title: Acute Glucagon-Like Peptide-1 Receptor Agonist Liraglutide Prevents Drug-Induced Heroin Seeking in Rats

abstract: Substance use disorder is a difficult disease to treat due to its relapsing nature. In the last decade, opioid use disorder has been a threat to public health, being declared an epidemic by the Centers for Disease Control and Prevention. This is a tragic situation, considering there are currently effective, yet not ideal, treatments to prevent relapse. Recent research has shown that hormones that modulate hunger and satiety also can modulate motivated behavior for drugs of abuse. For example, the short-acting analog of glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates homeostatic feeding, has been shown to reduce responding for rewarding stimuli such as food, cocaine, heroin and nicotine. Here, we tested the acute effects of the long-acting GLP-1 analog, liraglutide, on heroin seeking. We found that, in rats with heroin self-administration experience, subcutaneous (sc) administration of an acute dose of 0.3 mg/kg liraglutide was effective in preventing relapse after exposure to three major precipitators: drug-associated cues, stress, and the drug itself. However, the effects of the drug were contingent upon the pretreatment time, with the drug being fully effective when administered using a 6 h, rather than a 4 h pretreatment time. Finally, we confirmed that the reduction in drug seeking is not due to a locomotor impairment, as liraglutide did not significantly alter performance in a rotarod test. As such, this acute non-opioid treatment may serve as a new and effective bridge to treatment.


title: Relationships between individual differences in dual process and electrophysiological signatures of familiarity and recollection during retrieval

abstract: Our everyday memories can vary in terms of accuracy and phenomenology. According to one theoretical account, these differences hinge on whether the memories contain information about both an item itself as well as associated details (remember) versus those that are devoid of these associated contextual details (familiar). This distinction has been supported by computational modeling of behavior, studies in patients, and neuroimaging work including differences both in electrophysiological and functional magnetic resonance imaging. At present, however, little evidence has emerged to suggest that neurophysiological measures track individual differences in estimates of recollection and familiarity. Here, we conducted electrophysiological recordings of brain activity during a recognition memory task designed to differentiate between behavioral indices of recollection and familiarity. Non-parametric cluster-based permutation analyses revealed associations between electrophysiological signatures of familiarity and recollection with their respective behavioral estimates. These results support the idea that recollection and familiarity are distinct phenomena and is the first, to our knowledge, to identify distinct electrophysiological signatures that track individual differences in these processes.

category: neuroscience


title: The rt-TEP tool: real-time visualization of TMS-evoked potentials to maximize cortical activation and minimize artifacts

abstract:
BackgroundThe impact of transcranial magnetic stimulation (TMS) on cortical neurons is currently hard to predict based on a priori biophysical and anatomical knowledge alone. This problem can hamper the reliability and reproducibility of protocols aimed at measuring electroencephalographic (EEG) responses to TMS.

New MethodWe introduce and release a novel software tool to facilitate and standardize the acquisition of TMS-evoked potentials (TEPs). The tool, rt-TEP (real-time TEP), interfaces with different EEG amplifiers and offers a series of informative visualization modes to assess in real time the immediate impact of TMS on the underlying neuronal circuits.

ResultsWe show that rt-TEP can be used to abolish or minimize magnetic and muscle artifacts contaminating the post-stimulus period thus affording a clear visualization and quantification of the amplitude of the early (<50 ms) EEG response after averaging a limited number of trials. This real-time readout can then be used to adjust TMS parameters (e.g. site, orientation, intensity) and experimental settings (e.g. loudness and/or spectral features of the noise masking) to ultimately maximize direct cortical effects over the undesired sensory effects of the coils discharge.

Comparison with Existing MethodsThe ensemble of real-time visualization modes of rt-TEP are not implemented in any current commercial software and provide a key readout to titrate TMS parameters beyond the a priori information provided by anatomical models.

ConclusionsReal-time optimization of stimulation parameters with rt-TEP can facilitate the acquisition of reliable TEPs with a high signal-to-noise ratio and improve the standardization and reproducibility of data collection across laboratories.

HighlightsO_LIrt-TEP provides an immediate EEG readout to assess the quality of TEPs in real time
C_LIO_LIrt-TEP interfaces with most commercial EEG systems
C_LIO_LIInformative, real time visualization allows maximising the cortical impact of TMS while minimizing artifacts
C_LIO_LIrt-TEP facilitates the acquisition of reliable TEPs with a high signal-to-noise ratio
C_LI


title: The rt-TEP tool: real-time visualization of TMS-Evoked Potential to maximize cortical activation and minimize artifacts


title: Lifelong musical activity is associated with multi-domain cognitive and brain benefits in older adults

abstract: 1AO_SCPLOWBSTRACTC_SCPLOWRegular musical activity as a highly-stimulating lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimers disease (AD). This study investigated associations between lifelong regular musical instrument playing, late-life cognitive abilities and brain morphology in older adults. We show that musical activity over the life course is associated with better global cognition, working memory, executive functions, language, and visuospatial abilities accounting for reserve proxies. Playing music is not significantly associated with gray matter volume in regions most affected by aging and AD. Selectively in the musically active participants, multi-domain cognitive abilities were enhanced with preserved gray matter volume in frontal and temporal regions. Our correlational findings suggest that playing a musical instrument may improve the recruitment of existing brain resources to facilitate late-life cognitive capacities. We propose that engaging in regular musical activity could serve as a low-threshold multimodal enrichment strategy that may promote cognitive resilience in advanced age.


title: Evaluating an internet-delivered fear conditioning and extinction protocol using response times and affective ratings.

abstract: Pavlovian fear conditioning is widely used to study mechanisms of fear learning, but high-throughput studies are hampered by the labor-intensive nature of examining participants in the lab. To circumvent this bottle-neck, fear conditioning tasks have been developed for remote delivery. Previous studies have examined remotely delivered fear conditioning protocols using expectancy and affective ratings. Here we replicate and extend these findings using an internet-delivered version of the Screaming Lady paradigm, evaluating the effects on negative affective ratings and response time to an auditory probe during stimulus presentations. In a sample of 80 adults, we observed clear evidence of both fear acquisition and extinction using affective ratings. Response times were faster when probed early, but not later, during presentation of stimuli paired with an aversive scream. The response time findings are at odds with previous lab-based studies showing slower responses to threat-predicting cues. The findings underscore the feasibility of employing remotely delivered fear conditioning paradigms with affective ratings as outcome, and highlight the need for further research examining optimal parameters for concurrent response time measures or alternate modes of non-verbal estimation of conditioned responses in Pavlovian conditioning protocols.


title: Episodic memory precision and reality monitoring following stimulation of angular gyrus

abstract: The qualities of remembered experiences are often used to inform  reality monitoring judgments, our ability to distinguish real and imagined events (Johnson & Raye, 1981). Previous experiments have tended to investigate only whether reality monitoring decisions are accurate or not, providing little insight into the extent to which reality monitoring may be affected by qualities of the underlying mnemonic representations. We used a continuous-response memory precision task to measure the quality of remembered experiences that underlie two different types of reality monitoring decisions: agency decisions that distinguish actions performed by participants and the experimenter, and perceptual decisions that distinguish perceived and imagined experiences. The data revealed memory precision to be associated with higher accuracy in both agency and perceptual reality monitoring decisions, with reduced precision linked with a tendency to misattribute self-generated experiences to external sources. We then sought to investigate the possible neurocognitive basis of these observed associations by applying brain stimulation to a region that has been implicated in precise recollection of personal events, left angular gyrus. Stimulation of angular gyrus selectively reduced the association between memory precision and self-referential reality monitoring decisions, relative to control site stimulation. Angular gyrus may, therefore, be important for the ability to imbue remembered experiences with a sense of self-agency, a key component of  autonoetic consciousness that characterises episodic memory (Tulving, 1985).


