for ultrasensitive responses, for which underlying reaction mechanisms are often replaced by a single Hill equation. Also time delays are usually accounted for by using an explicit delay in delay differential equations. In contrast, however, S-shaped response curves, which are often encountered in bistable systems, are not easily modeled in such an explicit way. Here, we extend the classical Hill function into a mathematical expression that can be used to describe both ultrasensitive and S-shaped responses. We show how three ubiquitous modules (ultrasensitive responses, S-shaped responses and time delays) can be combined in different configurations and explore the dynamics of these systems. As an example, we apply our strategy to set up a model of the cell cycle consisting of multiple bistable switches, which can account for events such as DNA damage and coupling to the circadian clock in a phenomenological way.

Author summaryBistability plays an important role in many biochemical processes and typically emerges from complex interaction patterns such as positive and double negative feedback loops. Here, we propose to theoretically study the effect of bistability in a larger interaction network. We explicitly incorporate a functional expression describing an S-shaped input-output curve in the model equations, without the need for considering the underlying biochemical events. This expression can be converted into a functional module for an ultrasensitive response, and a time delay is easily included as well. Exploiting the fact that several of these modules can easily be combined in larger networks, we construct a cell cycle model consisting of multiple bistable switches and show how this approach can account for a number of known properties of the cell cycle.

category: systems biology


title: A strategy for mapping biophysical to abstract neuronal network models applied to primary visual cortex

abstract:
A fundamental challenge for the theoretical study of neuronal networks is to make the link between complex biophysical models based directly on experimental data, to progressively simpler mathematical models that allow the derivation of general operating principles. We present a strategy that successively maps a relatively detailed biophysical population model, comprising conductance-based Hodgkin-Huxley type neuron models with connectivity rules derived from anatomical data, to various representations with fewer parameters, finishing with a firing rate network model that permits analysis. We apply this methodology to primary visual cortex of higher mammals, focusing on the functional property of stimulus orientation selectivity of receptive fields of individual neurons. The mapping produces compact expressions for the parameters of the abstract model that clearly identify the impact of specific electrophysiological and anatomical parameters on the analytical results, in particular as manifested by specific functional signatures of visual cortex, including input-output sharpening, conductance invariance, virtual rotation and the tilt after effect. Importantly, qualitative differences between model behaviours point out consequences of various simplifications. The strategy may be applied to other neuronal systems with appropriate modifications.

Author summaryA hierarchy of theoretical approaches to study a neuronal network depends on a tradeoff between biological fidelity and mathematical tractibility. Biophysically-detailed models consider cellular mechanisms and anatomically defined synaptic circuits, but are often too complex to reveal insights into fundamental principles. In contrast, increasingly abstract reduced models facilitate analytical insights. To better ground the latter to the underlying biology, we describe a systematic procedure to move across the model hierarchy that allows understanding how changes in biological parameters - physiological, pathophysiological, or because of new data - impact the behaviour of the network. We apply this approach to mammalian primary visual cortex, and examine how the different models in the hierarchy reproduce functional signatures of this area, in particular the tuning of neurons to the orientation of a visual stimulus. Our work provides a navigation of the complex parameter space of neural network models faithful to biology, as well as highlighting how simplifications made for mathematical convenience can fundamentally change their behaviour.

category: neuroscience


title: Loss of SORCS2 is associated with neuronal DNA double-strand breaks

abstract: SORCS2 is one of five proteins that constitute the Vps10p-domain receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Genetic and functional studies implicate SORCS2 in cognitive function, as well as in neurodegenerative and psychiatric disorders. DNA damage and DNA repair deficits are linked to ageing and neurodegeneration, and transient neuronal DNA double-strand breaks (DSBs) also occur as a result of neuronal activity. Here, we report a novel role for SORCS2 in DSB formation. We show that SorCS2 loss is associated with elevated DSB levels in the mouse dentate gyrus and that knocking out SORCS2 in a human neuronal cell line increased Topoisomerase II{beta}-dependent DSB formation and reduced neuronal viability. Neuronal stimulation had no impact on levels of DNA breaks in vitro, suggesting that the observed differences may not be the result of aberrant neuronal activity in these cells. Our findings are consistent with studies linking the VPS10 receptors and DNA damage to neurodegenerative conditions.


title: Striatal and prefrontal D2R and SERT distributions contrastingly correlate with default-mode connectivity

abstract:
The molecular substrate of resting-state functional connectivity (rs-FC) remains poorly understood. We aimed to elucidate interactions of dopamine D2 receptor (D2R) and serotonin transporter (SERT) availabilities in main dopaminergic and serotonergic projection areas with the default-mode network (DMN) and two other resting-state networks (RSNs), the salience (SN) and sensorimotor networks (SMN). We performed simultaneous PET/fMRI scans in rats using [11C]raclopride and [11C]DASB to image D2R and SERT distributions, showing for the first time direct relationships between rs-FC and molecular properties of the rodent brain. We found negative associations between CPu D2R availability and all RSNs investigated. Strikingly, medial prefrontal SERT correlated both positively with anterior DMN rs-FC and negatively with rs-FC between the other networks, underlining serotonins intricate role in this region. By further elucidating the link between molecular brain properties and its network-level function, our data support future diagnostic and therapeutic strategies.

TeaserSimultaneous PET/fMRI indicates direct associations between monoaminergic neurotransmission and brain functional networks.


title: An organelle inheritance pathway during polarized cell growth

abstract:
Some organelles cannot be synthesized anew, so they are segregated into daughter cells during cell division. In Saccharomyces cerevisiae, daughter cells bud from mother cells and are populated by organelles inherited from the mothers. To determine whether this organelle inheritance occurs in a stereotyped manner, we tracked organelles using fluorescence microscopy. We describe a program for organelle inheritance in budding yeast. The cortical endoplasmic reticulum (ER) and peroxisomes are inherited concomitant with bud emergence. Next, vacuoles are inherited in small buds, followed closely by mitochondria. Finally, the nucleus and perinuclear ER are inherited when buds have nearly reached their maximal size. Because organelle inheritance timing correlates with bud morphology, which is coupled to the cell cycle, we tested whether organelle inheritance order is controlled by the cell cycle. By arresting cell cycle progression but allowing continued bud growth, we determined that organelle inheritance still occurs without cell cycle progression past S-phase, and that the general inheritance order is maintained. Thus, organelle inheritance follows a preferred order during polarized cell division, but it is not controlled exclusively by cell cycle signaling.

