title: A de novo genome assembly and annotation of the southern flying squirrel (Glaucomys volans)

abstract: Northern (Glaucomys sabrinus) and southern (Glaucomys volans) flying squirrels are widespread species distributed across much of North America. Northern flying squirrels are common inhabitants of the boreal forest, also occurring in coniferous forest remnants farther south, whereas the southern flying squirrel range is centered in eastern temperate woodlands. These two flying squirrel species exhibit a hybrid zone across a latitudinal gradient in an area of recent secondary contact. Glaucomys hybrid offspring are viable and can successfully backcross with either parental species, however, the fitness implications of such events are currently unknown. Some populations of G. sabrinus are endangered, and thus, interspecific hybridization is a key conservation concern in flying squirrels. We sequenced and assembled a de novo long-read genome from a G. volans individual sampled in southern Ontario, Canada, while four short-read genomes (2 G. sabrinus and 2 G. volans, all from Ontario) were re-sequenced on Illumina platforms. The final genome assembly consisted of approximately 2.40Gb with a scaffold N50 of 455.26Kb. Benchmarking Universal Single-Copy Orthologs reconstructed 3,742 (91.2%) complete mammalian genes and genome annotation using RNA-seq identified the locations of 19,124 protein-coding genes. The four short-read individuals were aligned to our reference genome to investigate the demographic history of the two species. A Principal Component Analysis clearly separated re-sequenced individuals, while inferring population size history using the Pairwise Sequentially Markovian Coalescent model noted an approximate species split one million years ago, and a single, possibly recently introgressed individual.


title: Targeted Delivery of Chloroquine to Plasmacytoid Dendritic Cells Enhances Inhibition of the Type I Interferon Response

abstract: Systemic lupus erythematosus (SLE) causes damaging inflammation in multiple organs via the accumulation of immune complexes. These complexes activate plasmacytoid DCs (pDCs) via TLR7 and TLR9, contributing to disease pathogenesis by driving secretion of inflammatory type I IFNs. Antimalarial drugs, such as chloroquine (CQ), are TLR antagonists used to alleviate inflammation in SLE. However, they require ~3 months of continuous use before achieving therapeutic efficacy and can accumulate in the retinal pigment epithelium with chronic use resulting in retinopathy. We hypothesized that poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) filamentous nanocarriers, filomicelles (FMs) could improve drug activity and reduce toxicity by directly delivering CQ to pDCs via passive, morphology-based targeting. Healthy human PBMCs were treated with soluble CQ or CQ-loaded FMs, stimulated with TLR agonists or SLE patient sera, and type I IFN secretion was quantified via multi-subtype IFN- ELISA and MX1 gene expression using real-time RT-qPCR. Our results showed that 50 {micro}g CQ/mg FM decreased MX1 expression and IFN- production after TLR activation with either synthetic nucleic acid agonists or immune complex rich sera from SLE patients. Cellular uptake and biodistribution studies showed that FMs preferentially accumulate in human pDCs in vitro and in tissues frequently damaged in SLE patients (i.e., liver and kidneys) while sparing the eye in vivo. These results showed that nanocarrier morphology enables drug delivery, and CQ-FMs may be equally effective and more targeted than soluble CQ at inhibiting SLE-relevant pathways.

category: bioengineering


title: Cas12a is a dynamic and precise RNA-guided nuclease without off-target activity on {lambda}-DNA

abstract: Cas12a is an RNA-guided endonuclease that is emerging as a powerful genome-editing tool. Here we combined optical tweezers with fluorescence to monitor Cas12a binding onto {lambda}-DNA, providing insight into its DNA binding and cleavage mechanisms. At low forces Cas12a binds DNA specifically with two off-target sites, while at higher forces numerous binding events appear driven by the mechanical distortion of the DNA and partial matches to the crRNA. Despite the multiple binding events, cleavage is only observed on the target site at low forces, when the DNA is flexible. Activity assays show that the preferential off-target sites are not cleaved, and the {lambda}-DNA is severed at the target site. This precision is also observed in Cas12a variants where the specific dsDNA and the unspecific ssDNA cleavage are dissociated or nick the target DNA. We propose that Cas12a and its variants are precise endonucleases that efficiently scan the DNA for its target but only cleave the selected site in the {lambda}-DNA.

category: biophysics


title: A light tunable differentiation system for the creation and control of consortia in yeast

abstract: Artificial microbial consortia seek to leverage division-of-labour to optimize function and possess immense potential for bioproduction. Co-culturing approaches, the preferred mode of generating a consortium, remain limited in their ability to give rise to stable consortia having finely tuned compositions. Here, we present an artificial differentiation system in budding yeast capable of generating stable microbial consortia with custom functionalities from a single strain at user-defined composition in space and in time based on optogenetically-driven genetic rewiring. Owing to fast, reproducible, and light-tunable dynamics, our system enables dynamic control of consortia composition in continuous cultures for extended periods. We further demonstrate that our system can be extended in a straightforward manner to give rise to consortia with multiple subpopulations. Our artificial differentiation strategy establishes a novel paradigm for the creation of complex microbial consortia that are simple to implement, precisely controllable, and versatile to use.

category: synthetic biology


title: Second Generation Antibodies Neutralize Emerging SARS-CoV-2 Variants of Concern

abstract: Recently emerged SARS-CoV-2 variants show resistance to some antibodies that were authorized for emergency use. We employed hybridoma technology combined with authentic virus assays to develop second-generation antibodies, which were specifically selected for their ability to neutralize new variants of SARS-CoV-2. AX290 and AX677, two monoclonal antibodies with non-overlapping epitopes, exhibit subnanomolar or nanomolar affinities to the receptor binding domain of the viral Spike protein carrying amino acid substitutions N501Y, N439K, E484K, K417N, and a combination N501Y/E484K/K417N found in the circulating virus variants. The antibodies showed excellent neutralization of an authentic SARS-CoV-2 virus representing strains circulating in Europe in spring 2020 and also the variants of concern B.1.1.7 and B.1.351. Finally, the combination of the two antibodies prevented the appearance of escape mutations of the authentic SARS-CoV-2 virus. The neutralizing properties were fully reproduced in chimeric mouse-human versions, which may represent a promising tool for COVID-19 therapy.

category: microbiology


title: A deep generative model of 3D single-cell organization

abstract:
1 AbstractWe introduce a framework for end-to-end integrative modeling of 3D single-cell multi-channel fluorescent image data of diverse subcellular structures. We employ stacked conditional {beta}-variational autoencoders to first learn a latent representation of cell morphology, and then learn a latent representation of subcellular structure localization which is conditioned on the learned cell morphology. Our model is flexible and can be trained on images of arbitrary subcellular structures and at varying degrees of sparsity and reconstruction fidelity. We train our full model on 3D cell image data and explore design trade-offs in the 2D setting. Once trained, our model can be used to impute structures in cells where they were not imaged and to quantify the variation in the location of all subcellular structures by generating plausible instantiations of each structure in arbitrary cell geometries. We apply our trained model to a small drug perturbation screen to demonstrate its applicability to new data. We show how the latent representations of drugged cells differ from unperturbed cells as expected by on-target effects of the drugs.

2 Author summaryIts impossible to acquire all the information we want about every cell were interested in in a single experiment. Even just limiting ourselves to imaging, we can only image a small set of subcellular structures in each cell. If we are interested in integrating those images into a holistic picture of cellular organization directly from data, there are a number of approaches one might take. Here, we leverage the fact that of the three channels we image in each cell, two stay the same across the data set; these two channels assess the cells shape and nuclear morphology. Given these two reference channels, we learn a model of cell and nuclear morphology, and then use this as a reference frame in which to learn a representation of the localization of each subcellular structure as measured by the third channel. We use {beta}-variational autoencoders to learn representations of both the reference channels and representations of each subcellular structure (conditioned on the reference channels of the cell in which it was imaged). Since these models are both probabilistic and generative, we can use them to understand the variation in the data from which they were trained, to generate instantiations of new cell morphologies, and to generate imputations of structures in real cell images to create an integrated model of subcellular organization.

category: cell biology


title: Caveolae, CAVIN1, and lipid peroxidation mediate the oxidative stress response

abstract: Caveolae have been linked to many biological functions, but their precise roles are unclear. Using quantitative whole cell proteomics of genome-edited cells, we show that the oxidative stress response is the major pathway dysregulated in cells lacking the key caveola structural protein, CAVIN1. CAVIN1 deletion compromised sensitivity to oxidative stress in cultured cells and in animals. Wound-induced accumulation of reactive oxygen species and apoptosis were suppressed in Cavin1-null zebrafish, negatively affecting regeneration. Oxidative stress triggered lipid peroxidation and induced caveolar disassembly. The resulting release of CAVIN1 from caveolae allowed direct interaction between CAVIN1 and NRF2, a key regulator of the antioxidant response, facilitating NRF2 degradation. CAVIN1-null cells with impaired negative regulation of NRF2 showed resistance to lipid peroxidation-induced ferroptosis. Thus, caveolae, via lipid peroxidation and CAVIN1 release, maintain cellular susceptibility to oxidative stress-induced cell death demonstrating a crucial role for this enigmatic organelle in cellular homeostasis and wound response.