title: Biomechanical interactions of Schistosoma mansoni eggs with vascular endothelial cells facilitate egg extravasation

abstract: The eggs of the parasitic blood fluke, Schistosoma, are the main drivers of the chronic pathologies associated with schistosomiasis, a disease of poverty afflicting approximately 220 million people worldwide. Eggs laid by Schistosoma mansoni in the bloodstream of the host are encapsulated by vascular endothelial cells (VECs), the first step in the migration of the egg from the blood stream into the lumen of the gut and eventual exit from the body. The biomechanics associated with encapsulation and extravasation of the egg are poorly understood. We demonstrate that S. mansoni eggs induce VECs to form two types of membrane extensions during encapsulation; filopodia that probe eggshell surfaces and intercellular nanotubes that presumably facilitate VEC communication. Encapsulation efficiency, the number of filopodia and intercellular nanotubes, and the length of these structures depend on the eggs vitality and, to a lesser degree, its maturation state. During encapsulation, live eggs induce VEC contractility and membranous structures formation, in a Rho/ROCK pathway-dependent manner. Using elastic hydrogels embedded with fluorescent microbeads as substrates to culture VECs, live eggs induce VECs to exert significantly greater contractile forces during encapsulation than dead eggs, which leads to 3D deformations on both the VEC monolayer and the flexible substrate underneath. These significant mechanical deformations cause the VEC monolayer tension to fluctuate with eventual rupture of VEC junctions, thus facilitating egg transit out of the blood vessel. Overall, our data on the mechanical interplay between host VECs and the schistosome egg improve our understanding of how this parasite manipulates its immediate environment to maintain disease transmission.

category: microbiology


title: Cbp1, a rapidly evolving fungal virulence factor, forms an effector complex that drives macrophage lysis

abstract:
Intracellular pathogens secrete effectors to manipulate their host cells. Histoplasma capsulatum (Hc) is a fungal intracellular pathogen of humans that grows in a yeast form in the host. Hc yeasts are phagocytosed by macrophages, where fungal intracellular replication precedes macrophage lysis. The most abundant virulence factor secreted by Hc yeast cells is Calcium Binding Protein 1 (Cbp1), which is absolutely required for macrophage lysis. Here we take an evolutionary, structural, and cell biological approach to understand Cbp1 function. We find that Cbp1 is present only in the genomes of closely related dimorphic fungal species of the Ajellomycetaceae family that lead primarily intracellular lifestyles in their mammalian hosts (Histoplasma, Paracoccidioides, and Emergomyces), but not conserved in the extracellular fungal pathogen Blastomyces dermatitidis. We determine the de novo structures of Hc H88 Cbp1 and the Paracoccidioides americana (Pb03) Cbp1, revealing a novel "binocular" fold consisting of a helical dimer arrangement wherein two helices from each monomer contribute to a four-helix bundle. In contrast to Pb03 Cbp1, we show that Emergomyces Cbp1 orthologs are unable to stimulate macrophage lysis when expressed in the Hc cbp1 mutant. Consistent with this result, we find that wild-type Emergomyces africanus yeast are able to grow within primary macrophages but are incapable of lysing them. Finally, we use subcellular fractionation of infected macrophages and indirect immunofluorescence to show that Cbp1 localizes to the macrophage cytosol during Hc infection, making this the first instance of a phagosomal human fungal pathogen directing an effector into the cytosol of the host cell. We additionally show that Cbp1 forms a complex with Yps-3, another known Hc virulence factor that accesses the cytosol. Taken together, these data imply that Cbp1 is a rapidly evolving fungal virulence factor that localizes to the cytosol to trigger host cell lysis.

Author SummaryThe members of the Ajellomycetaceae fungal family are human pathogens that are responsible for a rising number of mycoses around the world. Calcium binding protein 1 (Cbp1) is a rapidly evolving virulence factor that is present in the genomes of the Ajellomycetaceae species that lead primarily intracellular lifestyles, including Histoplasma, Paracoccidioides, and Emergomyces but not Blastomyces, which remains largely extracellular during infection. Both Paracoccidioides and Histoplasma Cbp1 homologs are able to cause lysis of macrophages whereas Emergomyces homologs cannot. This result is consistent with Emergomyces africanus natural infection of macrophages, during which the yeast cells can replicate but cannot actively lyse the host cell. Despite divergence of the primary sequence of Histoplasma and Paracoccidioides Cbp1 homologs, their protein structures are remarkably similar and reveal a novel fold. During infection, Cbp1 enters the cytosol of the host macrophage, making it the first known virulence factor from an intracellular human fungal pathogen that localizes to the cytosol of the host cell. We also show that Cbp1 forms a complex with another cytosolic virulence factor, Yps-3. Taken together, these studies significantly advance our understanding of Histoplasma virulence.


title: Diversity and Metabolic Potential of Microbial Communities in a Serpentinite-Hosted Spring at the Tablelands

abstract: The geochemical process of serpentinization releases energy and organic carbon: two of the basic requirements needed to support life. Sites of active serpentinization in the deep subsurface provide the intriguing possibility of a non-photosynthetically-supported biosphere. However, serpentinization also creates conditions, such as high pH and limited electron acceptors, which may limit microbial growth and diversity. Gaining an understanding of the identity and metabolic potential of microbes that thrive in these environments may provide insight as to whether serpentinization is sufficient to independently support life. Tablelands Ophiolite in Gros Morne National Park, Newfoundland, Canada is a continental site of serpentinization where serpentinite springs form surface pools. These pools provide easy sampling access to subsurface fluids and may allow for sampling of the subsurface microbial community. However, identification of members of the subsurface community in these pools is complicated by both surface contamination and contamination by organisms that inhabit the transition zone where hydrogen-rich subsurface fluids meet oxygen-rich surface fluids. This study was designed to distinguish among these potential sources of microorganisms by using a sampling technique that more effectively samples subsurface fluids. Community dissimilarity comparisons using environmental 16S rRNA gene sequencing indicate that the sampling design led to more direct access to subsurface fluids. These results are supported by metagenomic analyses that show metabolic pathways consistent with non-photosynthetic carbon fixation in the samples expected to represent subsurface fluids and that show hydrogen oxidation pathways in samples associated with the surface sources. These results provide a clearer picture of the diversity and metabolic potential of microbial communities potentially inhabiting subsurface, serpentinite-hosted habitats.


title: Computational capability of ecological dynamics

abstract: Ecological dynamics is driven by an ecological network consisting of complex interactions. Information processing capability of artificial networks has been exploited as a computational resource, yet whether an ecological network possesses a computational capability and how we can exploit it remain unclear. Here, we show that ecological dynamics can be exploited as a computational resource. We call this approach "Ecological Reservoir Computing" (ERC) and developed two types of ERC. In silico ERC reconstructs ecological dynamics from empirical time series and uses simulated system responses as reservoir states, which predicts near future of chaotic dynamics and emulates nonlinear dynamics. The real-time ERC uses population dynamics of a unicellular organism, Tetrahymena thermophila. Medium temperature is an input signal and changes in population abundance are reservoir states. Intriguingly, the real-time ERC has necessary conditions for reservoir computing and is able to make near future predictions of model and empirical time series.