Summary statementOrganelles are interconnected by contact sites, but they must be inherited from mother cells into buds during budding yeast mitosis. We report that this process occurs in a preferred sequence.


title: Quantitative multidimensional phenotypes improve genetic analysis of laterality traits

abstract: Handedness is the most commonly investigated lateralised phenotype and is usually measured as a binary left/right category. Its links with psychiatric and neurodevelopmental disorders prompted studies aimed at understanding the underlying genetics, while other measures and side preferences have been less studied. We investigated the heritability of hand, as well as foot, and eye preference by assessing parental effects (n [≤] 5 028 family trios) and SNP-based heritability (SNP-h2, n [≤] 5 931 children) in the Avon Longitudinal Study of Parents and Children (ALSPAC). An independent twin cohort from Hong Kong (n = 358) was used to replicate results from structural equation modelling (SEM). Parental left-side preference increased the chance of an individual to be left-sided for the same trait, with stronger maternal than paternal effects for footedness. By regressing out the effects of sex, age, and ancestry, we transformed laterality categories into quantitative measures. The SNP-h2 for quantitative handedness and footedness was .21 and .23, respectively, which is higher than the SNP-h2 reported in larger genetic studies using binary handedness measures. The heritability of the quantitative measure of handedness increased (.45) compared to a binary measure for writing hand (.27) in the Hong Kong twins. Genomic and behavioural SEM identified a shared genetic factor contributing to handedness, footedness, and eyedness, but no independent effects on individual phenotypes. Our analysis demonstrates how quantitative multidimensional laterality phenotypes are better suited to capture the underlying genetics than binary traits.


title: Adaptable internal representations drive cerebellum-mediated predictive control of an innate behavior

abstract:
Neural mechanisms that allow animals to keep track of multi-second time intervals are not clearly understood. Further, the role of the cerebellum in this process is under debate. We show that when periodic optic flow is presented, cerebellar Purkinje cells in larval zebrafish show simple spike and climbing fiber activity that ramps up in anticipation of flow onset. A distinct subset of Purkinje cells reports prediction error signals mediated solely by climbing fiber inputs when the stimulus interval is altered. These signals develop in 2 trials and can quickly adapt to new intervals if stimulus timing is altered. Robust predictive and prediction error signals are associated with faster behavioral responses and the modulation of behavioral latency is dependent on the cerebellum. Based on our results, we built an algorithmic model that explains how Purkinje cells mediate acquisition and updating of an internal model of stimulus time intervals.

HighlightsO_LILarval zebrafish learn the timing of optic flow stimuli with minimal sensory evidence.
C_LIO_LIThe cerebellum performs an innate, hitherto unknown, supra-second timing function.
C_LIO_LIPurkinje cells use prediction errors to acquire an internal model of stimulus timing.
C_LIO_LIRobust predictions lead to faster reaction times when stimulus arrives as expected.
C_LI


title: Rapid acquisition of internal models of timing by Purkinje cells enables faster behavioral responses


title: Systematic over-crediting in California's forest carbon offsets program

abstract:
Carbon offsets are widely used by individuals, corporations, and governments to mitigate their greenhouse gas emissions on the assumption that offsets reflect equivalent climate benefits achieved elsewhere. These climate-equivalence claims depend on offsets providing "additional" climate benefits beyond what would have happened, counterfactually, without the offsets project. Here, we evaluate the design of Californias prominent forest carbon offsets program and demonstrate that its climate-equivalence claims fall far short on the basis of directly observable evidence. By design, Californias program awards large volumes of offset credits to forest projects with carbon stocks that exceed regional averages. This paradigm allows for adverse selection, which could occur if project developers preferentially select forests that are ecologically distinct from unrepresentative regional averages. By digitizing and analyzing comprehensive offset project records alongside detailed forest inventory data, we provide direct evidence that comparing projects against coarse regional carbon averages has led to systematic over-crediting of 30.0 million tCO2e (90% CI: 20.5 to 38.6 million tCO2e) or 29.4% of the credits we analyzed (90% CI: 20.1 to 37.8%). These excess credits are worth an estimated $410 million (90% CI: $280 to $528 million) at recent market prices. Rather than improve forest management to store additional carbon, Californias offsets program creates incentives to generate offset credits that do not reflect real climate benefits.

Significance StatementForest carbon offsets are increasingly prominent in corporate and government "net zero" emission strategies, but face growing criticism about their efficacy. Californias forest offsets program is frequently promoted as a high-quality approach that improves on the failures of earlier efforts. Our analysis demonstrates, however, that substantial ecological and statistical shortcomings in the design of Californias forest offset protocol generate offset credits that do not reflect real climate benefits. Looking globally, our results illustrate how protocol designs with easily exploitable rules can undermine policy objectives and highlight the need for stronger governance in carbon offset markets.

category: ecology


title: Machine-Perception Nanosensor Platform to Detect Cancer Biomarkers

abstract: Conventional molecular recognition elements, such as antibodies, present issues for the development of biomolecular assays for use in point-of-care devices, implantable/wearables, and under-resourced settings. Additionally, antibody development and use, especially for highly multiplexed applications, can be slow and costly. We developed a perception-based platform based on an optical nanosensor array that leverages machine learning algorithms to detect multiple protein biomarkers in biofluids. We demonstrated this platform in gynecologic cancers, which are often diagnosed at advanced stages, leading to low survival rates. We investigated the platform for detection in uterine lavage samples, which are enriched with cancer biomarkers compared to blood. We found that the method enables the simultaneous detection of multiple biomarkers in patient samples, with F1-scores of ~0.95 in uterine lavage samples from cancer patients. This work demonstrates the potential of perception-based systems for the development of multiplexed sensors of disease biomarkers without the need for specific molecular recognition elements.


title: Quantitative systems pharmacology modeling of avadomide-induced neutropenia enables virtual clinical dose and schedule finding studies

abstract:
Avadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia, however the identification of optimal dosing schedules remains a clinical challenge.

Quantitative Systems Pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development.

We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage.

The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort.

Model utility was demonstrated by simulating avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low grade-neutropenia.

category: pharmacology and toxicology


title: UBP12 and UBP13 deubiquitinases destabilize the CRY2 blue-light receptor to regulate growth

abstract: All organisms undergo growth, which is precisely controlled by exogenous and endogenous signals. Unchecked growth often leads to neoplasia and other developmental defects, severely affecting an organisms fitness. Light is a vital exogenous signal sensed by cryptochrome (CRY) blue light receptors to modulate growth and the circadian clock in plants and animals. Yet, how CRYs interpret light quantity to regulate growth in plants remains poorly understood. We show that UBP12 and UBP13 deubiquitinases physically interact with CRY2 in light. UBP12/13 negatively regulated CRY2 protein levels by promoting its ubiquitination and turnover to fine-tune growth. Unexpectedly, the destabilization of CRY2 by UBP12/13 is contrary to the general view that deubiquitinases stabilize proteins by preventing their degradation. Growth and development were explicitly affected in blue light when UBP12/13 was disrupted or overexpressed, indicating their role alongside CRY2. UBP12/13 also interacted and stabilized COP1, which is partially required for the turnover of CRY2. Despite decades of studies on deubiquitinases, the knowledge on how they are regulated is limited. Our study offers an insight into how exogenous signals and their receptors regulate deubiquitinase activity by protein-protein interaction. Altogether, our results provide a new module of cryptochromes and deubiquitinases in sensing and interpreting light cues to control growth at the most appropriate time.

category: plant biology


title: Towards comprehensive plasma proteomics by orthogonal protease digestion

abstract: Rapid and consistent protein identification across large clinical cohorts is an important goal for clinical proteomics. With the development of data-independent technologies (DIA/SWATH-MS), it is now possible to analyze hundreds of samples with great reproducibility and quantitative accuracy. However, this technology benefits from empirically derived spectral libraries that define the detectable set of peptides and proteins. Here we apply a simple and accessible tip-based workflow for the generation of spectral libraries to provide a comprehensive overview on the plasma proteome in individuals with and without active tuberculosis (TB). To boost protein coverage, we utilized non-conventional proteases such as GluC and AspN together with the gold standard trypsin, identifying more than 30,000 peptides mapping to 3,309 proteins. Application of this library to quantify plasma proteome differences in TB infection recovered more than 400 proteins in 50 minutes of MS-acquisition, including diagnostic Mycobacterium tuberculosis (Mtb) proteins that have previously been detectable primarily by antibody-based assays and intracellular proteins not previously described to be in plasma.


title: Recovery from form-deprivation myopia in chicks is dependent upon the fullness and correlated colour temperature of the light spectrum

abstract:
BackgroundTo evaluate the impact of full-spectrum light-emitting diodes (LEDs) mimicking sunlight on ocular axial elongation and refractive error development in a chicken model of myopia.