title: Caveolae respond to acute oxidative stress through membrane lipid peroxidation, cytosolic release of CAVIN1, and downstream regulation of NRF2


title: Postnatal activation of hypoxia pathway disrupts β-cell functional maturation

abstract: Hypoxic insults in the perinatal period can lead to persistent hyperinsulinism and profound hypoglycemia in newborns. We studied the impact of the hypoxia-inducible factor 1A (HIF1A) pathway on postnatal {beta}-cell function. Rat pups were treated daily between postnatal day (P)7 to P10 with adaptaquin (AQ), an inhibitor of prolyl hydroxylases, which stabilizes HIF1A. AQ-treated pups were hypoglycemic and had higher plasma insulin concentrations. Their islets had a decreased glucose threshold for insulin secretion, indicative of a delay in {beta}-cell postnatal functional maturation. Histology analyses revealed that AQ-treated pups had increased pancreatic insulin-positive area but no changes in the number of islets or number of {beta}-cells per islet, suggesting larger average {beta}-cell size. AQ-treated rat pups had decreased expression of cell cycle genes and decreased numbers of proliferating {beta}-cells. In conclusion, pharmacologic activation of the HIF1A pathway in the early postnatal period leads to hyperinsulinism, due to the persistence of a low glucose threshold for insulin secretion, and to decreased early postnatal {beta}-cell proliferation, suggesting it can impact adult {beta}-cell mass and diabetes risk.

category: developmental biology


title: Early postnatal activation of the hypoxia pathway disrupts β-cell function


title: Unexpected similarity between HIV-1 reverse transcriptase and tumor necrosis factor revealed by binding site image processing

abstract:
Rationalizing the identification of hidden similarities across the repertoire of druggable protein cavities remains a major hurdle to a true proteome-wide structure-based discovery of novel drug candidates. We recently described a new computational approach (ProCare), inspired by numerical image processing, to identify local similarities in fragment-based subpockets. During the validation of the method, we unexpectedly identified a possible similarity in the binding pockets of two unrelated targets, human tumor necrosis factor alpha (TNF-) and HIV-1 reverse transcriptase (HIV-1 RT). Microscale thermophoresis experiments confirmed the ProCare prediction as two of the three tested and FDA-approved HIV-1 RT inhibitors indeed bind to soluble human TNF- trimer. Interestingly, the herein disclosed similarity could be revealed neither by state-of-the-art binding sites comparison methods nor by ligand-based pairwise similarity searches, suggesting that the point cloud registration approach implemented in ProCare, is uniquely suited to identify local and unobvious similarities among totally unrelated targets.

AUTHOR SUMMARYComputational comparison of binding sites in proteins can provide insights on potential unrelated proteins that may bind to similar ligands. However, accurate prediction of binding site similarity requires powerful methods, ideally able to detect even local similarities. We herewith applied a recently developed computer vision method to identify an unexpected binding site similarity between two totally unrelated proteins that was confirmed experimentally by in vitro biophysical binding assays. Considering more precisely local similarities can therefore efficiently guide drug discovery, notably to repurpose existing drug candidates.

category: bioinformatics


title: Towards the prediction of non-peptidic epitopes

abstract: In-silico methods for the prediction of epitopes can support and improve workflows for vaccine design, antibody production, and disease therapy. So far, the scope of B cell and T cell epitope prediction has been directed exclusively towards peptidic antigens. Nevertheless, various non-peptidic molecular classes can be recognized by immune cells. These compounds have not been systematically studied yet, and prediction approaches are lacking. The ability to predict the epitope activity of non-peptidic compounds could have vast implications; for example, for immunogenic risk assessment of the vast number of drugs and other xenobiotics. Here we present the first general attempt to predict the epitope activity of non-peptidic compounds using the Immune Epitope Database (IEDB) as a source for positive samples. The molecules stored in the Chemical Entities of Biological Interest (ChEBI) database were chosen as background samples. The molecules were clustered into eight homogeneous molecular groups, and classifiers were built for each cluster with the aim of separating the epitopes from the background. Different molecular feature encoding schemes and machine learning models were compared against each other. For those models where a high performance could be achieved based on simple decision rules, the molecular features were then further investigated. Additionally, the findings were used to build a web server that allows for the immunogenic investigation of non-peptidic molecules (http://tools-staging.iedb.org/np_epitope_predictor). The prediction quality was tested with samples from independent evaluation datasets, and the implemented method received noteworthy Receiver Operating Characteristic-Area Under Curve (ROC-AUC) values, ranging from 0.69-0.96 depending on the molecule cluster.


title: Contact guidance as a consequence of coupled morphological evolution and motility of adherent cells

abstract:
Adherent cells seeded on substrates spread and evolve their morphology while simultaneously displaying motility. Phenomena such as contact guidance viz. the alignment of cells on patterned substrates, are strongly linked to the coupling of morphological evolution with motility. Here we employ a recently developed statistical thermodynamics framework for modelling the non-thermal fluctuating response of the cells to probe this coupling. This thermodynamic framework is first extended to predict temporal responses via a Langevin style model. The Langevin model is then shown to not only predict the different experimentally observed temporal scales for morphological observables such as cell area and elongation but also the interplay of morphology with motility that ultimately leads to contact guidance.

Author SummaryThe evolution of cellular morphology and organization plays a crucial role in the micro-architecture of tissues and dictates their biological and mechanical functioning. Despite the importance of cellular organization in all facets of tissue biology, the fundamental question of how a cell organizes itself in an anisotropic environment is still poorly understood. We demonstrate, using a Langevin style model, that non-thermal fluctuations fuelled by nutrient exchanges between the cell and its environment are critical in allowing cells to explore their surroundings. The biochemical changes, associated with non-thermal fluctuations, drive cell motility and morphological changes and the interplay between these two emerging dynamics ultimately leads to contact guidance, a critical component for tissue morphogenesis.


title: Deciphering conformational selectivity in the A2A adenosine G protein-coupled receptor by Free Energy simulations

abstract:
Transmembranal G Protein-Coupled Receptors (GPCRs) transduce extracellular chemical signals to the cell, via conformational change from a resting (inactive) to an active (canonically bound to a G-protein) conformation. Receptor activation is normally modulated by extracellular ligand binding, but mutations in the receptor can also shift this equilibrium by stabilizing different conformational states. In this work, we built structure-energetic relationships of receptor activation based on original thermodynamic cycles that represent the conformational equilibrium of the prototypical A2A adenosine receptor (AR). These cycles were solved with efficient free energy perturbation (FEP) protocols, allowing to distinguish the pharmacological profile of different series of A2AAR agonists with different efficacies. The modulatory effects of point mutations on the basal activity of the receptor or on ligand efficacies could also be detected. This methodology can guide GPCR ligand design with tailored pharmacological properties, or allow the identification of mutations that modulate receptor activation with potential clinical implications.

Author SummaryThe design of new ligands as chemical modulators of G protein-coupled receptors (GPCRs) has benefited considerably during the last years of advances in both the structural and computational biology disciplines. Within the last, area, the use of free energy calculation methods has arisen as a computational tool to predict ligand affinities to explain structure-affinity relationships and guide lead optimization campaigns. However, our comprehension of the structural determinants of ligands with different pharmacological profile is scarce, and knowledge of the chemical modifications associated with an agonistic or antagonistic profile would be extremely valuable. We herein report an original implementation of the thermodynamic cycles associated with free energy perturbation (FEP) simulations, to mimic the conformational equilibrium between active and inactive GPCRs, and establish a framework to describe pharmacological profiles as a function of the ligands selectivity for a given receptor conformation. The advantage of this method resides into its simplicity of use, and the only consideration of active and inactive conformations of the receptor, with no simulation of the transitions between them. This model can accurately predict the pharmacological profile of series of full and partial agonists as opposed to antagonists of the A2A adenosine receptor, and moreover, how certain mutations associated with modulation of basal activity can influence this pharmacological profiles, which enables our understanding of such clinically relevant mutations.


title: Formation, collective motion, and merging of macroscopicbacterial aggregates

abstract:
Chemotactic bacteria form emergent spatial patterns of variable cell density within cultures that are initially spatially uniform. These patterns are the result of chemical gradients that are created from the directed movement and metabolic activity of billions of cells. A recent study on pattern formation in wild bacterial isolates has revealed unique collective behaviors of the bacteria Enterobacter cloacae. As in other bacteria species, Enterobacter cloacae form macroscopic aggregates. Once formed, these bacterial clusters can migrate several millimeters, sometimes resulting in the merging of two or more clusters. To better understand these phenomena, we examine the formation and dynamics of thousands of bacterial clusters that form within a 22 cm square culture dish filled with soft agar over two days. At the macroscale, the aggregates display spatial order at short length scales, and the migration of cell clusters is superdiffusive, with a merging acceleration that is correlated with aggregate size. At the microscale, aggregates are composed of immotile cells surrounded by low density regions of motile cells. The collective movement of the aggregates is the result of an asymmetric flux of bacteria at the boundary. An agent based model is developed to examine how these phenomena are the result of both chemotactic movement and a change in motility at high cell density. These results identify and characterize a new mechanism for collective bacterial motility driven by a transient, density-dependent change in motility.

Author summaryBacteria growing and swimming in soft agar often aggregate to form elaborate spatial patterns. Here we examine the patterns formed by the bacteria Enterobacter cloacae. An unusual behavior of this bacteria is the movement of cell clusters, millions of bacteria forming a tiny spot and moving together in the same direction. These spots sometimes run into each other and combine. By looking at the cells within these spots under a microscope, we find that cells within each spot stop swimming. The process of switching back and forth between swimming and not swimming causes the movement and fusion of the spots. A numerical simulation shows that the migration and merging of these spots can be expected if the cells swim towards regions of space with high concentrations of attractant molecules and stop swimming in locations crowded with many cells. This work identifies a novel process through which populations of bacteria cooperate and control the movement of large groups of cells.


title: Myofilament Glycation in Diabetes Reduces Contractility by Inhibiting Tropomyosin Movement, is Rescued by cMyBPC Domains

abstract: Diabetes doubles the risk of developing heart failure (HF). As the prevalence of diabetes grows, so will HF unless the mechanisms connecting these diseases can be identified. Methylglyoxal (MG) is a glycolysis by-product that forms irreversible modifications on lysine and arginine, called glycation. We previously found that myofilament MG glycation causes sarcomere contractile dysfunction and is increased in patients with diabetes and HF. The aim of this study was to discover the molecular mechanisms by which MG glycation of myofilament proteins cause sarcomere dysfunction and to identify therapeutic avenues to compensate. In humans with type 2 diabetes without HF, we found increased glycation of sarcomeric actin compared to non-diabetics and it correlated with decreased calcium sensitivity. Depressed calcium sensitivity is pathogenic for HF, therefore myofilament glycation represents a promising therapeutic target to inhibit the development of HF in diabetics. To identify possible therapeutic targets, we further defined the molecular actions of myofilament glycation. Skinned myocytes exposed to 100 M MG exhibited decreased calcium sensitivity, maximal calcium-activated force, and crossbridge kinetics. Replicating MGs functional affects using a computer simulation of sarcomere function predicted simultaneous decreases in tropomyosins blocked-to-closed rate transition and crossbridge duty cycle were consistent with all experimental findings. Stopped-flow experiments and ATPase activity confirmed MG decreased the blocked-to-closed transition rate. Currently, no therapeutics target tropomyosin, so as proof-of-principal, we used a n-terminal peptide of myosin-binding protein C, previously shown to alter tropomyosins position on actin. C0C2 completely rescued MG-induced calcium desensitization, suggesting a possible treatment for diabetic HF.


title: Genomic and Metabolic Hallmarks of SDH- and FH-Deficient Renal Cell Carcinomas

abstract:
PurposeSuccinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of metabolically proximal enzymes. We sought to define and compare the genomic and metabolomic hallmarks of these entities.