category: ecology


title: Seasonal variation of genotypes and reproductive plasticity in a facultative clonal freshwater invertebrate animal (Hydra oligactis) living in a temperate lake

abstract: Facultative sexual organisms combine sexual and asexual reproduction within a single life cycle, often switching between reproductive modes depending on environmental conditions. These organisms frequently inhabit variable seasonal environments, where favourable periods alternate with unfavourable periods, generating temporally varying selection pressures that strongly influence life history decisions and hence population dynamics. Due to the rapidly accelerating changes in our global environment today, understanding the dynamics of and genetic changes in facultative sexual populations inhabiting seasonal environments is critical to assess and prepare for additional challenges that will affect such ecosystems. In this study we aimed at obtaining insights of the seasonal population dynamics of the facultative sexual freshwater cnidarian Hydra oligactis through a combination of Restriction-site Associated Sequencing (RAD-Seq) genotyping and the collection of phenotypic data on the reproductive strategy of field-collected hydra strains. We found no significant genetic change during the two years in the study population. Clone lines were detected between seasons and even years, suggesting that clonal lineages can persist for a long time in a natural population. We also found that distinct genotypes differ in sexual reproduction frequency, but these differences did not affect whether genotypes reappeared across samplings. Our study describes changes in population genetic structure across the seasons in a hydra population for the first time, providing key insights into the biology of the species, while also contributing to understanding the population biology of facultative sexual species inhabiting freshwater ecosystems.


title: Antelope space-use and behavioural responses to varying anthropogenic influences may permit long-term persistence in a highly human-dominated landscape

abstract: The only means of conserving a species or a habitat in a human-dominated landscape is through promoting coexistence while minimizing conflict. To achieve this, it is vital to understand how wildlife are impacted by direct and indirect human activities. Such information is relatively rare from areas with high human densities. To investigate how animals respond to altered ecological conditions in human-dominated landscapes, we focussed on a wild herbivore of conservation concern in Krishnasaar Conservation Area (KrCA) in Nepal. Here, blackbuck Anticope cervicapra, a generalist grazer, lives in refugia located in a growing human population. We studied the impacts of humans on habitat-use and behaviour of blackbuck. We laid 250 x 250 m grid cells in the entire KrCA and carried out indirect sign surveys with three replications for habitat-use assessment. We observed herds of blackbuck for 89 hours in different possible habitat types, location and time of the day using scan sampling methods. Our habitat-use survey showed that habitats under intensive human use were hardly used by blackbuck, even when high-quality forage was available. In areas with low levels of human activity, natural risk factors, primarily habitat openness, was the major predictor of habitat-use. Interestingly, livestock presence positively influenced habitat-use by blackbuck. Blackbuck were substantially more vigilant when they were in forest than in grassland, again indicating an influence of risk. Overall, blackbuck appear to be sensitive to risk associated with both natural and anthropogenic factors. Our findings have direct implications for managing human-wildlife interactions in this landscape, specifically regarding strategies for livestock grazing in habitats highly used by blackbuck and concerning predictions of how changing land-use will impact long-term persistence of blackbuck. Our work suggests that wild herbivores may be able to persist in landscapes with high human densities so long as there are refuges where levels of human activity are relatively low.


title: Environmental correlates and functional consequences of bill divergence in island song sparrows

abstract:
Inferring the environmental selection pressures responsible for phenotypic variation is a challenge in adaptation studies as traits often have multiple functions and are shaped by complex selection regimes. We provide experimental evidence that morphology of the multifunctional avian bill is related to climate, not foraging efficiency, in song sparrows (Melospiza melodia) on the California Channel Islands. Our research builds on a study in song sparrow museum specimens that demonstrated a positive correlation between bill surface area and maximum temperature, suggesting a greater demand for dry heat dissipation in hotter, xeric environments. We sampled contemporary sparrow populations across three climatically distinct islands to test the alternate hypotheses that song sparrow bill morphology is either a product of vegetative differences with functional consequences for foraging efficiency or related to maximum temperature and, consequently, important for thermoregulation. Measurements of >500 live individuals indicated a significant, positive relationship between maximum temperature and bill surface area when correcting for body size. In contrast, maximum bite force, seed extraction time, and vegetation on breeding territories (a proxy for food resources) were not significantly associated with bill dimensions. While we cannot exclude the influence of foraging ability and diet on bill morphology, our results are consistent with the hypothesis that variation in song sparrows need for thermoregulatory capacity across the northern Channel Islands selects for divergence in bill surface area.

SUMMARY STATEMENTIsland song sparrow bill differences are correlated with climate, not vegetation, and experimental evidence finds no functional effect on foraging efficiency. This suggests many factors shape this multifunctional trait.


title: Environment-dependent expression of mutational load and species' range limits

abstract: Theoretical and empirical research on the causes of species range limits suggests the contribution of several intrinsic and extrinsic factors, with potentially complex interactions among them. An intrinsic factor proposed by recent theory is mutational load increasing towards range edges because of genetic drift. Furthermore, environmental quality may decline toward range edges and enhance the expression of load. Here we tested whether the expression of mutational load associated with range limits in the North American plant Arabidopsis lyrata is enhanced under stressful environmental conditions by comparing the performance of within- versus between-population crosses at common garden sites across the species distribution and beyond. Heterosis, reflecting the expression of load, increased with heightened estimates of genomic load and with environmental stress caused by warming, but the interaction was not significant. We conclude that range-edge populations suffer from a twofold genetic Allee effect caused by increased mutational load and stress-dependent load linked to general heterozygote deficiency, but no synergistic effect between them.

category: evolutionary biology


title: Environment-dependence of the expression of mutational load and species' range limits


title: Effect of tag attachment on flight parameters and energetic cost across five raptor species

abstract:
Bio-logging devices play a fundamental and indispensable role in movement ecology studies, particularly in the wild. However, researchers are becoming increasingly aware of the influence that attaching devices can have on animals, particularly on their behaviour, energy expenditure and survival. The way a device is attached to an animals body has also potential consequences for the collected data, and quantifying the type and magnitude of such potential effects is fundamental to enable researchers to combine and compare data from different studies, as much as it is to improve animal welfare.

For over two decades, large terrestrial birds have been in the focus of long-term movement ecology research, employing bio-logging devices attached with different types of harnesses. However, comparative studies investigating the effects of different harness types used on these species are scarce.

In this study, we tested for potential differences in data collected by two commonly used harness types, backpack and leg-loop, on the flight performance of 10 individuals from five raptor species, equipped with high resolution bio-logging devices, in the same area and time. We explored the effect of harness type on vertical speed, horizontal speed, glide ratio, height above sea level, distance travelled, proportion of soaring and flapping behaviour, and VeDBA (a proxy for energy expenditure) between and within individuals, all used as fine-scale measures of flight performance. Birds equipped with leg-loops climbed up to 0.65 ms-1 faster, reached 19% greater heights while soaring, and spent less time in active flight compared to birds equipped with backpacks, suggesting that backpack harnesses, compared to leg-loops, might cause additional drag affecting the birds flight performance. A lower rate of sinking while gliding, a slightly higher glide ratio, higher horizontal speed while soaring, and lower VeDBA, were also indicative of less drag using leg-loops. Our results add to the existing literature highlighting the design-related advantages of leg-loops, and support the use of leg-loops as a better alternative to backpack harnesses for large soaring birds, when possible. Our study also highlights how apparently small changes in device attachment can lead to notable improvements in tagging practice, with implications for animal welfare, data interpretation and comparability.

category: animal behavior and cognition


title: Effect of tag attachment on the flight performance of five raptor species


title: Collective dynamics support group drumming, reduce variability, and stabilize tempo drift

abstract: Humans are social animals who engage in a variety of collective activities requiring coordinated action. Among these, music is a defining and ancient aspect of human sociality. Social interaction has largely been studied in dyadic contexts. The presence of multiple agents engaged in the same task space creates different constraints and possibilities that have been studied more extensively in nonhuman animal behaviour. We addressed whether collective dynamics play a role in human circle drumming. The task was to synchronize in a group with an initial reference pattern and then maintain synchronization after it was muted. We varied the number of drummers, from solo to dyad, quartet, and octet. The observed lower variability, lack of speeding up, smoother individual dynamics, and leader-less inter-personal coordination indicated that stability increased as group size increased, a sort of temporal wisdom of crowds. We propose a hybrid continuous-discrete Kuramoto model for emergent group synchronization with pulse-based coupling that exhibits a mean field positive feedback loop. This research has theoretical implications about collective intentionality and social cognition.