MethodsA total of 39 chicks (Lohmann brown), 1 day-old, were randomly distributed into 3 groups. Animals were housed for 28 days in a temperature-controlled enclosure, under a 12/12h light/dark cycle of isoluminant ([~]285 Lux) fluorescent [n = 18, (4000K, FL-4000)] or Sunlike-LED [n=12, (4000K, SL-4000); n = 9, (6500K, SL-6500)] white lights. Myopia was induced monocularly in all chicks by random occlusion of one eye with a frosted diffuser, from day 1 post-hatching (D1) until D14. On D14, diffusers were removed, and recovery from myopia was monitored under the same experimental light condition. Axial length (AL), refractive status, choroidal thickness and anterior chamber depth were recorded on days 1, 7, 14, 22 and 28. Ex vivo scleral collagen fibre thicknesses were measured from scanning electron microscopy images. Differences in outcome measures between eyes and groups were compared using 2-way repeated-measures ANOVA.

ResultsThere was no significant difference between groups in the AL and refraction of form-deprived (FD) eyes during form-deprivation (D1 to D14). FD eyes of animals raised under SL-4000 and SL-6500 recovered more rapidly from excessive axial elongation than those of animals raised under FL-4000, by D22 and D28. Correspondingly, the refractive status of FD eyes exposed to SL-4000 and SL-6500 was close to that of control eyes by D28. The choroid became thicker during recovery in FD eyes compared to control eyes, in all groups. Choroidal thickness was significantly greater in FD eyes of chickens raised under SL-6500 than in animals raised under FL-4000 (P < 0.01). The diameter of scleral collagen fibrils was significantly greater in recovering FD eyes of chickens raised under SL-6500, than in those raised under FL-4000 (P = 0.04) and SL-4000 (P = 0.002).

ConclusionsCompared to fluorescent light, moderate intensities of full-spectrum Sunlike-LEDs can accelerate recovery from form-deprivation myopia in chickens, potentially through choroid-mediated pathways increasing the diameter of scleral collagen fibrils. This study highlights an important implication of the spectral content of white light on ocular growth and emmetropization.


title: Visual temporal integration by multi-level regularities fosters the emergence of dynamic conscious experience

abstract: The relationship between information integration and visual awareness is central to contemporary theories and research on human consciousness. While there is evidence that humans are adept at integrating spatially structured information to form a coherent conscious percept, to date, little is known about how we integrate visual information over time based on its temporal structure and whether such temporal integration process contributes to our awareness of the dynamic world. Using binocular rivalry, we demonstrated that a diverse set of structured visual streams, constituted either by idiom, shape, or motion stimuli, predominated over their non-structured but otherwise matched counterparts in the competition for conscious access. Despite the apparent resemblance, there was a substantial dissociation of these observed privileges between the semantic- and perceptual-level structures, specifically regarding their resistance to spatiotemporal perturbations and demands for conscious processing over the visual integration process. These findings corroborate the essential role of structure-guided information integration in the generation of conscious content and highlight temporal integration by multi-level regularities as a fundamental mechanism to foster the emergence of continuous conscious experience.


title: Social steerability modulates perceptual biases

abstract:
Verbal hints can bias perceptual decision-making, even when the information they provide is false. Whether individuals may be more or less susceptible to such perceptual influences, however, remains unclear. We asked naive participants to indicate the dominant color in a series of stimuli, after giving them a false statement about which color would likely dominate. As anticipated, this statement biased participants perception of the dominant color, as shown by a correlated shift of their perceptual decisions, confidence judgments and response times. Crucially, this perceptual bias was more pronounced in participants with higher levels of susceptibility to social influence, as measured by a standard suggestibility scale. Together, these results indicate that even without much apparatus, simple verbal hints can affect our perceptual reality, and that social steerability can determine how much they do so. Susceptibility to suggestion might thus be considered an integral part of perceptual processing.

Statement of relevanceAt a time when fake news soar, understanding the role that simple verbal descriptions play in how we perceive the world around us is paramount. Extensive research has shown that perception is permeable to well-orchestrated manipulation. Comparatively less attention has been paid to the perceptual impact of false information when the latter is imparted simply and straightforwardly, through short verbal hints and instructions. Here we show that even a single sentence suffices to bias perceptual decision-making, and that critically, this bias varies across individuals as a function of susceptibility to social influence. Considering how here perception was biased by a single, plain sentence, we argue that researchers, communicators and policy-makers should pay careful attention to the role that social suggestibility plays in how we build our perceptual reality.


title: Behavioural variability and cortical electrophysiological signals depend on recent outcomes during human reinforcement motor learning

abstract: The history of our actions and the outcomes of these represent important information, which can inform choices, and efficiently guide future behaviour. While unsuccessful (S-) outcomes are expected to lead to more explorative motor states and increased behavioural variability, successful (S+) outcomes lead to reinforcement of the previous action and thus exploitation. Here, we show that during reinforcement motor learning, humans attribute different values to previous actions when they experience S- vs. S+ outcomes. Behavioural variability after S- outcomes is influenced more by the previous outcomes compared to what is observed after S+ outcomes. Using electroencephalography, we show that neural oscillations of the prefrontal cortex encode the level of reinforcement (high beta frequencies) and reflect the detection of reward prediction errors (theta frequencies). The results suggest that S+ experiences  overwrite previous motor states to a greater extent than S- experiences and that modulations in neural oscillations in the prefrontal cortex play a potential role in encoding the (changes in) movement variability state during reinforcement motor learning.


title: Human interictal epileptiform discharges are traveling waves reflecting ictal self-organization

abstract: Interictal epileptiform discharges (IEDs), also known as interictal spikes, are large intermittent electrophysiological events observed between seizures in patients with epilepsy. Though they occur far more often than seizures, IEDs are less studied, and their relationship to seizures remains unclear. To better understand this relationship, we examined multi-day recordings of microelectrode arrays implanted in human epilepsy patients, allowing us to precisely observe the spatiotemporal propagation of IEDs, spontaneous seizures, and how they relate. These recordings showed that the majority of IEDs are traveling waves, traversing the same path as ictal discharges during seizures, and with a fixed direction relative to seizure propagation. Moreover, the majority of IEDs, like ictal discharges, were bidirectional, with one predominant and a second, less frequent antipodal direction. These results reveal a fundamental spatiotemporal similarity between IEDs and ictal discharges. These results also imply that most IEDs arise in brain tissue outside the site of seizure onset and propagate toward it, indicating that the propagation of IEDs provides useful information for localizing the seizure focus.


title: Human interictal epileptiform discharges are bidirectional traveling waves echoing ictal discharges


title: Adhesion-growth factor crosstalk regulates AURKB activation and ERK signaling in re-adherent fibroblasts.