Experimental DesignWe analyzed SDHRCC and FHRCC tumors with either immunohistochemical evidence of loss of protein expression or genomically-confirmed biallelic inactivation of SDHA/B/C/D/AF2 or FH. Somatic alterations were identified using clinical pipelines, and allele-specific copy number changes were identified using FACETS. Mass-spectrometry-based metabolomic profiling was performed on available SDHRCC and FHRCC tumors.

ResultsForty two patients were analyzed (25 FHRCC, 17 SDHRCC). In the germline analysis, 16/17 SDHRCC harbored a germline alteration in SDHB, whereas only 17/22 FHRCC had pathogenic germline FH variants. SDHRCC had a lower mutation burden (p = 0.02) and copy number alteration burden (p = 0.0002) than FHRCC. All SDHRCC presented with deletion of chromosome 1p (overlapping SDHB), whereas FHRCC demonstrated high but not ubiquitous loss of 1q (FH locus). Both SDHRCC and FHRCC demonstrated significant, idiopathic accumulation of the metabolite guanine. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC had elevation of numerous acylcarnitines. These characteristic metabolic changes enabled the identification of a previously unrecognized SDH-deficient RCC.

ConclusionDespite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities.

Translational RelevanceMutations to the TCA cycle enzymes Succinate Dehydrogenase (SDH) and Fumarate Hydratase (FH) predispose individuals to unique subtypes of renal cell carcinoma (SDHRCC and FHRCC, respectively). Defining the genetic and metabolic hallmarks of these diseases is critical for advancing new diagnostic and therapeutic approaches for these rare but biologically intriguing entities. Despite a superficially similar genetic etiology, SDHRCC and FHRCC demonstrated significantly fewer secondary mutations to other cancer-associated genes and copy number aberrations than FHRCC, and was distinguished by universal loss-of-heterozygosity of chromosome 1p. Metabolomic analysis identified pathways disrupted in both SDHRCC and FHRCC, including the massive accumulation of free guanine, as well as pathways uniquely disrupted in each of the two entities. These metabolomic findings enabled the identification of a previously unidentified case of unclassified RCC with SDH deficiency, suggesting that metabolomic profiling may aid in phenotypic classification of tumors and uncover novel therapeutic targets.

category: cancer biology


title: The role of migration in mutant evolution in fragmented populations

abstract: Mutant evolution in fragmented populations has been studied extensively in evolutionary biology. With an increased focus on evolutionary dynamics in medical research, quantification of mutant load in fragmented populations with varying levels of migration has become especially important. Examples of fragmented populations are hematopoietic stem cell niches in the bone marrow where cells can re-circulate between niches through the blood, or colonic crypts where movement of cells across different crypts is not thought to be common. Here we use a combination of experiments and theory to investigate the role of migration in mutant distribution. In the case of neutral mutants, the experiments confirmed that while the mean number of mutants is not influenced by migration, the probability distribution is, which manifested itself in a change in the skewedness of the distribution of the mutant numbers in the demes. In the case of disadvantageous mutants, we investigated the phenomenon of the increase in the expected number of mutants compared to that of the selection-mutation balance. In a single deme, this increase is observed when the deme size is lower than the critical size, Nc. In a fragmented system that consists of connected demes with a probability of migration, the increase in mutant numbers above the selection-mutation balance can be maintained in small (N < Nc) demes as long as the migration rate is sufficiently small. The migration rate above which the mutants approach the selection-mutation balance decays exponentially with N/Nc. These findings are relevant in the context of the complex and poorly understood processes that may lead to changes in the clonal composition in tissues and tumors.

category: evolutionary biology


title: Heightened condition dependent expression of structural colouration in the faces, but not wings, of male and female flies

abstract: Structurally coloured sexual signals are a conspicuous and widespread class of ornament used in mate choice, though the extent to which they encode information on the quality of their bearers is not fully resolved. Theory predicts that signalling traits under strong sexual selection as  honest indicators should evolve to be more developmentally integrated and exaggerated than nonsexual traits, thereby leading to heightened condition dependence. Here we test this prediction through examination of the sexually dimorphic faces and wings of the cursorial fly Lispe cana. Males and females possess structural UV-white and golden faces, respectively, and males present their faces and wings to females during close-range, ground-based courtship displays, thereby creating the opportunity for mutual inspection. Across a field-collected sample of individuals, we found that the appearance of the faces of both sexes scaled positively with individual condition, though along separate axes. Males in better condition expressed brighter faces as modelled according to conspecific flies, whereas condition scaled with facial saturation in females. We found no such relationships for their wing interference pattern nor abdomens, with the latter included as a nonsexual control. Our results suggest that the structurally coloured faces, but not the iridescent wings, of male and female Lispe cana are reliable guides to individual quality and support the broader potential for structural colours as honest signals. They also highlight the potential for mutual mate choice in this system, while arguing for one of several alternate signalling roles for wing interferences patterns among the myriad taxa which bear them.


title: Neonicotinoid and pyrethroid combination: A tool to manage insecticide resistance in malaria vectors? Insights from experimental evolution

abstract:
BackgroundThe introduction of neonicotinoids for managing insecticide resistance in mosquitoes is of high interest as they interact with a biochemical target not previously used in public health. In this concern, Bayer developed a combination of the neonicotinoid clothianidin and the pyrethroid deltamethrin (brand name Fludora(R) Fusion) as a new vector control tool. Although this combination proved to be efficient against pyrethroid-resistant mosquitoes, its ability to prevent the selection of pyrethroid and neonicotinoid resistance alleles was not investigated. In this context, the objective of this work was to study the dynamics and the molecular mechanisms of resistance of An. gambiae to the separated or combined components of this combination. A field-derived An. gambiae line carrying resistance alleles to multiple insecticides at low frequencies was used as a starting for 33 successive generations of controlled selection. Resistance levels to each insecticide and target site mutation frequencies were monitored throughout the selection process. Cross resistance to other public health insecticides were also investigated. RNA-seq was used to compare gene transcription variations and polymorphisms across all lines.

ResultsThis study confirmed the potential of this insecticide combination to impair the selection of resistance as compared to its two separated components. Deltamethrin selection led to the rapid enrichment of the kdr L1014F target-site mutation while clothianidin selection led to the over-transcription of multiple cytochrome P450s including some showing high homology with the ones conferring neonicotinoid resistance in other insects. A strong selection signature associated with clothianidin selection was observed on a cytochrome P450 gene cluster previously associated with resistance. Within this cluster, the gene CYP6M1 showed the highest selection signature together with a transcription profile supporting a role in clothianidin resistance. Modelling the impact of point mutations selected by clothianidin on CYP6M1 protein structure suggested that the selection of variants affecting its active site can enhance clothianidin metabolism.

ConclusionsIn the context of the recent deployment of neonicotinoids for mosquito control and their frequent usage in agriculture, the present study highlights the benefit of combining them with other insecticides for preventing the selection of resistance and sustaining vector control activities.


title: Characterisation of the symbionts in the Mediterranean fruitfly gut

abstract: Symbioses between bacteria and their insect hosts can range from very loose associations through to obligate interdependence. While fundamental evolutionary insights have been gained from the in-depth study of obligate mutualisms, there is increasing interest in the evolutionary potential of flexible symbiotic associations between hosts and their gut microbiomes. Understanding relationships between microbes and hosts also offers the potential for exploitation for insect control. Here, we investigate the gut microbiome of a global agricultural pest, the Mediterranean fruitfly (Ceratitis capitata). We used 16S rRNA profiling to compare the gut microbiomes of laboratory and wild strains raised on different diets and from flies collected from various natural plant hosts. The results showed that medfly guts harbour a fairly simple microbiome, primarily determined by the larval diet in both wild and laboratory flies. However, regardless of the laboratory diet or natural plant host on which flies were raised, Klebsiella spp dominated the medfly microbiomes and resisted removal by antibiotic treatment. We sequenced the genome of the dominant putative Klebsiella spp (designated  Medkleb) isolated from the gut of the Toliman wild type fruitfly strain. Genome-wide ANI analysis placed Medkleb within the K. oxytoca / michiganensis group. Molecular, sequence and phenotypic analyses supported its identity as K. oxytoca. Medkleb has a genome size (5 825 435 bp) which is 1.6 standard deviations smaller than the mean genome size of free-living Klebsiella spp, and lacks some genes involved in environmental sensing. Moreover, the Medkleb genome contains at least two recently acquired unique genomic islands as well as genes that encode pectinolytic enzymes capable of degrading plant cell walls. This may be advantageous given that the medfly diet includes unripe fruits containing high proportions of pectin. These results suggest that the medfly harbours a commensal gut bacterium that may have developed a mutualistic association with its host and provide nutritional benefits.