title: Pre-copulatory reproductive behaviours are preserved in Drosophila melanogaster infected with bacteria.

abstract: Reproduction and immunity are crucial traits that determine an animals fitness. Terminal investment hypothesis predicts that reproductive investment should increase in the face of a mortality risk caused by infection. However, due to competitive allocation of energetic resources, individuals fighting infections are expected to decrease reproductive efforts. While there is evidence for both hypotheses, the factors that determine the choice between these strategies are poorly understood. Here, we assess the impact of bacterial infection on pre-copulatory behaviours in the fruit fly Drosophila melanogaster. We found that male flies infected with six different bacteria, including pathogenic and non-pathogenic strains, show no significant differences in courtship intensity and mating success. Similarly, bacterial infections did not affect sexual receptivity in female flies. Our data suggest that pre-copulatory reproductive behaviours remain preserved in infected animals, despite the huge metabolic cost of infection.


title: Vascular lung triculture organoid via soluble extracellular matrix suspension

abstract: Micropatterned suspension culture creates consistently sized and shaped cell aggregates but has not produced organotypic structures from stable cells, thus restricting its use in accurate disease modeling. Here, we show that organotypic structure is achieved in hybrid suspension culture via supplementation of soluble extracellular matrix (ECM). We created a viable lung organoid from epithelial, endothelial, and fibroblast human stable cell lines in suspension culture. We demonstrate the importance of soluble ECM in organotypic patterning with the emergence of lumen-like structures with airspace showing feasible gas exchange units, formation of branching, perfusable vasculature, and long-term 70-day maintenance of lumen structure. Our results show a dependent relationship between enhanced fibronectin fibril assembly and the incorporation of ECM in the organoid. We successfully applied this technology in modeling lung fibrosis via bleomycin induction and test a potential antifibrotic drug in vitro while maintaining fundamental cell-cell interactions in lung tissue. Our human fluorescent lung organoid (hFLO) model represents features of pulmonary fibrosis which were ameliorated by fasudil treatment. We also demonstrate a 3D culture method with potential of creating organoids from mature cells, thus opening avenues for disease modeling and regenerative medicine, enhancing understanding of lung cell biology in health and lung disease.

category: bioengineering


title: Soluble ECM promotes organotypic formation in lung alveolar model


title: Accurate Name Entity Recognition for Biomedical Literatures: A Combined High-quality Manual Annotation and Deep-learning Natural Language Processing Study

abstract: A combined high-quality manual annotation and deep-learning natural language processing study is reported to make accurate name entity recognition (NER) for biomedical literatures. A home-made version of entity annotation guidelines on biomedical literatures was constructed. Our manual annotations have an overall over 92% consistency for all the four entity types -- gene, variant, disease and species --with the same publicly available annotated corpora from other experts previously. A total of 400 full biomedical articles from PubMed are annotated based on our home-made entity annotation guidelines. Both a BERT-based large model and a DistilBERT-based simplified model were constructed, trained and optimized for offline and online inference, respectively. The F1-scores of NER of gene, variant, disease and species for the BERT-based model are 97.28%, 93.52%, 92.54% and 95.76%, respectively, while those for the DistilBERT-based model are 95.14%, 86.26%, 91.37% and 89.92%, respectively. The F1 scores of the DistilBERT-based NER model retains 97.8%, 92.2%, 98.7% and 93.9% of those of BERT-based NER for gene, variant, disease and species, respectively. Moreover, the performance for both our BERT-based NER model and DistilBERT-based NER model outperforms that of the state-of-art model--BioBERT, indicating the significance to train an NER model on biomedical-domain literatures jointly with high-quality annotated datasets.

category: bioinformatics


title: OmicsView: omics data analysis through interactive visual analytics

abstract:
With advances in NGS technologies, transcriptional profiling of human tissue across many diseases is becoming more routine, leading to the generation of petabytes of data deposited in public repositories. There is a need for bench scientists with little computational expertise to be able to access and mine this data to understand disease pathology, identify robust biomarkers of disease and the effect of interventions (in vivo or in vitro). To this end we release an open source analytics and visualization platform for expression data called OmicsView, http://omicsview.org.

This platform comes preloaded with 1000s of samples across many disease areas and normal tissue, including the GTEx database, all processed with a harmonized pipeline. We demonstrate the power and ease-of-use of the platform by means of a Crohns disease data mining exercise where we can quickly uncover disease pathology and identify strong biomarkers of disease and response to treatment.


title: A novel algorithm to flag columns associated in any way with others or a dependent variable is computationally tractable in large data matrices and has much higher power when columns are linked like mutations in chromosomes.

abstract:
When a data matrix DM has many independent variables IVs, it is not computationally tractable to assess the association of every distinct IV subset with the dependent variable DV of the DM, because the number of subsets explodes combinatorially as IVs increase. But model selection and correcting for multiple tests is complex even with few IVs.

DMs in genomics will soon summarize millions of mutation markers and genomes. Searching exhaustively in such DMs for markers that alone or synergistically with others are associated with a trait is therefore computationally tractable only for 1- and 2-marker effects. Also population geneticists study mainly 2-marker combinations.

I present a computationally tractable, fully parallelizable Participation in Association Score (PAS) that in a DM with markers detects one by one every column that is strongly associated in any way with others. PAS does not examine column subsets and its computational cost grows linearly with the number of columns, remaining reasonable even when DMs have millions of columns.

PAS exploits how associations of markers in the rows of a DM cause associations of matches in the rows pairwise comparisons. For every such comparison with a match at a tested column, PAS computes the matches at other columns by modifying the comparisons total matches (scored once per DM), yielding a distribution of conditional matches that reacts diagnostically to the associations of the tested column. Equally computationally tractable is dvPAS that flags DV-associated IVs by also probing the matches at the DV.

P values for the scores are readily obtained by permutation and accurately Sidak-corrected for multiple tests, bypassing model selection. The P values of a columns PASs for different orders of association are i.i.d. and readily turned into a single P value.

Simulations show that i) PAS and dvPAS generate uniform-(0,1)-distributed type I error in null DMs and ii) detect randomly encountered binary and trinary models of significant n-column association and n-IV association with a binary DV, respectively, with power in the order of magnitude of exhaustive evaluations and false positives that are uniform-(0,1)-distributed or straightforwardly tuned to be so. Power to detect 2-way associations that extend over 100+ columns is non-parametrically ultimate but that to detect pure n-column associations and pure n-IV DV associations sinks exponentially as n increases.

Important for geneticists, dvPAS power increases about twofold in trinary vs. binary DMs and by orders of magnitude with markers linked like mutations in chromosomes, specially in trinary DMs where furthermore dvPAS fine-maps with highest resolution.


title: A novel, computationally tractable algorithm flags in big matrices every column associated in any way with others or a dependent variable, with much higher power when columns are linked like mutations in chromosomes


title: Acoustic array biochip combined with allele-specific PCR for multiple cancer mutation analysis in tissue and liquid biopsy

abstract: Regular screening of cancerous point mutations is of importance to cancer management and treatment selection. Although excellent techniques like next generation sequencing and droplet digital PCR are available, these are still lacking in speed, simplicity and cost-effectiveness. Here a new approach is presented where allele-specific PCR (AS-PCR) is combined with a novel High Fundamental Frequency Quartz Crystal Microbalance (HFF-QCM) array biosensor for the amplification and detection, respectively, of cancer point mutations. For the proof-of-concept, the method was applied to the screening of the BRAF V600E and KRAS G12D mutations in spiked-in and clinical samples. Regarding the BRAF target, an analytical sensitivity of 0.01%, i.e., detection of 1 mutant copy of genomic DNA in an excess of 104 wild type molecules, was demonstrated; moreover, quantitative results during KRAS detection were obtained when an optimized assay was employed with a sensitivity of 0.05%. The assays were validated using tissue and plasma samples obtained from melanoma, colorectal and lung cancer patients. Results are in full agreement with Sanger sequencing and droplet digital PCR, demonstrating efficient detection of BRAF and KRAS mutations in samples having an allele frequency below 1%. The high sensitivity and technology-readiness level of the methodology, together with the ability for multiple sample analysis (24 array biochip), cost-effectiveness and compatibility with routine work-flow, hold promise for the implementation of this AS-PCR/acoustic methodology in clinical oncology as a tool for tissue and liquid biopsy.