abstract: Aurora kinases despite their similarity have distinct roles in the cell cycle, which is regulated by cell-matrix adhesion and growth factors. This study reveals loss of adhesion and re-adhesion to differentially regulate Aurora kinases. AURKB activation that drops on the loss of adhesion recovers on re-adhesion in serum-deprived conditions but not in the presence of serum growth factors. A rapid 30min serum treatment of serum-deprived cells blocks the adhesion-dependent recovery of AURKB, which negatively corelates with Erk activation. AZD mediated inhibition of AURKB in serum-deprived re-adherent cells promotes Erk activation and membrane ruffling, comparable to presence of serum. These studies thus define a novel adhesion-growth factor-dependent regulation of AURKB that controls adhesion-dependent Erk activation in re-adherent fibroblasts.


title: Generation of specialized blood vessels through transdifferentiation of lymphatic endothelial cells

abstract: The lineage and developmental trajectory of a cell are key determinants of cellular identity. Yet, the functional relevance of deriving a specific cell type from ontologically distinct progenitors, remains an open question. In the case of the vascular system, blood and lymphatic vessels are composed of endothelial cells (ECs) that differentiate and diversify to cater the different physiological demands of each organ. While lymphatic vessels have been shown to originate from multiple cell sources, lymphatic ECs (LECs) themselves seem to have a unipotent cell fate. In this work we uncover a novel mechanism of blood vessel formation through transdifferentiation of LECs. Using advanced long-term reiterative imaging and lineage-tracing of ECs in zebrafish, from embryonic development through adulthood, we reveal a hitherto unknown process of LEC-to-BEC transdifferentiation, underlying vascularization of the anal fin (AF). Moreover, we demonstrate distinct functional implications for deriving AF vessels from either LECs or BECs, uncovering for the first time a clear link between cell ontogeny and functionality. Molecularly, we identify Sox17 as a negative regulator of lymphatic fate specification, whose specific expression in AF LECs suppresses its lymphatic cell fate. Finally, we show that akin to the developmental process, during adult AF regeneration the vasculature is re-derived from lymphatics, demonstrating that LECs in the mature fish retain both potency and plasticity for generating specialized blood vessels. Overall, our work highlights a novel mechanism of blood vessel formation through LEC trans-differentiation, and provides the first in vivo evidence for a link between cell ontogeny and functionality in ECs.

category: developmental biology


title: Lizard feeding enhances Ixodes pacificus vector competency

abstract: A vectors susceptibility and ability to transmit a pathogen-- termed vector competency--determines disease outcomes, yet the ecological factors influencing tick vector competency remain largely unknown. Ixodes pacificus, the vector of Borrelia burgdorferi (Bb) in the western U.S., feeds on rodents, birds, and lizards. While rodents and birds are reservoirs for Bb and infect juvenile ticks, lizards are Bb-refractory. Despite I. pacificus feeding on a range of hosts, it is undetermined how larval host bloodmeal identity affects future nymphal vector competency. We experimentally evaluate the influence of larval host bloodmeal on Bb acquisition by nymphal I. pacificus. Larval I. pacificus were fed on either lizards or mice and after molting, nymphs were fed on Bb-infected mice. We found that lizard-fed larvae were significantly more likely to become infected with Bb during their next bloodmeal than mouse-fed larvae. We also conducted the first RNA-seq analysis on whole-bodied I. pacificus and found significant upregulation of antioxidants and antimicrobial peptides in the lizard-fed group. Our results indicate that the lizard bloodmeal significantly alters vector competency and gene regulation in ticks, highlighting the importance of host bloodmeal identity in disease transmission and upends prior notions about the role of lizards in Lyme disease transmission.


title: Floral scents of a deceptive plant are hyperdiverse and under population-specific phenotypic selection

abstract: Floral scent is a key mediator in plant-pollinator interactions; however, little is known to what extent intraspecific scent variation is shaped by phenotypic selection, with no information yet in deceptive plants. We recorded 291 scent compounds in deceptive moth fly-pollinated Arum maculatum from various populations north vs. south of the Alps, the highest number so far reported in a single plant species. Scent and fruit set differed between regions, and some, but not all differences in scent could be explained by differential phenotypic selection in northern vs. southern populations. Our study is the first to provide evidence that phenotypic selection is involved in shaping geographic patterns of floral scent in deceptive plants. The hyperdiverse scent of A. maculatum might result from the plants imitation of various brood substrates of its pollinators.


title: Will Current Protected Areas Harbour Refugia for Threatened Arctic Vegetation Types until 2050? A First Assessment

abstract: Arctic vegetation types provide food and shelter for fauna, support livelihoods of Northern peoples, and are tightly linked to climate, permafrost soils, lakes, rivers, and the ocean through carbon, energy, water, and nutrient fluxes. Despite its significant role, a comprehensive understanding of climate change effects on Arctic vegetation is lacking. We compare the 2003 baseline with existing 2050 predictions of circumpolar Arctic vegetation type distributions and demonstrate that abundant vegetation types with a proclivity for expansion contribute most to current protected areas. Applying IUCN criteria, we categorize five out of the eight assessed vegetation types as threatened by 2050. Our analyses show that current protected areas are insufficient for the mitigation of climate-imposed threats to these Arctic vegetation types. Therefore, we located potential climate change refugia, areas where vegetation may remain unchanged, at least until 2050, providing the highest potential for safeguarding threatened vegetation types. Our study provides an essential first step to assessing vegetation type vulnerability in the Arctic, but is based on predictions covering only 46% of Arctic landscapes. The co-development of new protective measures by policymakers and indigenous peoples at a pan-Arctic scale requires more robust and spatially complete vegetation predictions. This is essential as increasing pressures from resource exploration and rapid infrastructure development complicate the road to a sustainable development of the rapidly thawing and greening Arctic.


title: Capturing site-to-site variability through Hierarchical Bayesian calibration of a process-based dynamic vegetation model

abstract: Process-based ecosystem models help us understand and predict ecosystem processes, but using them has long involved a difficult choice between performing data- and labor-intensive site-level calibrations or relying on general parameters that may not reflect local conditions. Hierarchical Bayesian (HB) calibration provides a third option that frees modelers from assuming model parameters to be completely generic or completely site-specific and allows a formal distinction between prediction at known calibration sites and "out-of-sample" prediction to new sites. Here, we compare calibrations of a process-based dynamic vegetation model to eddy-covariance data across 12 temperate deciduous Ameriflux sites fit using either site-specific, joint cross-site, or HB approaches. To be able to apply HB to computationally demanding process-based models we introduce a novel emulator-based HB calibration tool, which we make available through the PEcAn community cyberinfrastructure. Using these calibrations to make predictions at held-out tower sites, we show that the joint cross-site calibration is falsely over-confident because it neglects parameter variability across sites and therefore underestimates variance in parameter distributions. By showing which parameters show high site-to-site variability, HB calibration also formally gives us a structure that can detect which process representations are missing from the models and prioritize errors based on the magnitude of the associated uncertainty. For example, in our case-study, we were able to identify large site-to-site variability in the parameters related to the temperature responses of respiration and photosynthesis, associated with a lack of thermal acclimation and adaptation in the model. Moving forward, HB approaches present important new opportunities for statistical modeling of the spatiotemporal variability in modeled parameters and processes that yields both new insights and improved predictions.