title: Brain charts for the human lifespan

abstract: Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here, we built an interactive resource to benchmark brain morphology, www.brainchart.io, derived from any current or future sample of magnetic resonance imaging (MRI) data. With the goal of basing these reference charts on the largest and most inclusive dataset available, we aggregated 123,984 MRI scans from 101,457 participants aged from 115 days post-conception through 100 postnatal years, across more than 100 primary research studies. Cerebrum tissue volumes and other global or regional MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3; showed high stability of individual centile scores over longitudinal assessments; and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared to non-centiled MRI phenotypes, and provided a standardised measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In sum, brain charts are an essential first step towards robust quantification of individual deviations from normative trajectories in multiple, commonly-used neuroimaging phenotypes. Our collaborative study proves the principle that brain charts are achievable on a global scale over the entire lifespan, and applicable to analysis of diverse developmental and clinical effects on human brain structure. Furthermore, we provide open resources to support future advances towards adoption of brain charts as standards for quantitative benchmarking of typical or atypical brain MRI scans.

category: neuroscience


title: An outbreak of SARS-CoV-2 with high mortality in mink (Neovison vison) on multiple Utah farms

abstract:
The breadth of animal hosts that are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and may serve as reservoirs for continued viral transmission are not known entirely. In August 2020, an outbreak of SARS-CoV-2 occurred in multiple mink farms in Utah and was associated with high mink mortality and rapid viral transmission between animals. The outbreaks epidemiology, pathology, molecular characterization, and tissue distribution of virus within infected mink is provided. Infection of mink was likely by reverse zoonosis. Once established, infection spread rapidly between independently housed animals and farms, and caused severe respiratory disease and death. Clinical signs were most notably sudden death, anorexia, and increased respiratory effort. Gross pathology examination revealed severe pulmonary congestion and edema. Microscopically there was pulmonary edema with moderate vasculitis, perivasculitis, and fibrinous interstitial pneumonia. Reverse transcriptase polymerase chain reaction (RT-PCR) of tissues collected at necropsy demonstrated the presence of SARS-CoV-2 viral RNA in multiple organs including nasal turbinates, lung, tracheobronchial lymph node, epithelial surfaces, and others. Whole genome sequencing from multiple mink was consistent with published SARS-CoV-2 genomes with few polymorphisms. The Utah mink SARS-CoV-2 strain fell into Clade GH, which is unique among mink and other animal strains sequenced to date and did not share other spike RBD mutations Y453F and F486L found in mink. Localization of viral RNA by in situ hybridization revealed a more localized infection, particularly of the upper respiratory tract. Mink in the outbreak reported herein had high levels of virus in the upper respiratory tract associated with mink-to-mink transmission in a confined housing environment and were particularly susceptible to disease and death due to SARS-CoV-2 infection.

Author SummaryThe recent emergence and worldwide spread of the novel coronavirus has resulted in worldwide disease and economic hardship. The virus, known as SARS-CoV-2 is believed to have originated in bats and has spread worldwide through human-to-human virus transmission. It remains unclear which animal species, other than humans, may also be susceptible to viral infection and could naturally transmit the virus to susceptible hosts. In this study, we describe an outbreak of disease and death due to SARS-CoV-2 infection in farmed mink in Utah, United States. The investigation reveals that mink can spread the virus rapidly between animals and that the disease in mink is due to the viral infection and damage to tissues of the upper and lower respiratory system. The determination that mink are susceptible to SARS-CoV-2 indicates the need for strict biosecurity measures on mink farms to remediate mink-to-mink and human-to-mink transmission for the protection of mink, as well as prevent potential transmission from mink to humans.


title: Behavioral and neural markers of social vision

abstract:
Research on face perception has revealed highly specialized visual mechanisms such as configural processing, and provided markers of interindividual differences -including disease risks and alterations- in visuoperceptual abilities that traffic in social cognition. Is face perception unique in degree or kind of mechanisms, and in its relevance for social cognition? Combining functional MRI and behavioral methods, we address the processing of an uncharted class of socially relevant stimuli: minimal social scenes involving configurations of two bodies spatially close and face-to-face as if interacting (hereafter, facing dyads). We report category-specific activity for facing (vs. non-facing) two-body configurations in selective areas of the visual cortex. That activity shows face-like signatures of configural processing -i.e., stronger response, and greater susceptibility to stimulus inversion for facing (vs. non-facing) dyads-, and is predicted by performance-based measures of body-dyad perception (i.e., accuracy in a fast visual categorization task). Moreover, individual performance in body-dyad perception is reliable, stable-over-time and correlated with the individual social sensitivity, coarsely captured by the Autism-Spectrum Quotient. Further analyses clarify the relationship between single-body and body-dyad perception. We propose that facing dyads are processed through highly specialized mechanisms (and brain areas), analogously to other biologically/socially relevant stimuli such as faces. Like face perception, facing-dyad perception can reveal basic visual processes that lay the foundations for understanding others, their relationships and interactions.

Significance statementWith its specialization to faces and biological motion, vision houses the foundations of human social ability. Using a multimodal approach (meta-analysis, fMRI, visual-perception tasks and self-administered survey), we introduce a new class of visual stimuli -minimal social scenes with two face-to-face bodies-, whose processing highlights new behavioral and neural markers of visuoperceptual abilities that traffic in social cognition. Behavioral and neural effects of body-dyad perception reveal the recruitment of specialized configural processing, previously described for face perception. Furthermore, individual performance in body-dyad perception is stable over time, and predicts an individuals social sensitivity, measured in terms of autism-spectrum traits. Thus, body-dyad perception reveals uncharted aspects of visual functioning and specialization, which may critically contribute to human social life.


title: A new behavioral and neural marker of social vision


title: Multi-domain touchscreen-based cognitive assessment of C57BL/6J female mice shows whole body exposure to 56Fe particle space radiation in maturity improves discrimination learning yet impairs stimulus-response habit learning

abstract: Astronauts during interplanetary missions will be exposed to galactic cosmic radiation, including charged particles like 56Fe. Preclinical studies with mature, "astronaut-aged" rodents suggest space radiation diminishes performance in classical hippocampal- and prefrontal cortex-dependent tasks. However, a rodent cognitive touchscreen battery unexpectedly revealed 56Fe radiation improves the performance of C57BL/6J male mice in a hippocampal-dependent task (discrimination learning) without changing performance in a striatal-dependent task (rule-based learning). As other preclinical work suggests the female rodent brain may be relatively resistant to charged particle-induced injury, and as the proportion of female vs. male astronauts is increasing, further study on how charged particles influence the touchscreen cognitive performance of female mice is warranted. We hypothesized that, similar to mature male mice, mature female C57BL/6J mice exposed to whole-body 56Fe irradiation (3 x 6.7cGy 56Fe over 5 days, 600MeV/n) would improve performance vs.Sham conditions in touchscreen tasks relevant to hippocampal and prefrontal cortical function (e.g. location discrimination reversal [LDR] and extinction, respectively). In LDR, 56Fe female mice more accurately discriminated two discrete conditioned stimuli relative to Sham mice, suggesting improved hippocampal function. However, 56Fe and Sham female mice acquired a new simple stimulus-response behavior and extinguished this acquired behavior at similar rates, suggesting similar prefrontal cortical function. Based on prior work on multiple memory systems, we next tested whether improved hippocampal-dependent function (discrimination learning) came at the expense of striatal rule-based learning (visuomotor conditional learning). Interestingly, 56Fe female mice took more days to reach criteria in this striatal-dependent rule-based test relative to Sham mice. Together, our data support the idea of competition between memory systems, as an 56Fe-induced decrease in striatal-based learning is associated with enhanced hippocampal-based learning. These data emphasize the power of using a touchscreen-based battery to advance our understanding of the effects of space radiation on mission critical cognitive function in females, and underscore the importance of preclinical space radiation risk studies measuring multiple cognitive processes, thereby preventing NASAs risk assessments from being based on a single cognitive domain.

category: animal behavior and cognition


title: Discovering fragment length signatures of circulating tumor DNA using Non-negative Matrix Factorization

abstract:
Sequencing of cell-free DNA (cfDNA) is currently being used to detect cancer by searching both for mutational and non-mutational alterations. Recent work has shown that the length distribution of cfDNA fragments from a cancer patient can inform tumor load and type. Here, we propose non-negative matrix factorization (NMF) of fragment length distributions as a novel method to study fragment lengths in cfDNA samples.

Using shallow whole-genome sequencing (sWGS) of cfDNA from a cohort of patients with metastatic castration-resistant prostate cancer (mCRPC), we demonstrate how NMF accurately infers the true tumor fragment length distribution as an NMF component - and that the sample weights of this component correlate with ctDNA levels (r=0.75). We further demonstrate how using several NMF components enables accurate cancer detection on data from various early stage cancers (AUC=0.96). Finally, we show that NMF, when applied across genomic regions, can be used to discover fragment length signatures associated with open chromatin.


title: Integrative Epigenomic and High-Throughput Functional Enhancer Profiling Reveals Determinants of Enhancer Heterogeneity in Gastric Cancer

abstract:
BackgroundEnhancers are distal cis-regulatory elements required for cell-specific gene expression and cell fate determination. In cancer, enhancer variation has been proposed as a major cause of inter-patient heterogeneity - however, most predicted enhancer regions remain to be functionally tested.