category: biophysics


title: Developing selective FPR2 agonists can be a potential approach to treat moderate to severe asthma.

abstract: Formyl peptide receptor (FPR) family members have been reported to play important role in the resolution of inflammation. A few FPR2/FPR1 dual agonists are reported in the public domain for their anti-inflammatory properties. None of these molecules, however, have been successful as a therapy yet. Recent reports bring forward the ambiguous role of FPR1 in inflammation. These include both positive and negative outcomes. We, therefore, aimed to develop selective FPR2 agonists and evaluated their potential in mitigating the non-resolving inflammation in mouse models of moderate to severe asthma. Extensive structure-activity-relationship (SAR) studies were conducted on the imidazole and benzimidazole chemotype series to identify potent and selective FPR2 agonists. A few molecules were shortlisted based on their in vitro profile and absorption, distribution, metabolism and excretion (ADME) properties and were further evaluated in mouse models of asthma. We report herewith identification of 3 RCI compounds with low nanomolar potency for FPR2 agonism and >10,000 fold selectivity over FPR1 in Ca2+ release assay. These molecules also showed potency in other in vitro assays and potent efficacy in three distinct animal models of asthma. Our data suggest that FPR2 agonism can be a potential therapeutic approach to treat asthma. Our findings also propose that FPR1 can be spared to achieve the desired pharmacological activity.

category: pharmacology and toxicology


title: Cardiotoxic effects of methamphetamine associated with electrophysiological and epigenetic aberrations in Zebrafish

abstract: Long-term methamphetamine (Meth) abuse damages functional and molecular changes in the brain that causes chronic and relapsing disease. In this study, we sought to investigate a relationship between cardiotoxicity and arrhythmia with associated Meth abuse in zebrafish to identify and to understand the adverse cardiac symptoms associated with Meth as well as to assess the applicability of zebrafish as an appropriate model for cardiac-related drug screening studies. Over a two-week duration, zebrafish were first treated with various concentrations of Meth, ranging from 0 to 50 M. Immediately after treatment, zebrafish underwent electrocardiogram (ECG) measurement for electrophysiological analysis. Results show that a higher incidence of increased heart rate over the duration of the experiment, corroborating with results from previous human case studies involving Meth users. However, abnormalities commonly cited in those same case studies, such as prolongation of QTc, were not significantly presented in obtained ECG recordings. We have also conducted genetic, epigenetic, and histochemical analysis in an attempt to understand the cardiotoxic effects of Meth on zebrafish cardiac function. These results suggested myocardial damage and decrease in gene expression associated with normal physiological function. Finally, this paper provides insights into potential reasons for the apparent discrepancies in our data with prior research as well as an outlook of zebrafish cardiotoxic drug screening studies.

category: physiology


title: Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice

abstract: The loss of skeletal muscle function with age, known as sarcopenia, significantly reduces independence and quality of life and can have significant metabolic consequences. Although exercise is effective in treating sarcopenia it is not always a viable option clinically, and currently there are no pharmacological therapeutic interventions for sarcopenia. Here we show that chronic treatment with pan-adiponectin receptor agonist AdipoRon improved muscle function in male mice by a mechanism linked to skeletal muscle metabolism and tissue remodeling. In aged mice, 6 weeks of AdipoRon treatment improved skeletal muscle functional measures in vivo and ex vivo. Improvements were linked to changes in fiber type, including an enrichment of oxidative fibers, and an increase in mitochondrial activity. In young mice, 6 weeks of AdipoRon treatment improved contractile force and activated the energy sensing kinase AMPK and the mitochondrial regulator PGC-1a (peroxisome proliferator activated receptor gamma coactivator 1 alpha). In cultured cells, the AdipoRon induced stimulation of AMPK and PGC-1a was associated with increased mitochondrial membrane potential, reorganization of mitochondrial architecture, increased respiration, and increased ATP production. Furthermore, the ability of AdipoRon to stimulate AMPK and PGC1a was conserved in nonhuman primate cultured cells. These data show that AdipoRon is an effective agent for the prevention of sarcopenia in mice and indicate that its effects translate to primates, suggesting it may also be a suitable therapeutic for sarcopenia in clinical application.


title: Adipocyte-specific modulation of KLF14 expression in mice leads to sex-dependent impacts in adiposity and lipid metabolism

abstract: Genome-wide association studies identified single nucleotide polymorphisms on chromosome 7 upstream of KLF14 to be associated with metabolic syndrome traits and increased risk for Type 2 Diabetes (T2D). The associations were more significant in women than in men. The risk allele carriers expressed lower levels of the transcription factor KLF14 in adipose tissues than non-risk allele carriers. To investigate how adipocyte KLF14 regulates metabolic traits in a sex-dependent manner, we characterized high-fat diet fed male and female mice with adipocyte-specific Klf14 deletion or overexpression. Klf14 deletion resulted in increased fat mass in female mice and decreased fat mass in male mice. Female Klf14-deficient mice had overall smaller adipocytes in subcutaneous fat depots but larger adipocytes in parametrial depots, indicating a shift in lipid storage from subcutaneous to visceral fat depots. They had reduced metabolic rates and increased respiratory exchange ratios consistent with increased utilization of carbohydrates as an energy source. Fasting and isoproterenol-induced adipocyte lipolysis was defective in female Klf14-deficient mice and concomitantly adipocyte triglycerides lipase mRNA levels were downregulated. Female Klf14-deficient mice cleared blood triglyceride and NEFA less efficiently than wild type. Finally, adipocyte-specific overexpression of Klf14 resulted in lower total body fat in female but not male mice. Taken together, consistent with human studies, adipocyte KLF14 deficiency in female but not in male mice causes increased adiposity and redistribution of lipid storage from subcutaneous to visceral adipose tissues. Increasing KLF14 abundance in adipocytes of females with obesity and T2D may provide a novel treatment option to alleviate metabolic abnormalities.


title: Hepatocyte serine palmitoyl transferase 2 deficiency promotes liver C16:0-ceramide accumulation through sphingomyelin hydrolysis and leads to liver damage and dysfunction in mice

abstract:
Ceramides (Cer) have been shown as lipotoxic inducers, which disturb numerous cell signalling pathways especially insulin signalling pathway leading to metabolic disorders such as type 2 diabetes. In this study, we aimed to determine the role of de novo hepatic Cer synthesis on energy and liver homeostasis in mice. We generated mice lacking serine palmitoyltransferase 2 (Sptlc2), the rate limiting enzyme of Cer de novo synthesis, in hepatocytes.

Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic Cer, especially C16:0-Cer and C18:0-Cer associated with an increased neutral sphingomyelinase 2 expression, and a decreased sphingomyelin content in the liver. Sptlc2{Delta}Hep mice were protected against obesity induced by high fat diet. Bile acid (BA) hydrophobicity was drastically decreased in KO mice, and was associated with a defect in lipid absorption. In addition, an important increase of tauro-muricholic acid in BA pool composition was associated with a downregulation of the nuclear BA receptor FXR target genes. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production. Finally, Sptlc2 disruption promoted apoptosis, inflammation and progressive development of hepatic fibrosis worsening with age.