title: Time-averaging and emerging nonergodicity upon resetting of fractional Brownian motion and heterogeneous diffusion processes

abstract: How different are the results of constant-rate resetting of anomalous-diffusion processes in terms of their ensemble-averaged versus time-averaged mean-squared displacements (MSDs versus TAMSDs) and how does the process of stochastic resetting impact nonergodicity? These are the main questions addressed in this study. Specifically, we examine, both analytically and by stochastic simulations, the implications of resetting on the MSD-and TAMSD-based spreading dynamics of fractional Brownian motion (FBM) with a long-time memory, of heterogeneous diffusion processes (HDPs) with a power-law-like space-dependent diffusivity D(x) = D0 |x| {gamma}, and of their "combined" process of HDP-FBM. We find, i.a., that the resetting dynamics of originally ergodic FBM for superdiffusive choices of the Hurst exponent develops distinct disparities in the scaling behavior and magnitudes of the MSDs and mean TAMSDs, indicating so-called weak ergodicity breaking (WEB). For subdiffusive HDPs we also quantify the nonequivalence of the MSD and TAMSD, and additionally observe a new trimodal form of the probability density function (PDF) of particle displacements. For all three reset processes (FBM, HDPs, and HDP-FBM) we compute analytically and verify by stochastic computer simulations the short-time (normal and anomalous) MSD and TAMSD asymptotes (making conclusions about WEB) as well as the long-time MSD and TAMSD plateaus, reminiscent of those for "confined" processes. We show that certain characteristics of the reset processes studied are functionally similar, despite the very different stochastic nature of their nonreset variants. Importantly, we discover nonmonotonicity of the ergodicity breaking parameter EB as a function of the resetting rate r. For all the reset processes studied, we unveil a pronounced resetting-induced nonergodicity with a maximum of EB at intermediate r and EB [~] (1/r)-decay at large r values. Together with the emerging MSD-versus-TAMSD disparity, this pronounced r-dependence of the EB parameter can be an experimentally testable prediction. We conclude via discussing some implications of our results to experimental systems featuring resetting dynamics.


title: Experience-dependent plasticity modulates ongoing activity in the antennal lobe and enhance odor representations

abstract: Ongoing neural activity has been observed across several brain regions and thought to reflect the internal state of the brain. Yet, it is not fully understood how ongoing brain activity interacts with sensory experience and shape sensory representations. Here, we show that projection neurons of the fruit fly antennal lobe exhibit spatiotemporally organized ongoing activity in the absence of odor stimulation. Upon repeated exposure to odors, we observe a gradual and long-lasting decrease in the amplitude and frequency of spontaneous calcium events, as well as a reorganization of correlations between olfactory glomeruli during ongoing activity. Accompanying these plastic changes, we find that repeated odor experience reduces trial-to-trial variability and enhances the specificity of odor representations. Our results reveal a previously undescribed experience-dependent plasticity of ongoing and sensory driven activity at peripheral levels of the fruit fly olfactory system.


title: Experience-dependent plasticity modulates ongoing activity in the antennal lobe and enhances odor representations


title: Testing the adaptive walk model of gene evolution

abstract: Understanding the dynamics of species adaptation to their environments has long been a central focus of the study of evolution. Theories of adaptation propose that populations evolve by "walking" in a fitness landscape. This "adaptive walk" is characterised by a pattern of diminishing returns, where populations further away from their fitness optimum take larger steps than those closer to their optimal conditions. Hence, we expect young genes to evolve faster and experience mutations with stronger fitness effects than older genes because they are further away from their fitness optimum. Testing this hypothesis, however, constitutes an arduous task. Young genes are small, encode proteins with a higher degree of intrinsic disorder, are expressed at lower levels, and are involved in species-specific adaptations. Since all these factors lead to increased protein evolutionary rates, they could be masking the effect of gene age. While controlling for these factors, we fitted models of the distribution of fitness effects to population genomic datasets of Arabidopsis and Drosophila. We found that a genes evolutionary age significantly impacts the molecular rate of adaptation. Moreover, we observed that substitutions in young genes tend to have larger fitness effects. Our study, therefore, provides strong evidence that molecular evolution follows an adaptive walk model across large evolutionary timescale.

category: evolutionary biology


title: Thermodynamic stability of G-quadruplex and overlapping m6A: Position-dependent collaborators in allele frequency and fitness?

abstract:
BackgroundPost-transcriptional modifications like m6A, and secondary structures like G-quadruplex (G4), play an important role in RNA processing. Despite an emerging number of studies focusing on m6A and G4 separately, there are less studies about their synergy.

AimSince m6A is known to be enzymatically created in DRACH-motif, and genetic variants may create a novel DRACH-motif or abolish a pre-existing DRACH-motif, we can suppose that the variants may affect gene product level through modulating m6A-G4 colocalization, which consequently may affect fitness and change allele frequency. To test this hypothesis, rare and common variants in selected human genes were investigated in terms of their effect on m6A-G4 colocalization.

MethodsGenomic sequences and variant features were fetched from GRCh37/hg19 and Biomart-Ensembl databases, respectively. Counting the number of putative m6A- and G4-motifs in sequences and statistical analysis were performed with appropriate libraries of Python3.7.

ResultsCommon variants creating novel m6A-motif were found more frequently inside than outside G4, and displayed unequal distribution throughout pre-mRNA. Unequal distribution of m6A-creating variants seemed to be related to their effect on thermodynamic stability of the overlapping-G4.

DiscussionSelective m6A-G4 colocalization suggests that m6A-motif is favorable when overlapping with G4. Besides, thermodynamic stability may lead to unequal distribution of m6A-G4 colocalization, because m6A-creating alleles seem to have lower frequency if stabilizes overlapping-G4 in 3-prime-side, but not in 5-prime-side. We can conclude that the fitness, and consequently frequency of an m6A-creating variant is prone to become higher or lower depending on its position and effect on the overlapping-G4 stability.

category: genetics


title: Formic acid modulates latency and accuracy of nestmate recognition in carpenter ants

abstract:
Decision-making processes face the dilemma of being accurate or faster, a phenomenon that has been described as speed-accuracy trade-off (SAT) in numerous studies on animal behaviour. In social insects, discriminating between colony members and aliens is subjected to this trade-off as rapid and accurate rejection of enemies is of primary importance for the maintenance and ecological success of insect societies. Recognition cues distinguishing aliens from nestmates are embedded in the cuticular hydrocarbon (CHC) layer and vary among colonies. In walking carpenter ants, exposure to formic acid (FA), an alarm pheromone, improves accuracy of nestmate recognition by decreasing both alien acceptance and nestmate rejection. Here we studied the effect of FA exposure on the spontaneous aggressive mandible opening response of harnessed Camponotus aethiops ants presented with either nestmate or alien CHCs. FA modulated both MOR accuracy and the latency to respond to odours of conspecifics. In particular, FA decreased MOR towards nestmates but increased it towards aliens. Furthermore, FA decreased MOR latency towards aliens but not towards nestmates. As response latency can be used as a proxy of response speed, we conclude that contrary to the prediction of the SAT theory, ants did not trade off speed against accuracy in the process of nestmate recognition.