ResultsAnalyzing 128 epigenomic histone modification profiles of primary GC samples, normal gastric tissues, and GC cell lines, we report a comprehensive catalog of 75,730 recurrent predicted enhancers, the majority of which are tumor-associated in vivo (>50,000) and associated with lower somatic mutation rates inferred by whole-genome sequencing. Applying Capture-based Self-Transcribing Active Regulatory Region sequencing (CapSTARR-seq) to the enhancer catalog, we observed significant correlations between CapSTARR-seq functional activity and H3K27ac/H3K4me1 levels. Super-enhancer regions exhibited increased CapSTARR-seq signals compared to regular enhancers even when decoupled from native chromatin contexture. We show that combining histone modification and CapSTARR-seq functional enhancer data improves the prediction of enhancer-promoter interactions and pinpointing of germline single nucleotide polymorphisms (SNPs), somatic copy number alterations (SCNAs), and trans-acting TFs involved in GC expression. Specifically, we identified cancer-relevant genes (e.g. ING1, ARL4C) whose expression between patients is influenced by enhancer differences in genomic copy number and germline SNPs, and HNF4 as a master trans-acting factor associated with GC enhancer heterogeneity.

ConclusionsOur study indicates that combining histone modification and functional assay data may provide a more accurate metric to assess enhancer activity than either platform individually, and provides insights into the relative contribution of genetic (cis) and regulatory (trans) mechanisms to GC enhancer functional heterogeneity.


title: The mitotic checkpoint protein MAD2 delivers monoamine transporters to endocytosis.

abstract: Monoamine transporters retrieve serotonin (SERT), dopamine (DAT) and norepinephrine (NET) from the synaptic cleft. Surface levels of transporters are also regulated by internalization. Clathrin-mediated endocytosis of cargo proteins requires adaptor protein 2 (AP2), which recruits cargo to the nascent clathrin-cage. The transporter C-terminus is required for internalization but lacks an AP2-binding site. In the present work, we show that internalization of SERT and DAT relies on MAD2, a protein of the mitotic spindle assembly checkpoint (SAC). A MAD2-interaction motif in the transporter C-terminus interacts with MAD2. This binding is contingent on the closed conformation of MAD2 and allowed for the recruitment of two additional SAC proteins, BubR1 and p31COMET as well as AP2. MAD2, BubR1 and p31COMET are present in serotoninergic neurons of the dorsal raphe, corroborating a biological role of the identified interactions. Depletion of MAD2 in HEK-293 cells stably expressing SERT and DAT decreases constitutive and triggered endocytosis, respectively. Altogether, our study describes a candidate mechanism, which connects monoamine transporters to the endocytic machinery and thus supports their internalization.


title: Somatic HCN channels augment and speed up GABAergic basket cell input-output function in human neocortex

abstract: Neurons in the mammalian brain exhibit evolution-driven species-specific differences in their functional properties. Therefore, understanding the human brain requires unraveling the human neuron "uniqueness" and how it contributes to the operation of specific neuronal circuits. We show here that a highly abundant type of inhibitory neurons in the neocortex, GABAergic parvalbumin-expressing basket cell (pv+BC), exhibits in the human brain a specific somatic leak current mechanism, which is absent in their rodent neuronal counterparts. Human pv+BC soma shows electric leak conductance mediated by hyperpolarization-activated cyclic nucleotide-gated channels. This leak conductance has depolarizing effects on the resting membrane potential and it accelerates the rise of synaptic potentials in the cell soma. The leak facilitates the human pv+BC input-to-output fidelity and shortens the action potential generation to excitatory inputs. This mechanism constitutes an adaptation that enhances signal transmission fidelity and speed in the common inhibitory circuit in the human but not in the rodent neocortex.


title: Frontal cortical functional connectivity is impacted by anaesthesia in macaques

abstract: AO_SCPLOWBSTRACTC_SCPLOWA critical aspect of neuroscience is to establish whether and how brain networks evolved across primates. To date, most comparative studies have used resting-state functional Magnetic Resonance Imaging (rs-fMRI) in anaesthetized non-human primates and in awake humans. However, anaesthesia strongly affects rs-fMRI signals. The present study investigated the impact of the awareness state (anaesthesia vs. awake) within the same group of macaque monkeys on the rs-fMRI functional connectivity (FC) organization of a well characterized network in the human brain, the cingulo-frontal lateral network. Results in awake macaques revealed a similar FC pattern to that previously uncovered in the human brain. Rostral seeds in the cingulate sulcus exhibited stronger correlation strength with rostral compared to caudal lateral frontal cortical areas while caudal seeds in the cingulate sulcus displayed stronger correlation strength with caudal compared to anterior lateral frontal cortical areas. Critically, this inverse rostro-caudal functional gradient was abolished under anaesthesia. This study demonstrates that the FC pattern of cingulo-frontal cortical networks is preserved from macaque to human but some of its properties can only be observed in the awake state, warranting significant caution when comparing FC patterns across species under different states.


title: Single-cell RNA sequencing uncovers the excitatory/inhibitory synaptic unbalance in the retrosplenial cortex after peripheral nerve injury

abstract: Nerve injury in the somatosensory pathway may induce maladaptive changes at the transcriptional or protein level, contributing to the development and maintenance of neuropathic pain. In contrast to the retrosplenial cortex (RSC), which processes nociceptive information and exhibits structural and molecular changes after nerve injury, detailed transcriptional changes in the RSC are not yet known. Here we confirm the involvement of the RSC in regulating pain sensation and observe that the same peripheral stimulation activates more retrosplenial neurons after nerve injury; reducing the activities of CaMKII+ splenial cells relieves peripheral pain hypersensitivity after nerve injury. Using a single-cell RNA sequencing (scRNA-seq) approach, we identified cell-type-specific gene expression changes after nerve injury, and the gene set enrichment analysis results revealed suppressed ion homeostasis in CaMKII+ neurons. Furthermore, examination of the expression of genes encoding ligand-gated ion channels showed a decrease in Gabar1a but an increase in Gria1 in CaMKII+ neurons; consistently, we confirmed the unbalanced excitatory/inhibitory synaptic transmission by using the electrophysiological recording approach. Moreover, micro-infusion of 1-Naphthyl acetyl spermine in the RSC to reduce excitatory synaptic transmission alleviated peripheral pain hypersensitivity. Our data confirm the involvement of the RSC in pain regulation and provide information on cell type-dependent transcriptomic changes after nerve injury, which will contribute to the understanding of the mechanisms mediating neuropathic pain.


title: Adolescent to young adult longitudinal development of subcortical volumes in two European sites with four waves

abstract: Adolescent subcortical structural brain development might underlie psychopathological symptoms, which often emerge in adolescence. At the same time, sex differences exist in psychopathology, which might be mirrored in underlying sex differences in structural development. However, previous studies showed inconsistencies in subcortical trajectories and potential sex differences. Therefore, we aimed to investigate the subcortical structural trajectories and their sex differences across adolescence using for the first time a single cohort design, the same quality control procedure, software and a general additive mixed modeling approach. We investigated two large European sites from ages 14 to 24 with 503 participants and 1408 total scans from France and Germany as part of the IMAGEN project including four waves of data acquisition. We found significantly larger volumes in males versus females in both sites and across all seven subcortical regions. Sex differences in age-related trajectories were observed across all regions in both sites. Our findings provide further evidence of sex differences in longitudinal adolescent brain development of subcortical regions and thus might eventually support the relationship of underlying brain development and different adolescent psychopathology in boys and girls.


title: Interpersonal synchronization of movement intermittency

abstract: Most animal species group together and coordinate their behavior in quite sophisticated manners for mating, hunting or defense purposes. In humans, coordination at a macroscopic level (the pacing of movements) is evident both in daily life (e.g., walking) and skilled (e.g., music and dance) behaviors. By examining the fine structure of movement, we here show that interpersonal coordination is established also at a microscopic - sub-movement - level. Natural movements appear as marked by recurrent (2-3 Hz) speed breaks, i.e., submovements, that are traditionally considered the result of intermittency in (visuo)motor control. In a series of interpersonal motor coordination tasks, we demonstrate that submovements are not independent between interacting partners but produced in a tight temporal relation that reflects the directionality in the partners informational coupling. These findings unveil a potential core mechanism for behavioral coordination that is based on between-persons synchronization of the intrinsic dynamics of action-perception cycles.


title: Typical resting state activity of the brain requires visual input during an early sensitive period

abstract:
Sensory deprivation, following a total loss of one sensory modality e.g. vision, has been demonstrated to result in intra- and cross-modal plasticity. It is yet not known to which extent intra- and cross-modal plasticity as a consequence of blindness reverse if sight is restored.

Here, we used functional magnetic resonance imaging to acquire blood oxygen level dependent (BOLD) resting state activity during an eyes open and an eyes closed state in congenital cataract-reversal individuals, developmental cataract-reversal individuals, congenitally permanently blind individuals and sighted controls. The amplitude of low frequency fluctuations (ALFF) of the BOLD signal - a neural marker of spontaneous brain activity during rest - was analyzed.

As has been shown before, in normally sighted controls we observed an increase in ALFF during rest with the eyes open compared to rest with eyes closed in visual association areas and in parietal cortex but a decrease in auditory and sensorimotor regions. In congenital cataract-reversal individuals, we found an increase of the amplitude of slow BOLD fluctuations in visual cortex during rest with eyes open compared to rest with eyes closed too but this increase was larger in amplitude than in normally sighted controls. At the same time, congenital cataract-reversal individuals lagged a similar increase in parietal regions and did not show the typical decrease of ALFF in auditory and sensorimotor cortex. Congenitally blind individuals displayed an overall higher amplitude in slow BOLD fluctuations in visual cortex compared to sighted individuals and compared to congenital cataract-reversal individuals in the eyes closed condition.