Our data suggest a compensatory mechanism to regulate hepatic Cer content from sphingomyelin hydrolysis, with deleterious impact on liver homeostasis. In addition, our results show the implication of hepatic sphingolipid modulation on BA metabolism and hepatic glucose production in an insulinin-dependent manner, which demonstrates the role of Cer in many metabolic functions still under-researched.


title: Water stress-associated isolation barriers between two sympatric oak species

abstract: Drought and waterlogging impede tree growth and may even lead to tree death. With climate change, these environmental factors are a growing source of concern, particularly for temperate forests. Oaks, an emblematic group of tree species, have evolved a range of adaptations to cope with these constraints. The two most widely distributed European species -- pedunculate oak (PO) and sessile oaks (SO) -- have overlapping ranges, but are highly constrained locally by soil water content variation. These differences in local ecological requirements provide a powerful biological model for studying the role of ecological barriers in speciation. We used an experimental set-up mimicking the ecological preferences of these species, in which seedlings were subjected to waterlogging and drought. We studied gene expression in roots by RNA-seq and identified genes differentially expressed between treatments with different outcomes depending on species. These "species x environment"-responsive genes revealed adaptive molecular strategies involving adventitious and lateral root formation, aerenchyma formation in PO, and osmoregulation and ABA regulation in SO. With this experimental design, we also identified genes with expression profiles presenting a "species" effect regardless of imposed constraints with important roles in intrinsic reproductive barriers. Finally, we compared our findings with those for a genome scan of species divergence and found that the candidate genes were enriched in highly differentiated SNPs. This suggests that many of the genes involved in the contrasting transcriptomic responses are subject to natural selection and that gene regulation helps to maintain these two different oak species in sympatry.

category: plant biology


title: Combi-Seq: Multiplexed transcriptome-based profiling of drug combinations using 1deterministic barcoding in single-cell droplets

abstract: Anti-cancer therapies often exhibit only short-term effects. Tumors typically develop drug resistance causing relapses that might be tackled with drug combinations. Identification of the right combination is challenging and would benefit from high-content, high-throughput combinatorial screens directly on patient biopsies. However, such screens require a large amount of material, normally not available from patients. To address these challenges, we developed a scalable microfluidic workflow to screen hundreds of drug combinations in picoliter-size droplets using transcriptome changes as a readout for drug effects. We devised a deterministic combinatorial DNA barcoding approach to encode treatment conditions, enabling the gene expression-based readout of drug effects in a highly multiplexed fashion. We applied our method to screen the effect of 420 drug combinations on the transcriptome of K562 cells using only [~]250 single cell droplets per condition, to successfully predict synergistic and antagonistic drug pairs, as well as their pathway activities.

category: systems biology


title: Deletion or inhibition of astrocytic transglutaminase 2 promotes functional recovery after spinal cord injury

abstract: Following CNS injury astrocytes become "reactive" and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here we used mice in which TG2 was specifically deleted in astrocytes (Gfap-Cre+/-TG2fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO_mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days postinjury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis reveals a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron-astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries.


title: Task-level value affects trial-level reward processing and control

abstract: Despite disagreement about how anterior cingulate cortex (ACC) supports decision making, a recent hypothesis suggests that activity in this region is best understood in the context of a task or series of tasks. One important task-level variable is average reward because it is both a known driver of effortful behaviour and an important determiner of the tasks in which we choose to engage. Here we asked how average task value affects reward-related ACC activity. To answer this question, we measured a reward-related signal said to be generated in ACC called the reward positivity (RewP) while participants gambled in three tasks of differing average value. The RewP was reduced in the high-value task, an effect that was not explainable by either reward magnitude or outcome expectancy. Average task value also affected cue-locked frontal midline theta (FMT), an ACC signal linked to cognitive control: FMT was enhanced for low-value cues relative to high-value cues. This effect was related to behaviour, as the more FMT a participant exhibited, the better they performed. These results suggest that ACC does not evaluate outcomes and cues in isolation, but in the context of the value of the current task.


title: Correlated variability in primate superior colliculus depends on functional class

abstract: Correlated variability (spike count correlations, rSC) in a population of neurons can constrain how information is read out, depending on behavioral task and neuronal tuning. Here we tested whether rSC also depends on neuronal functional class. We recorded from populations of neurons in macaque superior colliculus (SC), a structure that contains well-defined functional classes. We found that during a guided saccade task, different classes of neurons exhibited differing degrees of rSC. "Delay class" neurons displayed the highest rSC, especially during the delay epoch of saccade tasks that relied on working memory. This was only present among Delay class neurons within the same hemisphere. The dependence of rSC on functional class indicates that subpopulations of SC neurons occupy distinct circuit niches with distinct inputs. Such subpopulations should be accounted for differentially when attempting to model or infer population coding principles in the SC, or elsewhere in the primate brain.


title: ppGpp Is Present in, and Regulates Sleep of, Drosophila

abstract: Discovery of molecules in living systems and demonstration of their functional roles are pivotal in furthering our understanding of the molecular basis of biology. ppGpp (guanosine-5-diphosphate, 3-diphosphate) has been detected in prokaryotes for more than five decades. Here we report that a genetic screen followed by chemical analysis revealed the presence of ppGpp in Drosophila. It can be detected in germ-free Drosophila and its level is controlled by an enzyme encoded by the mesh1 gene in Drosophila. Loss of function mutations in mesh1, which encoded the ppGpp degrading enzyme led to longer sleep latency and less total sleep. These phenotypes could be rescued by wild type mesh1, but not by the enzymatically defective mutant Mesh1E66A, functionally implicating ppGpp. Ectopic expression of RelA, the E. coli synthetase for ppGpp, phenocopied mesh1 knockout mutants, whereas overexpression of mesh1 resulted in the opposite phenotypes, supporting that ppGpp is both necessary and sufficient in sleep regulation. mesh1 is expressed in a specific population of neurons, and a chemoconnectomic screen followed by genetic intersection experiments implicate the pars intercerebralis (PI) as the site of ppGpp function. Our results have thus revealed that ppGpp is present in animals after long lag since its discovery in bacteria. Furthermore, we have demonstrated that ppGpp in a specific subset of neurons plays a physiological role in regulating sleep. We speculate that ppGpp may play function in mammals.


title: Alzheimer's disease alters astrocytic functions related to neuronal support andtranscellular internalization of mitochondria

abstract: Under physiological conditions in vivo astrocytes internalize and degrade neuronal mitochondria in a process called transmitophagy. Mitophagy is widely reported to be impaired in neurodegeneration but it is unknown whether and how transmitophagy is altered in Alzheimers disease (AD). Here we report that the internalization and degradation of neuronal mitochondria are significantly increased in astrocytes isolated from aged AD mouse brains. We also demonstrate for the first time a similar phenomenon between human neurons and AD astrocytes, and in murine hippocampi in vivo. The results suggest the involvement of S100a4 in impaired mitochondrial transfer between neurons and aged AD astrocytes. Significant increases in the mitophagy regulator Ambra1 were observed in the aged AD astrocytes. These findings demonstrate altered neuron-supporting functions of aged AD astrocytes and provide a starting point for studying the molecular mechanisms of transmitophagy in AD.


title: Hippocampus maintains a flexible and coherent map under reward flavor-landmark cue conflict.

abstract: Animals predominantly use salient visual cues (landmarks) for efficient navigation over other sensory modalities. When the relative position of the visual cues is altered, the hippocampal population exhibits heterogeneous responses and constructs context-specific spatial maps. Another critical factor that can strongly modulate spatial representation is the presence of reward. Reward features can drive behavior and are known to bias spatial attention. However, it is unclear whether reward flavors are used for spatial reference in the presence of distal cues and how the hippocampus population dynamics changes when the association between reward flavors and distal cues is altered. We investigated these questions by recording place cells from the CA1 while the rats ran in an environment with the conflicting association between reward flavors and distal cues. We report that the hippocampal place cells coherently and dynamically bind to reward flavors or distal cues across sessions, but not simultaneously suggesting the use of a single spatial map. We found that place cells maintained their spatial offset in the cue conflict conditions, thus showing a robust spatial coupling featuring an attractor-like property in the CA1. When the textures were added on the track, the coherency of the CA1 is degraded, as the hippocampus showed a heterogeneous response and weak spatial coupling of co-recorded cells suggesting a break away from the attractor network. These results indicate that reward flavors alone may be used for spatial reference but may not cause sufficient input difference to create context-specific spatial maps in the CA1.