Summary statementExposure to an alarm pheromone increases both latency and accuracy of the response to recognition cues in ants

category: animal behavior and cognition


title: Imprinting on time-structured acoustic stimuli in ducklings

abstract: Filial imprinting is a dedicated learning process that lacks explicit reinforcement. The phenomenon itself is narrowly heritably canalized, but its content, the representation of the parental object, reflects the circumstances of the newborn. Imprinting has recently been shown to be even more subtle and complex than previously envisaged, since ducklings and chicks are now known to select and represent for later generalization abstract conceptual properties of the objects they perceive as neonates, including movement pattern, heterogeneity, and inter-component relationships of same or different. Here we investigate whether day-old Mallard ducklings (Anas platyrhynchos) imprint on the temporal separation between duos of brief acoustic stimuli, and whether they generalize such timing information to novel sound types. Subjects did discriminate temporal structure when imprinted and tested on natural duck calls, but not when using white noise for imprinting or testing. Our data confirm that imprinting includes the establishment of neural representations of both primary percepts and abstract properties of candidate objects, meshing together genetically transmitted prior knowledge with selected perceptual input.


title: Fetal maturation revealed by amniotic fluid cell-free transcriptome in rhesus macaques

abstract: Accurate estimate of fetal maturity could provide individualized guidance for delivery of complicated pregnancies. However, current methods are invasive, have low accuracy, and are limited to fetal lung maturation. To identify diagnostic gestational biomarkers, we performed transcriptomic profiling of lung and brain, as well as cell-free RNA from amniotic fluid of preterm and term rhesus macaque fetuses. These data predict new and prior associated gestational age differences in distinct lung and neuronal cell populations when compared to existing single-cell and bulk RNA-Seq data. Comparative analyses found over 200 genes coincidently induced in lung and amniotic fluid, and dozens in brain and amniotic fluid. This data enabled creation of computational models that accurately predicted lung compliance from amniotic fluid and lung transcriptome of preterm fetuses treated with antenatal corticosteroids. Cell-free RNA in amniotic fluid may provide a substrate of global fetal maturation markers for personalized management of at-risk pregnancies.


title: Differential role of spinal and supraspinal processing of proprioceptive information in mouse locomotion

abstract: Robust locomotion relies on information from proprioceptors: sensory organs that communicate the position of body parts to the spinal cord and brain. Proprioceptive circuits in the spinal cord are known to regulate locomotion in challenging environments. Yet, the regulatory importance of the brain remains less clear. Here, through mouse genetic studies and in vivo electrophysiology, we examined the role of the brain in integrating proprioceptive information during locomotion. The systemic removal of proprioceptors left the animals in a constantly perturbed state, similar to that observed during mechanically perturbed locomotion in wild type and characterised by longer and less accurate activation patterns. In contrast, after surgically interrupting the ascending proprioceptive projection to the brain through the dorsal column pathway, wild-type mice showed normal walking behaviour, but lost the ability to respond to external perturbations. Our findings provide direct evidence of a pivotal role for ascending proprioceptive information in achieving safe locomotion.


title: The brain integrates proprioceptive information to ensure robust locomotion


title: Feature-based attention enables robust, long-lasting location transfer in human perceptual learning

abstract: Visual perceptual learning (VPL) is typically specific to the trained location and feature. However, the degree of specificity depends upon particular training protocols. Manipulating covert spatial attention during training facilitates learning transfer to other locations. Here we investigated whether feature-based attention (FBA), which enhances the representation of particular features throughout the visual field, facilitates VPL transfer, and how long such an effect would last. To do so, we implemented a novel task in which observers discriminated a stimulus orientation relative to two reference angles presented simultaneously before each block. We found that training with FBA enabled remarkable location transfer, reminiscent of its global effect across the visual field, but preserved orientation specificity in VPL. Critically, both the perceptual improvement and location transfer persisted after one year. Our results reveal robust, long-lasting benefits induced by FBA in VPL, and have translational implications for improving generalization of training protocols in visual rehabilitation.


title: Selective neural coding of object, feature, and geometry spatial cues in humans

abstract:
Orienting in space requires the processing and encoding of visual spatial cues. The dominant hypothesis about the brain structures mediating the coding of spatial cues stipulates the existence of a hippocampal-dependent system for the representation of geometry and a striatal-dependent system for the representation of landmarks. However, this dual-system hypothesis is based on paradigms that presented spatial cues conveying either conflicting or ambiguous spatial information and that amalgamated the concept of landmark into both discrete 3D objects and wall features. These confounded designs introduce difficulties in interpreting the spatial learning process. Here, we test the hypothesis of a complex interaction between the hippocampus and the striatum during landmark and geometry visual coding in humans. We also postulate that object-based and feature-based navigation are not equivalent instances of landmark-based navigation as currently considered in human spatial cognition. We examined the neural networks associated with geometry-, object-, and feature-based spatial navigation in an unbiased, two-choice behavioral paradigm using fMRI. We showed evidence of a synergistic interaction between hippocampal and striatal coding underlying flexible navigation behavior. The hippocampus was involved in all three types of cue-based navigation, whereas the striatum was more strongly recruited in the presence of geometric cues than object or feature cues. We also found that unique, specific neural signatures were associated with each spatial cue. Critically, object-based navigation elicited a widespread pattern of activity in temporal and occipital regions relative to feature-based navigation. These findings challenge and extend the current view of a dual, juxtaposed hippocampal-striatal system for visual spatial coding in humans. They also provide novel insights into the neural networks mediating object vs. feature spatial coding, suggesting a need to distinguish these two types of landmarks in the context of human navigation.

Highlights O_LIComplex hippocampal-striatal interaction during visual spatial coding for flexible human navigation behavior.
C_LIO_LIDistinct neural signatures associated with object-, feature-, and geometry-based navigation.
C_LIO_LIObject- and feature-based navigation are not equivalent instances of landmark-based navigation.
C_LI


title: The right time and place: time- and age-dependent vaccine-enhanced mucosal immunity to parasite infection

abstract: Individuals vary broadly in their response to vaccination and subsequent exposure to infection, causing persistence of both infection and transmission. The prevalence of poor vaccine responders hampers the development of vaccines, especially against parasitic helminths. Yet despite having substantial economic and societal impact, the immune mechanisms that underlie such variability, especially at the site of parasite infection, remain poorly understood. Previous trials using a prototype vaccine for the control of the gastric parasitic Teladorsagia circumcincta, one of the highest impact parasites affecting sheep, revealed substantial variation in protection between individuals, which we hypothesised may in part be driven by age at vaccination. Here, to characterise how immunity at the mucosal site of infection developed in vaccinated lambs, we inserted gastric cannulae into the abomasa (true stomachs) of three-month- and six-month-old lambs before vaccination, and performed a longitudinal analysis of their local immune response during subsequent challenge infection. We found that the vaccine caused systemic changes in the baseline immune profile within the abomasum before any parasite exposure had occurred and reduced parasite burden and egg output once lambs were infected, regardless of age. However, age affected how vaccinated lambs responded to subsequent infection across multiple immune pathways, with only a minority of protective immune pathways being independent of age. This resulted in younger lambs being more susceptible to infection regardless of vaccine status. The identification of age-dependent (mostly adaptive) and age-independent (mostly innate) protective immune pathways should help refine the formulation of vaccines against these and potentially other helminth parasites of ruminants, and could indicate specificities of anti-helminth immunity more generally.