Higher ALFF in visual cortex of congenital cataract-reversal individuals than in normally sighted controls during eyes open might indicate an altered excitatory-inhibitory balance of visual neural circuits. By contrast, the lower parietal increase and the missing downregulation in auditory and sensorimotor regions suggest a reduced influence of the visual system on multisensory and the remaining sensory systems after restoring sight in congenitally blind individuals. These results demonstrate a crucial dependence of multisensory neural networks on visual experience during a sensitive phase in human brain development.


title: Computational modelling of cell motility modes emerging from cell-matrix adhesion dynamics

abstract:
Lymphocytes have been described to perform different motility patterns such as Brownian random walks, persistent random walks, and Levy walks. Depending on the conditions, such as confinement or the distribution of target cells, either Brownian or Levy walks lead to more efficient interaction with the targets. The diversity of these motility patterns may be explained by an adaptive response to the surrounding extracellular matrix (ECM). Indeed, depending on the ECM composition, lymphocytes either display a floating motion without attaching to the ECM, or sliding and stepping motion with respectively continuous or discontinuous attachment to the ECM, or pivoting behaviour with sustained attachment to the ECM. Moreover, on the long term, lymphocytes either perform a persistent random walk or a Brownian-like movement depending on the ECM composition. How the ECM affects cell motility is still incompletely understood. Here, we integrate essential mechanistic details of the lymphocyte-matrix adhesions and lymphocyte intrinsic cytoskeletal induced cell propulsion into a Cellular Potts model (CPM). We show that the combination of de novo cell-matrix adhesion formation, adhesion growth and shrinkage, adhesion rupture, and feedback of adhesions onto cell propulsion recapitulates multiple lymphocyte behaviours, for different lymphocyte subsets and various substrates. With an increasing attachment area and increased adhesion strength, the cells speed and persistence decreases. Additionally, the model can predict short-term persistent with long-term subdiffusive motility, showing a pivoting motion. For small adhesion areas, we observe that the spatial distribution of adhesions influences cell motility. Small adhesions at the front allow for more persistent motion than larger clusters at the back, despite a similar total adhesion area. In conclusion, we present an integrated framework to simulate the effects of ECM proteins on cell-matrix adhesion dynamics. The model reveals a sufficient set of principles explaining the plasticity of lymphocyte motility.

Author summaryDuring immunosurveillance, lymphocytes patrol through tissues to interact with cancer cells, other immune cells, and pathogens. The efficiency of this process depends on the kinds of trajectories taken, ranging from simple Brownian walks to Levy walks. The composition of the extracellular matrix (ECM), a network of macromolecules, affects the formation of cell-matrix adhesions, thus strongly influencing the way lymphocytes move. Here, we present a model of lymphocyte motility driven by adhesions that grow, shrink and rupture in response to the ECM and cellular forces. Compared to other models, our model is computationally light making it suitable for generating long term cell track data, while still capturing actin dynamics and adhesion turnover. Our model suggests that cell motility is affected by the force required to break adhesions and the rate at which new adhesions form. Adhesions can promote cell protrusion by inhibiting retrograde actin flow. After introducing this effect into the model, we found that it reduces the cellular diffusivity and that it promotes stick-slip behaviour. Furthermore, location and size of adhesion clusters determined cell persistence. Overall, our model explains the plasticity of lymphocyte behaviour in response to the ECM.


title: Habitat Protection Indexes - new monitoring measures for the conservation of coastal and marine habitats

abstract: A worldwide call to implement habitat protection aims to halt biodiversity loss. To monitor the extent of coastal and marine habitats within protected areas (PAs) in a standardized, open source, and reproducible way, we constructed the Local and the Global Habitat Protection Indexes (LHPI and GHPI, respectively). The LHPI pinpoints the jurisdictions with the greatest opportunity to expand their own PAs, while the GHPI showcases which jurisdictions contribute the most in area to the protection of these habitats globally. Jurisdictions were evaluated to understand which have the highest opportunity to contribute globally to the protection of habitats by meeting a target of 30% coverage of PAs with Areas Beyond National Jurisdiction (ABNJ) having the greatest opportunity to do so. While we focus on marine and coastal habitats, our workflow can be extended to terrestrial and freshwater habitats. These indexes are useful to monitor aspects of Sustainable Development Goal 14 and the emerging post-2020 Global Biodiversity Framework, to understand the current status of international cooperation on coastal and marine habitats conservation.

category: ecology


title: The mating system affects the temperature sensitivity of male and female fertility

abstract:
O_LITo mitigate effects of climate change it is important to understand species responses to increasing temperatures. This has often been done by studying survival or activity at temperature extremes. Before such extremes are reached, however, effects on fertility may already be apparent.
C_LIO_LISex differences in the thermal sensitivity of fertility (TSF) could impact species persistence under climate warming because female fertility is typically more limiting to population growth than male fertility. However, little is known about sex differences in TSF.
C_LIO_LIHere we first demonstrate that the mating system can strongly influence TSF using the seed beetle Callosobruchus maculatus. We exposed populations carrying artificially induced mutations to two generations of short-term experimental evolution under alternative mating systems, manipulating the opportunity for natural and sexual selection on the mutations. We then measured TSF in males and females subjected to juvenile or adult heat stress.
C_LIO_LIPopulations kept under natural and sexual selection had higher fitness, but similar TSF, compared to control populations kept under relaxed selection. However, females had higher TSF than males, and strikingly, this sex difference had increased over only two generations in populations evolving under sexual selection.
C_LIO_LIWe hypothesized that an increase in male-induced harm to females during mating had played a central role in driving this evolved sex difference, and indeed, remating under conditions limiting male harassment of females reduced both male and female TSF. Moreover, we show that manipulation of mating system parameters in C. maculatus generates intraspecific variation in the sex difference in TSF equal to that found among a diverse set of studies on insects.
C_LIO_LIOur study provides a causal link between the mating system and TSF. Sexual conflict, (re)mating rates, and genetic responses to sexual selection differ among ecological settings, mating systems and species. Our study therefore also provides mechanistic understanding for the variability in previously reported TSFs which can inform future experimental assays and predictions of species responses to climate warming.
C_LI


title: Bee foraging preferences, microbiota and pathogens revealed by direct shotgun metagenomics of honey

abstract: Honeybees (Apis mellifera) continue to succumb to human and environmental pressures despite their crucial role in providing essential ecosystem services. Owing to their foraging and honey production activities, honeybees form complex relationships with species across all domains, such as plants, viruses, bacteria (symbiotic and pathogenic), and other hive pests, making honey a valuable biomonitoring tool for assessing their ecological niche. Thus, the application of honey shotgun metagenomics (SM) has paved the way for a detailed description of the species honeybees interact with, in order to better assess the multiple factors governing their health. Here, we describe the implementation of optimized honey DNA extraction methodology coupled to direct shotgun metagenomics (Direct-SM) analysis, and to a computationally optimised and validated pipeline for taxonomic classification of species detected in honey. By comparing honey collected across 3 harvesting seasons in a stable apiary, we show that Direct-SM can describe the variability of sampled plant species, revealing honeybee behavioural adaptation. In addition, we reveal that Direct-SM can non-invasively capture the diversity of species comprising the core and non-core bacterial communities of the gut microbiome. Finally, we show that this methodology is applicable for the monitoring of pathogens and particularly for the biomonitoring varroa infestation. These results suggest that Direct-SM can accurately and comprehensively describe honeybee ecological niches and can be deployed to assess bee health in the field.


title: Landscape and climatic variations of the Quaternary shaped multiple secondary contacts among barn owls (Tyto alba) of the Western Palearctic

abstract: The combined actions of climatic variations and landscape barriers shape the history of natural populations. When organisms follow their shifting niches, obstacles in the landscape can lead to the splitting of populations, on which evolution will then act independently. When two such populations are reunited, secondary contact occurs in a broad range of admixture patterns, from narrow hybrid zones to the complete dissolution of lineages. A previous study suggested that barn owls colonized the Western Palearctic after the last glaciation in a ring-like fashion around the Mediterranean Sea, and conjectured an admixture zone in the Balkans. Here, we take advantage of whole-genome sequences of 94 individuals across the Western Palearctic to reveal the complex history of the species in the region using observational and modeling approaches. Even though our results confirm that two distinct lineages colonized the region, one in Europe and one in the Levant, they suggest that it predates the last glaciation and identify a narrow secondary contact zone between the two in Anatolia. Nonetheless, we also show that barn owls re-colonized Europe after the glaciation from two distinct glacial refugia: a western one in Iberia and an eastern one in Italy. Both glacial lineages now communicate via eastern Europe, in a wide and permeable contact zone. This complex history of populations enlightens the taxonomy of Tyto alba in the region, highlights the key role played by mountain ranges and large water bodies as barriers and illustrates the power of population genomics in uncovering intricate demographic patterns.


title: Draft genome assembly data of Anoxybacillus sp. strain MB8 isolated from Tattapani hot springs, India

abstract:
Discovery of novel thermophiles has shown promising applications in the field of biotechnology. Due to their thermal stability, they can survive the harsh processes in the industries, which make them important to be characterized and studied. Members of Anoxybacillus are alkaline tolerant thermophiles and have been extensively isolated from manure, dairy-processed plants, and geothermal hot springs. This article reports the assembled data of an aerobic bacterium Anoxybacillus sp. strain MB8, isolated from the Tattapani hot springs in Central India, where the 16S rRNA gene shares an identity of 97% (99% coverage) with Anoxybacillus kamchatkensis strain G10. The de novo assembly and annotation performed on the genome of Anoxybacillus sp. strain MB8 comprises of 2,898,780 bp (in 190 contigs) with a GC content of 41.8% and includes 2,976 protein-coding genes,1 rRNA operon, 73 tRNAs, 1 tm-RNA and 10 CRISPR arrays. The predicted protein-coding genes have been classified into 21 eggNOG categories. The KEGG Automated Annotation Server (KAAS) analysis indicated the presence of assimilatory sulfate reduction pathway, nitrate reducing pathway, and genes for glycoside hydrolases (GHs) and glycoside transferase (GTs). GHs and GTs hold widespread applications, in the baking and food industry for bread manufacturing, and in the paper, detergent and cosmetic industry. Hence, Anoxybacillus sp. strain MB8 holds the potential to be screened and characterized for such commercially relevant enzymes.