title: White Matter Signals Reflect Information Transmission Between Brain Regions During Seizures

abstract: White matter supports critical brain functions such as learning and memory, modulates the distribution of action potentials, and acts as a relay of neural communication between different brain regions. Interestingly, neuronal cell bodies exist in deeper white matter tissue, neurotransmitter vesicles are released directly in white matter, and white matter blood-oxygenation level dependent (BOLD) signals are detectable across a range of different tasks--all appearing to reflect intrinsic electrical signals in white matter. Yet, such signals within white matter have largely been ignored. Here, we elucidate the properties of white matter signals using intracranial EEG. We show that such signals capture the communication between brain regions and differentiate pathophysiologies of epilepsy. In direct contradiction to past assumptions about white matter in-activity, we show that white matter recordings can elucidate brain function and pathophysiology not apparent in gray matter. Broadly, white matter functional recordings acquired through implantable devices may provide a wealth of currently untapped knowledge about the neurobiology of disease.


title: Classifying the Unknown: Identification of Insectsby Deep Open-set Bayesian Learning

abstract: Insects represent a large majority of biodiversity on Earth, yet only 20% of the estimated 5.5 million insect species are currently described (1). While describing new species typically requires specific taxonomic expertise to identify morphological characters that distinguish it from other potential species, DNA-based methods have aided in providing additional evidence of separate species (2). Machine learning (ML) is emerging as a potential new approach in identifying new species, given that this analysis may be more sensitive to subtle differences humans may not process. Existing ML algorithms are limited by image repositories that do not include undescribed species. We developed a Bayesian deep learning method for the open-set classification of species. The proposed approach forms a Bayesian hierarchy of species around corresponding genera and uses deep embeddings of images and barcodes together to identify insects at the lowest level of abstraction possible. To demonstrate proof of concept, we used a database of 32,848 insect instances from 1,040 described species split into training and test data. The test data included 243 species not present in the training data. Our results demonstrate that using DNA sequences and images together, insect instances of described species can be classified with 96.66% accuracy while achieving accuracy of 81.39% in identifying genera of insect instances of undescribed species. The proposed deep open-set Bayesian model demonstrates a powerful new approach that can be used for the gargantuan task of identifying new insect species.


title: Global trade-offs in tree functional traits

abstract: AO_SCPLOWBSTRACTC_SCPLOWDue to massive energetic investments in woody support structures, trees are subject to unique physiological, mechanical, and ecological pressures not experienced by herbaceous plants. When considering trait relationships across the entire plant kingdom, plant trait frameworks typically must omit traits unique to large woody species, thereby limiting our understanding of how these distinct ecological pressures shape trait relationships in trees. Here, by considering 18 functional traits--reflecting leaf economics, wood structure, tree size, reproduction, and below-ground allocation--we quantify the major axes of variation governing trait expression of trees worldwide. We show that trait variation within and across angiosperms and gymnosperms is captured by two independent processes: one reflecting tree size and competition for light, the other reflecting leaf photosynthetic capacity and nutrient economies. By exploring multidimensional relationships across clusters of traits, we further identify a representative set of seven traits which captures the majority of variation in form and function in trees: maximum tree height, stem conduit diameter, specific leaf area, seed mass, bark thickness, root depth, and wood density. Collectively, this work informs future trait-based research into the functional biogeography of trees, and contributes to our fundamental understanding of the ecological and evolutionary controls on forest biodiversity and productivity worldwide.


title: Modelling potential range expansion of an underutilised food security crop in Sub-Saharan Africa

abstract: Despite substantial growth in global agricultural production, food and nutritional insecurity is rising in Sub-Saharan Africa. Identification of underutilised indigenous crops with useful food security traits may provide part of the solution. Enset (Ensete ventricosum) is a perennial banana relative with cultivation restricted to southwestern Ethiopia, where high productivity and harvest flexibility enables it to provide a starch staple for ~20 million people. An extensive wild distribution suggests that a much larger region may be climatically suitable for cultivation. Here we use ensemble ecological niche modelling to predict the potential range for enset cultivation within southern and eastern Africa. We find contemporary bioclimatic suitability for a 12-fold range expansion, equating to 21.9% of crop land and 28.4% of the population in the region. Integration of crop wild relative diversity, which has broader climate tolerance, could enable a 19-fold expansion, particularly to dryer and warmer regions. Whilst climate change may cause a 37% - 52% reduction in potential range by 2070, large centres of suitability remain in the Ethiopian Highlands, Lake Victoria region and the Drakensberg Range. We combine our bioclimatic assessment with socioeconomic data to identify priority areas with high population density, seasonal food deficits and predominantly small-scale subsistence agriculture, where integrating enset may be particularly feasible and deliver climate resilience. When incorporating the genetic potential of wild populations, enset cultivation might prove feasible for an additional 87.2 - 111.5 million people, 27.7 - 33 million of which are in Ethiopia outside of ensets current cultivation range. Finally, we consider explanations why enset cultivation has not expanded historically, and ethical implications of expanding previously underutilised species.


title: Receptor-wide Determinants of G Protein Coupling Selectivity in Aminergic GPCRs

abstract: G protein-coupled receptors (GPCRs) induce signal transduction pathways through coupling to four main subtypes of G proteins (Gs, Gi, Gq, G12/13), selectively. However, G protein selective activation mechanisms and residual determinants in GPCRs have remained obscure. Herein, we performed an extensive phylogenetic analysis and identified specifically conserved residues for the receptors having similar coupling profiles in each aminergic receptor. By integrating our methodology of differential evolutionary conservation of G protein-specific amino acids with structural analyses, we identified selective activation networks for Gs, Gi1, Go, and Gq. To validate that these networks could determine coupling selectivity we further analyzed Gs specific activation network and associated it with the larger TM6 tilt which is a signature of Gs-coupled receptors. Through molecular dynamics simulations, we showed that previously uncharacterized Glycine at position 7x41 plays an important role in both receptor activation and Gs coupling selectivity by inducing a larger TM6 movement. Finally, we gathered our results into a comprehensive model of G protein selectivity called "sequential switches of activation" describing three main molecular switches controlling GPCR activation: ligand binding, G protein selective activation mechanisms and G protein contact.


title: Evolutionary association of receptor-wide amino acids with G protein coupling selectivity in aminergic GPCRs


title: Influence of Rule and Reward-based Strategies on Inferences of Serial Order by Monkeys

abstract: Knowledge of transitive relationships between items can contribute to learning the order of a set of stimuli from pairwise comparisons. However, cognitive mechanisms of transitive inferences based on rank order remain unclear, as are contributions of reward magnitude and rule-based inference. To explore these issues, we created a conflict between rule- and reward-based learning during a serial ordering task. Rhesus macaques learned two lists, each containing five stimuli, that were trained exclusively with adjacent pairs. Selection of the higher-ranked item resulted in rewards. "Small reward" lists yielded 2 drops of fluid reward, while "large reward" lists yielded 5 drops. Following training of adjacent pairs, monkeys were tested on novels pairs. One item was selected from each list, such that a ranking rule could conflict with preferences for large rewards. Differences in associated reward magnitude had a strong influence on accuracy, but we also observed a symbolic distance effect. That provided evidence of a rule-based influence on decisions. Reaction time comparisons suggested a conflict between rule and reward-based processes. We conclude that performance reflects the contributions of two strategies, and that a model-based strategy is employed in the face of a strong countervailing reward incentive.


title: Tourmaline: a workflow for rapid and reproducible amplicon sequence analysis using QIIME 2 and Snakemake

abstract:
BackgroundAmplicon sequencing (metabarcoding) is a common method to survey diversity of environmental communities whereby a single genetic locus is amplified and sequenced from the DNA of whole or partial organisms, organismal traces (e.g., skin, mucus, feces), or microbes in an environmental sample. Several software packages exist for analyzing amplicon data, among which QIIME 2 has emerged as a popular option because of its broad functionality, plugin architecture, provenance tracking, and interactive visualizations. However, each new analysis requires the user to keep track of input and output file names, parameters, and commands; this lack of automation and standardization is inefficient and creates barriers to meta-analysis and sharing of results.