title: Illuminati, a novel form of gene expression plasticity in Drosophila neural stem cells

abstract: With the aim of developing a genetic instability (GI) sensor in vivo we used the well-established Gal80/Gal4-UAS system combined with a visual GFP marker in Drosophila. We generated a collection of 25 Drosophila lines carrying GAL80 transgenes in different locations in all major chromosomes (X, Y, II, and III). We found low rates of GFP cells in epithelial tissues such as wing discs. In contrast, in larval brains, GFP positive clusters containing neural stem cells- also called neuroblasts (NBs)- and their offspring, were highly frequent. Using genetic and imaging-based approaches, we show that GFP NBs do not result from aneuploidy or mutations in the GAL80 gene, but rather by stochastic repression of GAL80 expression. We named this novel type of gene expression instability Illuminati. Importantly, Illuminati frequency is influenced by environmental and stress conditions. Further, we found that once established, Illuminati can be propagated over many cell cycles.


title: Above- and below-ground biodiversity responses to the prolonged flood pulse in central-western Amazonia, Brazil.

abstract: Amazonia encompasses forests that grow in areas that are periodically inundated by overflowing rivers. The inundation depth and duration vary according to the slope of the terrain, creating a flooding gradient. This gradient directly affects the biota, but the effect on soil organisms remains elusive. Here, we use DNA metabarcoding to estimate prokaryote and eukaryote diversity from soil and litter samples in a seasonally flooded forest and its adjacent unflooded forest in central-western Amazonia using 16S and 18S gene sequences, respectively. We characterize the below-ground diversity and community composition based on Amplicon Sequence Variants (ASVs) along the flooding gradient. We test for the relationship of soil biota with the flooding gradient, soil properties and above-ground woody plant diversity. The flooding gradient did not explain below-ground biodiversity. Nor was the below-ground diversity explained by the above-ground woody plant diversity. However, we found taxonomic groups not previously reported in Amazonian seasonally flooded forests. Also, the flooding gradient and woody plant diversity did, in part, explain the community composition of soil bacteria. Although the effects of the flooding gradient, soil properties and above-ground woody plant diversity is hard to quantify, our results thus indicate that flood stress could influence below-ground bacterial community composition.


title: Soil microbes mediate the effects of nitrogen supply and co-inoculation on Barley Yellow Dwarf Virus in Avena sativa

abstract:
O_LINutrient supply rates to hosts can mediate host-pathogen interactions. In terrestrial systems, nutrient supply to plants is mediated by soil microbes, suggesting a potential indirect effect of soil microbes on plant-pathogen interactions. Soil microbes also may affect plant pathogens by inducing plant defenses.
C_LIO_LIWe tested the role of soil microbes, nitrogen supply to plant hosts, and co-inoculation on infection by aphid-vectored RNA viruses, Barley Yellow Dwarf Virus (BYDV-PAV) and Cereal Yellow Dwarf Virus (CYDV-RPV), in a grass host grown in soil microbes collected from a long-term nitrogen enrichment experiment.
C_LIO_LIBYDV-PAV incidence declined with high nitrogen supply, co-inoculation, or presence of soil microbes exposed to long-term low nitrogen enrichment. However, when combined, the negative effects of these treatments were sub-additive: nitrogen and co-inoculation did not reduce BYDV-PAV incidence in plants grown with the soil microbes. While soil microbes impacted leaf chlorophyll, they did not alter biomass or CYDV-RPV incidence.
C_LIO_LISoil microbes mediated the effects of nitrogen supply and co-inoculation on infection incidence and the effects of infection on host symptoms. Thus, soil microbial communities can indirectly control disease dynamics, altering the effects of nitrogen enrichment on plant-pathogen and pathogen-pathogen interactions in terrestrial systems.
C_LI


title: Effect of anthropogenic vibratory noise on plant development and herbivory

abstract: A growth in anthropogenic activities and infrastructure has led to increasing subterranean vibratory noise levels. Inland wind energy turbines, which are mostly located in agricultural fields, are a fast growing source of vibrational noise. Plants, which are rooted in the soil are constantly exposed to windmill-induced vibrations propagating through the ground. We have little understanding on how anthropogenic seismic vibrations affect plant development and how that in turn can affect plant-insect interactions. In this study we investigated the effect of windmill-like underground vibrational noise on plant development and on a plant-herbivore interaction. We experimentally exposed Pisum sativum plants from seed stage to seed production stage to high and low vibrational noise levels and monitored them daily. We recorded germination, flowering and fruiting time, as well as daily shoot-length growth. Moreover, we tested the direct and indirect effects of vibrational noise on herbivory intensity by the generalist caterpillar Spodoptera exigua. We found that plants exposed to high vibrational noise grew significantly faster and taller than plants exposed to low vibrational noise. Additionally, plants treated with high noise germinated, flowered and produced fruits quicker than those treated with low noise. However, the differences in germination time, flowering time and fruiting time between the treatments were not statistically significant. Furthermore, we did not find an effect of vibrational noise on herbivory intensity. Vibrational noise could have consequences for both natural plant communities and agricultural crops by altering interspecific competition and by shifting growth-defence activation trade-offs.


title: DE-STRESS: A user-friendly web application for the evaluation of protein designs

abstract:
De novo protein design is a rapidly growing field and there are now many interesting and useful examples of designed proteins in the literature. However, most designs could be classed as failures when characterised in the lab, usually as a result of low expression, misfolding, aggregation or lack of function. This high attrition rate makes protein design unreliable and costly. It is possible that some of these failures could be caught earlier in the design process if it were quick and easy to generate information and a set of high-quality metrics regarding designs, which could be used to make reproducible and data-driven decisions about which designs to characterise experimentally.

We present DE-STRESS (DEsigned STRucture Evaluation ServiceS), a web application for evaluating structural models of designed and engineered proteins. DE-STRESS has been designed to be simple, intuitive to use and responsive. It provides a wealth of information regarding designs, as well as tools to help contextualise the results and formally describe the properties that a design requires to be fit for purpose.

AvailabilityDE-STRESS is available for non-commercial use, without registration, through the following website: https://pragmaticproteindesign.bio.ed.ac.uk/de-stress/. Source code for the application is available on GitHub: https://github.com/wells-wood-research/de-stress. The data used to generate reference sets is available through a GraphQL API, with the following URL: https://pragmaticproteindesign.bio.ed.ac.uk/big-structure/graphql.

category: bioinformatics


title: Validation of predicted anonymous proteins simply using Fisher's exact test

abstract:
MotivationGenomes sequencing has become the primary (and often the sole) experimental method to characterize newly discovered organisms, in particular from the microbial world (bacteria, archaea, viruses). This generates an ever increasing number of predicted proteins the existence of which is unwarranted, in particular among those without homolog in model organisms. As a last resort, the computation of the selection pressure from pairwise alignments of the corresponding "Open Reading Frames" (ORFs) can be used to validate their existences. However, this approach is error-prone, as not usually associated with a significance test.

ResultsWe introduce the use of the straightforward Fishers exact test as a post processing of the results provided by the popular CODEML sequence comparison software. The respective rates of nucleotide changes at the non-synonymous vs. synonymous position (as determined by CODEML), are turned into entries into a 2x2 contingency table, the probability of which is computed under the Null hypothesis that they should not behave differently if the ORFs do not encode actual proteins. Using the genome sequences of two recently isolated giant viruses, we show that strong negative selection pressures do not always provide a solid argument in favor of the existence of proteins.