Specifications Table

O_TBL View this table:
org.highwire.dtl.DTLVardef@46be2org.highwire.dtl.DTLVardef@46fbe2org.highwire.dtl.DTLVardef@42cc37org.highwire.dtl.DTLVardef@16d5912org.highwire.dtl.DTLVardef@1f2bcdc_HPS_FORMAT_FIGEXP  M_TBL C_TBL Values of DataO_LIThe Anoxybacillus sp. strain MB8 genome assembly data provides insights into functional potential of thermophilic enzymes of this thermotolerant microbe.
C_LIO_LIThe presence of genes for Glycoside Hydrolase (GHs) like alpha-amylase, pullulanase, neopullulanase, alpha-glucosidase, beta-fructofuranosidase etc. and genes for Glycosyl Transferase (GTs) like sucrose synthase, maltodextrin phosphorylase, starch synthase, and glycogen phosphorylase were identified, which hold strong industrial values.
C_LIO_LIThe taxonomic annotation of Anoxybacillus sp. strain MB8 using different approaches indicates that the closest relatives were Anoxybacillus gonensis NZ CP012152T (96.86% ANI) and Anoxybacillus kamchatkensis G10 NZ CP025535 (96.83% ANI) obtained from. The strain MB8 most likely belongs to the same subspecies of Anoxybacillus gonensis NZ CP012152T.
C_LI

category: genomics


title: Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2

abstract: The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein-coupled receptor (GPCR) involved in regulation of calcium transport, nociception mediation, and wound healing. Naturally occurring mutations in PTH2R were reported to cause hereditary diseases, including syndromic short stature. Here we report the cryo-electron microscopy structure of PTH2R bound to its endogenous ligand, tuberoinfundibular peptide (TIP39), and a heterotrimeric Gs protein at a global resolution of 2.8 [A]. The structure reveals that TIP39 adopts a unique loop conformation at N terminus and deeply inserts into the orthosteric ligand-binding pocket in the transmembrane (TM) domain. Molecular dynamics (MD) simulation and site-directed mutagenesis studies uncover the basis of ligand specificity relative to three PTH2R agonists, TIP39, PTH, and PTH-related peptide (PTHrP). We also compare the action of TIP39 with an antagonist lacking six residues from the peptide N terminus, TIP(7-39), which underscores the indispensable role of the N terminus of TIP39 in PTH2R activation. Additionally, we unveil that a disease-associated mutation G258D significantly diminished cAMP accumulation induced by TIP39. Together, these results not only provide structural insights into ligand specificity and receptor activation of class B1 GPCRs, but also offer a foundation to systematically rationalize the available pharmacological data to develop novel therapies for various disorders associated with PTH2R.

category: biochemistry


title: A Comprehensive Model of Glucose-Insulin Regulation Including Acute and Prolonged Effects of Physical Activity in Type 1 Diabetes

abstract:
ObjectiveFor type 1 diabetic patients, accurate adjustment of insulin treatment to physical activity (PA) is a challenging open problem. Glucose uptake by the exercising muscles increases acutely, causing increased hepatic glucose production to maintain glucose homeostasis. Meanwhile, insulin sensitivity is elevated for a prolonged period to drive glycogen repletion during recovery. These processes strongly depend on PA duration and intensity, making their combined effects difficult to predict accurately. In this work, we develop a model of glucose-insulin regulation that captures PA from low to high intensity including acute and prolonged effects on glucose metabolism.

MethodsWe extended an existing minimal model of glucose-insulin regulation to capture PA-driven changes in glucose metabolism. We incorporated the insulin-independent increase in glucose uptake and production, including the effects of glycogen depletion and of high-intensity PA on production. The model also captures the prolonged increase in insulin sensitivity.

ResultsThe model accurately predicts glucose dynamics of published data during short and prolonged PA of moderate to high intensity and during subsequent recovery. In-silico full-day studies elucidate the effects of timing, duration and intensity of PA and of insulin bolus reduction on glucose levels during and after the activity.

ConclusionThe proposed model captures the blood glucose dynamics during all main PA regimes.

SignificanceMathematical models of glucose-insulin regulation are critical components of closed-loop insulin delivery and clinical decision support systems for achieving good glycemic control. The presented model shows potential for the development and assessment of algorithms targeting treatment adjustment to PA.


title: Minimizer-space de Bruijn graphs

abstract: DNA sequencing data continues to progress towards longer reads with increasingly lower sequencing error rates. We focus on the problem of assembling such reads into genomes, which poses challenges in terms of accuracy and computational resources when using cutting-edge assembly approaches, e.g. those based on overlapping reads using minimizer sketches. Here, we introduce the concept of minimizer-space sequencing data analysis, where the minimizers rather than DNA nucleotides are the atomic tokens of the alphabet. By projecting DNA sequences into ordered lists of minimizers, our key idea is to enumerate what we call k-min-mers, that are k-mers over a larger alphabet consisting of minimizer tokens. Our approach, mdBG or minimizer-dBG, achieves orders-of-magnitude improvement in both speed and memory usage over existing methods without much loss of accuracy. We demonstrate three uses cases of mdBG: human genome assembly, metagenome assembly, and the representation of large pangenomes. For assembly, we implemented mdBG in software we call rust-mdbg, resulting in ultra-fast, low memory and highly-contiguous assembly of PacBio HiFi reads. A human genome is assembled in under 10 minutes using 8 cores and 10 GB RAM, and 60 Gbp of metagenome reads are assembled in 4 minutes using 1 GB RAM. For pangenome graphs, we newly allow a graphical representation of a collection of 661,405 bacterial genomes as an mdBG and successfully search it (in minimizer-space) for anti-microbial resistance (AMR) genes. We expect our advances to be essential to sequence analysis, given the rise of long-read sequencing in genomics, metagenomics and pangenomics.


title: Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor

abstract: Ghrelin, also called "the hunger hormone", is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. The multifaceted roles of ghrelin make ghrelin receptor a highly attractive drug target for growth retardation, obesity, and metabolic disorders. Here we present two cryo-electron microscopy structures of Gq-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. Together with mutational and functional data, our structures define the rules for recognition of the acylated peptide hormone and activation of ghrelin receptor, and provide structural templates to facilitate drug design targeting ghrelin receptor.


title: Multi-Level DBSCAN: A Hierarchical Density-Based Clustering Method for Analyzing Molecular Dynamics Simulation Trajectories

abstract: Molecular Dynamic (MD) simulations have been extensively used as a powerful tool to investigate dynamics of biological molecules in recent decades. Generally, MD simulations generate high-dimensional data that is very hard to visualize and comprehend. As a result, clustering algorithms have been commonly used to reduce the dimensionality of MD data with the key benefit being their ability to reduce the dimensionality of MD data without prior knowledge of structural details or dynamic mechanisms. In this paper, we propose a new algorithm, the Multi-Level Density-Based Spatial Clustering of Applications with Noise (ML-DBSCAN), which combines the clustering results at different resolution of density levels to obtain the hierarchical structure of the free energy landscape and the metastable state assignment. At relatively low resolutions, the ML-DBSCAN can efficiently detect high population regions that contain all metastable states, while at higher resolutions, the ML-DBSCAN can find all metastable states and structural details of the free energy landscape. We demonstrate the powerfulness of the ML-DBSCAN in generating metastable states with a particle moving in a Mexican hat-like potential, and four peptide and protein examples are used to demonstrate how hierarchical structures of free energy landscapes can be found. Furthermore, we developed a GPU implementation of the ML-DBSCAN, which allows the algorithm to handle larger MD datasets and be up to two orders of magnitude faster than the CPU implementation. We demonstrate the power of the ML-DBSCAN on MD simulation datasets of five systems: a 2D-potential, alanine dipeptide, {beta}-hairpin Tryptophan Zipper 2 (Trpzip2), Human Islet Amyloid Polypeptide (hIAPP), and Maltose Binding Protein (MBP). Our code is available at https://github.com/liusong299/ML-DBSCAN.


title: Emerging single cell endothelial heterogeneity supports sprouting tumour angiogenesis and growth

abstract: Blood vessels supplying tumors are often dysfunctional and generally heterogeneous. The mechanisms underlying this heterogeneity remain poorly understood. Here, using multicolor lineage tracing, in vivo time-lapse imaging and single cell RNA sequencing in a mouse glioma model, we identify tumour-specific blood endothelial cells that originate from cells expressing the receptor for colony stimulating factor 1, Csf1r, a cytokine which controls macrophage biology. These Csf1r lineage endothelial cells (CLECs) form up to 10% of the tumour vasculature and express, besides classical blood endothelial cell markers, a gene signature that is distinct from brain endothelium but shares similarities with lymphatic endothelial cell populations. in silico analysis of pan-cancer single cell RNAseq datasets highlights the presence of a comparable subpopulation in the endothelium of a wide spectrum of human tumours. We show that CLECs actively contribute to sprouting and remodeling of tumour blood vessels and that selective depletion of CLECs reduces vascular branching and tumour growth. Our findings indicate that a non-tumour resident Csf1r-positive population is recruited to tumours, differentiates into blood endothelial cells to contribute to vascularization and, thereby, tumour growth.


title: A Thyroid Hormone Receptor Beta Specific Agonist Suppresses Anaplastic Thyroid Cancer Cell Phenotype and Increases Efficacy of Therapeutic Agents

abstract:
BackgroundAnaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers, with an average survival time of six months after diagnosis. These aggressive tumors have very limited treatment options highlighting a need for a deeper understanding of its mechanisms for development of more effective therapies. We have previously shown that the liganded thyroid hormone receptor beta (TR{beta}) can function as a tumor suppressor and induce re-differentiation in ATC cells. We therefore tested the hypothesis that selective activation of TR{beta} with sobetirome (GC-1) could reduce the tumorigenic phenotypes of ATC cell lines and improve the efficacy of clinically relevant therapeutics.

MethodsWe used a panel of four ATC cell lines with variable genetic backgrounds to assess the ability of GC-1 to reduce the aggressive phenotype. The effects of GC-1 alone or in combination with buparlisib, alpelisib, sorafenib, and palbociclib on cell growth, viability, and migration were determined and compared with the gene expression levels of selected markers. The impact of these treatments on the cancer stem cell population was assessed by tumorsphere assay. Thyroid differentiation markers were measured by gene analysis, and sodium iodide symporter (NIS) protein level and function were determined.

ResultsOur results show that GC-1 alone can decrease cell viability, growth, and slow cell migration in all four ATC cell lines. In addition, GC-1 is able to further block each of these phenotypes when combined with buparlisib, alpelisib, sorafenib, or palbociclib. GC-1 alone blocks thyrosphere outgrowth in all cell lines and increases the efficacy of each of the therapeutic agents tested. GC-1 increased NIS transcript and protein levels to allow for increased iodide uptake in ATC cells.

ConclusionActivation of TR{beta} with selective agonist sobetirome (GC-1) reduces the aggressive phenotype and induced re-differentiation in ATC cells and increases the efficacy of therapeutic agents that are currently used in the treatment of ATC. These results indicate that selective activation of TR{beta} not only induces a tumor suppression program de novo but enhances the effectiveness of anti-cancer agents.


title: An Unsupervised Graph Embeddings Approach to Multiplex Immunofluorescence Image Exploration

abstract: Understanding the complex biology of the tumor microenvironment (TME) is necessary to understand the mechanisms of action of immuno-oncology therapies and to match the right therapies to the right patients. Multiplex immunofluorescence (mIF) is a useful technology that has tremendous potential to further our understanding of cancer patho-biology; however, tools that fully leverage the high dimensionality of this data are still in their infancy. We describe here a novel deep learning pipeline aimed to allow Graph-based Inspection of Tissues via Embeddings, GraphITE. GraphITE transforms mIF data into a graph representation, where unsupervised learning algorithms can be utilised to generate embeddings representing cellular  neighbourhoods. The embeddings can be downprojected and explored for clustering analysis, and patterns can be mapped back to the image as well as interrogated for phenotypical, morphological, or structural distinctiveness. GraphITE supports the extraction of information not only on the phenotypes of individual cells or the relationships between specific cell types, but is able to characterize cell neighborhoods to look for more complex interactions, thereby allowing pathologists and data scientists to explore mIF data sets, uncovering patterns that are otherwise obscured by the high-dimensionality of the data. In this work, we showcase the current setup of the system, going from raw input data all the way to a user friendly exploration tool. Using this tool, we show how the data can be navigated in a way previously not possible.

category: pathology


title: Synthetic Cooling Agents in US-marketed E-cigarette Refill Liquids and Disposable E-cigarettes: Chemical Analysis and Risk Assessment.

abstract:
BackgroundMenthol, through its cooling and pleasant sensory effects, facilitates smoking and tobacco product initiation, resulting in the high popularity of mint/menthol-flavored E-cigarettes. More recently, E-cigarette vendors started marketing synthetic cooling agents as additives that impart a cooling effect but lack a characteristic minty odor. Knowledge about content of synthetic coolants in US-marketed E-cigarette products and associated health risks is limited.

MethodsE-liquid vendor sites were searched with the terms "koolada", "kool/cool", "ice", or WS-3/WS-23, denoting individual cooling agents, and relevant refill E-liquids were purchased. "Ice" flavor varieties of Puffbar, the most popular disposable E-cigarette brand, were compared with non-"Ice" varieties. E-liquids were characterized, and synthetic coolants quantified using GC/MS. Margin of exposure (MOE), a risk assessment parameter, was calculated to assess the risk associated with synthetic coolant exposure from E-cigarette use.

ResultsWS-3 was detected in 24/25 refill E-liquids analyzed. All Puffbar flavor varieties contained either WS-23 (13/14) or WS-3 (5/14), in both "Ice"- and non-"Ice" flavors. Modeling consumption of WS-3 from vaped E-liquids, resulted in MOEs below the safe margin of 100 for most daily use scenarios. MOEs for WS-23 were <100 for 10/13 Puffbar flavors in all use scenarios. Puffbar power specifications are identical to Juul devices.

ConclusionsSynthetic cooling agents (WS-3/WS-23) were present in US-marketed E-cigarettes, at levels that may result in consumer exposures exceeding safety thresholds set by regulatory agencies. Synthetic coolants are not only found in mint-or menthol-flavored products, but also in fruit- and candy-flavored products, including popular disposable E-cigarette products such as Puffbar.

ImplicationsSynthetic cooling agents are widely used in "kool/cool"- and "ice"-flavored E-liquids and in E-liquids without these labels, both as a potential replacement for menthol or to add cooling  notes to non-menthol flavors. These agents may be used to bypass current and future regulatory limits on menthol content in tobacco products, and not just E-cigarettes. Since synthetic cooling agents are odorless, they may not fall under the category of "characterizing flavor", potentially circumventing regulatory measures based on this concept. Regulators need to consider the additional health risks associated with exposure to synthetic cooling agents.

category: pharmacology and toxicology


title: Synthetic Cooling Agents in US-marketed E-cigarette Refill Liquids and Popular Disposable E-cigarettes: Chemical Analysis and Risk Assessment.


title: Placental polyamines regulate acetyl-coA and histone acetylation in a sex-dependent manner

abstract: Fetal sex differences play an important role in the pathophysiology of several placenta-related pregnancy complications. We previously reported that the maternal circulating level of a polyamine metabolite was altered in a fetal sex-specific manner, and was associated with pre-eclampsia and fetal growth restriction. Here we show that placental polyamine metabolism is altered in these disorders and that polyamines influence widespread changes in gene expression by regulating the availability of acetyl-CoA which is necessary for histone acetylation. Sex differences in polyamine metabolism are associated with escape from X chromosome inactivation of the gene encoding the enzyme spermine synthase in female placentas, as evidenced by biallelic expression of the gene in female trophoblasts. Polyamine depletion in primary human trophoblasts impairs glycolysis and mitochondrial metabolism resulting in decreased availability of acetyl-CoA and global histone hypoacetylation, in a sex-dependent manner. Chromatin-immunoprecipitation sequencing and RNA-sequencing identifies downregulation of progesterone biosynthetic pathways as a key target and polyamine depletion reduced progesterone release in male trophoblasts. Collectively, these findings suggest that polyamines regulate placental endocrine function through metabolic regulation of gene expression, and that sex differences in polyamine metabolism due to XCI escape may buffer the effects of placental dysfunction in pregnancy disorders.

category: physiology


title: FMRI multi-scale cortical spontaneous activity: 7T vs. 3T

abstract: This paper describes the use of the Human Connectome Project (HCP) data for mapping the distribution of spontaneous activity in the human brain across different spatial scales, magnets and individuals. Specifically, the resting-state functional MRI signals acquired under the HCP 3 tesla (T) and 7T magnet protocols were measured by computational methods at multiple spatial scales across the cerebral cortex using: 1) an amplitude metric on a single measuring unit (ALFF), 2) a functional homogeneity metric on a set of neighboring measuring units (ReHo) and 3) a homotopic functional connectivity metric on pairs of symmetric measuring units between the two hemispheres (VMHC). Statistical assessments on these measurements revealed that all the raw metrics were enhanced by the higher magnetic field, highlighting their dependence on magnet field strength. Measurement reliability of these global measurements were moderate to high and comparable between between 3T and 7T magnets. The differences in these measurements introduced by the higher magnetic field were spatially dependent and varied according to specific cortical regions. Specifically, the spatial contrasts of ALFF were enhanced by the 7T magnet within the anterior cortex while weakened in the posterior cortex. This is opposite for ReHo and VMHC. This scale-dependent phenomena also held true for measurement reliabilities, which were enhanced by the 7T magnet for ReHo and VMHC and weakened for ALFF. These reliability differences were primarily located in high-order associate cortex, reflecting the corresponding changes of individual differences: higher between-subject variability and lower within-subject variability for ReHo and VMHC, lower between-subject variability and higher within-subject variability for ReHo and VMHC with respect to higher magnetic field strength. Our work, for the first time, demonstrates the spatial-scale dependence of spontaneous cortical activity measurements in the human brain and their test-retest reliability across different magnet strengths, and discussed about the statistical implications for experimental design using resting-state fMRI.


title: Transcriptomic similarities and differences between mouse models and human Alzheimer's Disease

abstract: Alzheimers disease (AD) is a multifactorial pathology with most cases having a sporadic presentation. Yet, preclinical research studies relied for decades on transgenic models overexpressing human genes found in AD autosomal dominant patients. Recently, knock-in (KI) models, such as the novel hA{beta}-KI mouse, were introduced; however, its translational potential is still being addressed. To unveil core molecular programs in AD, we compared hippocampal transcriptomic profiles of transgenic (5xFAD and APP/PS1) and KI (hA{beta}-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. Comparison of differential expression analyses showed seven genes (S100A6, C1QB, CD33, CD14, SLC11A1, KCNK1 and SST) consistently already among models and human AD. Experimental validation of these genes revealed four altered in mice (SLC11A1, S100A6, CD14, CD33, C1QB) and three in humans (S100A6, SLC11A1, KCNK). Our analysis revealed that all three mouse models presented more Gene Ontology biological processes (GOBP) terms and enriched signaling pathways in common with LOAD than with EOAD subjects. Furthermore, semantic similarity of enriched GOBP terms highlighted model-specific biological alterations that might be further explored. Finally, we identified 17 transcription factors potentially acting as master regulators of AD in all models. Our cross-species exploratory analyses evidenced that the three mouse models presented a remarkable specificity of GOBP to LOAD, but the representation of processes in each model may differ. Thus, the molecular and cellular mechanisms under study should be a factor during mouse model selection in AD.