ContactJean-Michel.Claverie@univ-amu.fr


title: ePlant in 2021: New Species, Viewers, Data Sets, and Widgets

abstract: ePlant was introduced in 2017 for exploring large Arabidopsis thaliana data sets from the kilometre to nanometre scales. In the past four years we have used the ePlant framework to develop ePlants for 15 agronomically-important species: maize, poplar, tomato, Camelina sativa, soybean, potato, barley, Medicago truncatula, eucalyptus, rice, willow, sunflower, Cannabis sativa, wheat and sugarcane. We also updated the interface to improve performance and accessibility, and added two new views to the Arabidopsis ePlant - the Navigator and Pathways viewers. The former shows phylogenetic relationships between homologs in other species and their expression pattern similarities, with links to view data for those genes in the respective ePlants. The latter shows Plant Reactome metabolic reactions. We also describe new Arabidopsis data sets including single cell RNA-seq data from roots, and how to embed ePlant eFP expression pictographs into any web page.


title: Tributyltin Protects Against Ovariectomy-Induced Trabecular Bone Loss in C57BL/6J Mice with an Attenuated Effect in High Fat Fed Mice

abstract: Risk factors for poor bone quality include estrogen loss at menopause, a high fat diet and exposures to drugs/chemicals that activate peroxisome proliferator activated receptor gamma (PPAR{gamma}). We observed that the PPAR{gamma} and retinoid X receptor dual ligand, tributyltin (TBT), repressed periosteal bone formation but enhanced trabecular bone formation in female C57BL6/J mice. Here, we examined the interaction of diet, ovariectomy (OVX) and TBT exposure on bone structure. C57BL/6J mice underwent either sham surgery or OVX at 10 weeks of age. At 12 weeks of age, they were placed on a low (10% kcal) or high (45% kcal) fat, sucrose-matched diet and treated with Vh or TBT (1 or 5 mg/kg) for 14 weeks. OVX increased body weight gain in mice on either diet. TBT enhanced body weight gain in intact mice fed a high fat diet, but decreased weight gain in OVX mice. Elemental tin concentrations increased dose-dependently in bone. TBT had marginal effects on cortical and trabecular bone in intact mice fed a low- or high- fat diet. OVX caused a reduction in cortical and trabecular bone, regardless of diet. In high-fat fed OVX mice, TBT further reduced cortical thickness, bone area and total area. Interestingly, TBT protected against OVX-induced trabecular bone loss in low fat fed mice. The protective effect of TBT was nullified by the high fat diet and accompanied by a significant decrease in serum bone formation markers. Our novel observations will provide new information on basic bone biology, potential therapeutic targets and toxicological pathways.


title: Mechanism and role of astrogliosis in the pathogenesis of HIV-associated pain

abstract: Pathological pain is the most common neurological disorder in people living with HIV-1/AIDS (PLWHA), and rationale-based effective treatment is not available. Multiple neuropathologies develop in the pain transmission pathways in of HIV patients, consistent with their nociceptive dysfunction1,2. One of the prominent neuropathologies associating with the manifestation of pain in HIV patients is astrogliosis (a.k.a. reactive astrocytes) in the spinal dorsal horn (SDH)1, the spinal center for the transmission of pain signals from peripheral organs to the brain. However, the pathogenic role and the activation mechanism of astrogliosis are unclear. Here, we show that the astrogliosis is crucial for the pain pathogenesis induced by HIV-1 gp120, a key etiologically relevant protein2, and that a neuron-to-astrocyte Wnt5a signal controls the astrogliosis. We found that ablation of astrogliosis blocked the development of gp120-induced mechanical hyperalgesia, and concomitantly the expression of neural circuit polarization (NCP) in the SDH. In addition, we demonstrated that conditional knockout (CKO) of either Wnt5a in neurons or its receptor ROR2 in astrocytes abolished not only gp120-induced astrogliosis but also the hyperalgesia and the NCP. Furthermore, we found that the astrogliosis promoted expression of the NCP and the hyperalgesia via IL-1{beta} regulated by a Wnt5a-ROR2-MMP2 axis. Our results elucidate an important role and a novel mechanism of astrogliosis in the pathogenesis of HIV-associated pain. Targeting reactive astrocytes by manipulating the mechanistic processes identified here may lead to the development of effective therapy to treat the pain syndrome in HIV patients.


title: In search for the most optimal EEG method: A practical evaluation of a water-based electrode EEG system.

abstract: The study assessed a mobile electroencephalography (EEG) system with water-based electrodes for its applicability in cognitive and behavioural neuroscience. It was compared to a standard gel-based wired system. EEG was recorded on two occasions (first with gel-based, then water-based system) as participants completed the flanker task. Technical and practical considerations for the application of the water-based system are reported based on participant and experimenter experiences. Empirical comparisons focused on EEG data noise levels, frequency power across four bands (theta, alpha, low beta and high beta) and event-related components (P300 and ERN). The water-based system registered more noise compared to the gel-based system which resulted in increased loss of data during artefact rejection. Signal to noise ratio was significantly lower for the water-based system in the parietal channels which impacted the observed parietal beta power. It also led to a shift in topography of the maximal P300 activity from parietal to frontal regions. It is also evident, that the water-based system may be prone to slow drift noise which may affect the reliability and consistency of low frequency band analyses. Practical considerations for the use of water-based electrode EEG systems are provided.


title: Cannabis Vapour Exposure Alters Neural Circuit Oscillatory Activity In A Neurodevelopmental Model Of Schizophrenia: Exploring The Differential Impact Of Cannabis Constituents

abstract: Cannabis use is highly prevalent in patients with schizophrenia and worsens the course of the disorder. To understand the causal impacts of cannabis on schizophrenia-related oscillatory disruptions, we herein investigated the impact of exposure to cannabis vapour (containing delta-9-tetrahydrocannabinol [THC] or balanced THC and cannabidiol [CBD]) on oscillatory activity in the neonatal ventral hippocampal lesion (NVHL) rat model of schizophrenia. Male Sprague Dawley rats underwent NVHL or sham surgeries on postnatal day 7. In adulthood, electrodes were implanted targeting the cingulate cortex (Cg), the prefrontal cortex (PFC), the dorsal hippocampus (HIP), and the nucleus accumbens (NAc). Local field potential recordings were obtained following exposure to two strains of vapourized cannabis flower (with ~10% THC or ~10% balanced THC:CBD) in a cross-over design with a two-week wash-out period between exposures. Compared to controls, NVHL rats had reduced baseline gamma power in the Cg, dHIP, and NAc, and reduced high-gamma coherence between the dHIP-Cg. THC-only vapour broadly suppressed oscillatory power and coherence, even beyond the baseline suppressions observed in NHVL rats. Balanced THC:CBD vapour appeared to ameliorate the THC-induced impacts on power and coherence in both sham and NVHL rats. For NVHL rats, THC-only vapour also normalized the baseline dHIP-Cg high-gamma coherence deficits. NHVL rats also demonstrated a 20ms delay in dHIP theta to high-gamma phase coupling, which was ameliorated by both exposures in the PFC and NAc. In conclusion, THC-only cannabis vapour suppressed oscillatory activity in NVHL and sham rats, while balanced THC:CBD vapour may ameliorate some of these effects.