FindingsWe developed Tourmaline, a Python-based workflow that implements QIIME 2 and is built using the Snakemake workflow management system. Starting from a configuration file that defines parameters and input files--a reference database, a sample metadata file, and a manifest or archive of FASTQ sequences--it uses QIIME 2 to run either the DADA2 or Deblur denoising algorithm, assigns taxonomy to the resulting representative sequences, performs analyses of taxonomic, alpha, and beta diversity, and generates an HTML report summarizing and linking to the output files. Features include support for multiple cores, automatic determination of trimming parameters using quality scores, representative sequence filtering (taxonomy, length, abundance, prevalence, or ID), support for multiple taxonomic classification and sequence alignment methods, outlier detection, and automated initialization of a new analysis using previous settings. The workflow runs natively on Linux and macOS or via a Docker container. We ran Tourmaline on a 16S rRNA amplicon dataset from Lake Erie surface water, showing its utility for parameter optimization and the ability to easily view interactive visualizations through the HTML report, QIIME 2 viewer, and R- and Python-based Jupyter notebooks.

ConclusionsAutomated workflows like Tourmaline enable rapid analysis of environmental and biomedical amplicon data, decreasing the time from data generation to actionable results. Tourmaline is available for download at github.com/aomlomics/tourmaline.


title: Tourmaline: a containerized workflow for rapid and iterable amplicon sequence analysis using QIIME 2 and Snakemake


title: Metabolic Derangement in Polycystic Kidney Disease Mouse Models Is Ameliorated by Mitochondrial-Targeted Antioxidants

abstract: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressively enlarging cysts. Here we elucidate the interplay between oxidative stress, mitochondrial dysfunction, and metabolic derangement using two mouse models of PKD1 mutation, PKD1RC/null and PKD1RC/RC. Mouse kidneys with PKD1 mutation have decreased mitochondrial complexes activity. Targeted proteomics analysis shows a significant decrease in proteins involved in the TCA cycle, fatty acid oxidation (FAO), respiratory complexes, and endogenous antioxidants. Overexpressing mitochondrial-targeted catalase (mCAT) using adeno-associated virus reduces mitochondrial ROS, oxidative damage, ameliorates the progression of PKD and partially restores expression of proteins involved in FAO and the TCA cycle. In human ADPKD cells, inducing mitochondrial ROS increased ERK1/2 phosphorylation and decreased AMPK phosphorylation, whereas the converse was observed with increased scavenging of ROS in the mitochondria. Treatment with the mitochondrial protective peptide, SS31, recapitulates the beneficial effects of mCAT, supporting its potential application as a novel therapeutic for ADPKD.

category: pathology


title: Spatiotemporal components of sustained functional hyperemia are differentially modulated by locomotion and silenced with vascular chemogenetics

abstract: Neural activity underlying sensation, movement or cognition drives regional blood flow enhancement - termed functional hyperemia - to increase the oxygen supply to respiring cells for as long as needed to meet energy demands. However, functional hyperemia is often studied under anesthesia which typically yields response profiles that appear temporally and spatially homogenous. We have insufficient understanding of the underlying kinetics of oxygen delivery in awake animals, especially during specific behaviours that may influence neurally-driven enhancements in cerebral blood flow. Using widefield intrinsic optical signal imaging in awake, head-fixed but active mice, we demonstrated distinct early and late components to changes in intravascular oxygenation in response to sustained (30s) whisker stimulation. We found that the late component (20-30s), but not the early component (1-5s), was strongly influenced by level of whisking/locomotion in the region of highest response and in surrounding regions. Optical flow analyses revealed complex yet stereotyped spatial properties of the early and late components that were related to location within the optical window and the initial state of the cerebral vasculature. In attempt to control these complex response characteristics, we drove a canonical microvasculature constriction pathway using mural cell Gq-chemogenetic mice. A low-dose of systemic C21 strongly limited both the magnitude and spatial extent of the sensory-evoked hemodynamic response, showing that functional hyperemia can be severely limited by direct mural cell activation. These data provide new insights into the cerebral microcirculation in the awake state and may have implications for interpreting functional imaging data.


title: Circuit contributions to sensory-driven glutamatergic drive of olfactory bulb mitral and tufted cells during odorant inhalation

abstract: In the mammalian olfactory bulb (OB), mitral/tufted (MT) cells respond to odorant inhalation with diverse temporal patterns that are thought to encode odor information. Much of this diversity is already apparent at the level of glutamatergic input to MT cells, which receive direct, monosynaptic excitatory input from olfactory sensory neurons (OSNs) as well as multisynaptic excitatory drive via glutamatergic interneurons. Both pathways are also subject to modulation by inhibitory circuits in the glomerular layer of the OB. To understand the role of direct OSN input versus postsynaptic OB circuit mechanisms in shaping diverse dynamics of glutamatergic drive to MT cells, we imaged glutamate signaling onto MT cell dendrites in anesthetized mice while blocking multisynaptic excitatory drive with ionotropic glutamate receptor antagonists and blocking presynaptic modulation of glutamate release from OSNs with GABAB receptor antagonists. GABAB receptor blockade increased the magnitude of inhalation-linked glutamate transients onto MT cell apical dendrites without altering their inhalation-linked dynamics, confirming that presynaptic inhibition impacts the gain of OSN inputs to the OB. Surprisingly, blockade of multisynaptic excitation only modestly impacted glutamatergic input to MT cells, causing a slight reduction in the amplitude of inhalation-linked glutamate transients in response to low odorant concentrations and no change in the dynamics of each transient. Postsynaptic blockade also modestly impacted glutamate dynamics over a slower timescale, mainly by reducing adaptation of the glutamate response across multiple inhalations of odorant. These results suggest that direct glutamatergic input from OSNs provides the bulk of excitatory drive to MT cells, and that diversity in the dynamics of this input may be a primary determinant of the temporal diversity in MT cell responses that underlies odor representations at this stage.


title: DYNAMICS OF NEUROMUSCULAR TRANSMISSION REPRODUCED BY CALCIUM-DEPENDENT SERIAL TRANSITIONS IN THE VESICLE FUSION COMPLEX

abstract: Neuromuscular transmission, from spontaneous release to facilitation and depression was accurately reproduced by a mechanistic kinetic model of sequential maturation transitions in the molecular fusion complex. The model incorporates three predictions. First, sequential calcium-dependent forward transitions take vesicles from docked to pre-primed to primed states, followed by fusion. Second, pre-priming and priming are reversible. Third, fusion and recycling are unidirectional. The model was fed with experimental data from previous studies while the backward ({beta}) and recycling ({rho}) rate constant values were fitted. Classical experiments were successfully reproduced when every forward () rate constant had the same value, and both backward rate constants were 50-100 times larger. Such disproportion originated an abruptly decreasing gradient of resting vesicles from docked to primed states. Simulations also predict that: i. Spontaneous release reflects primed to fusion spontaneous transitions. ii. Calcium elevations synchronize the series of forward transitions that lead to fusion. iii Facilitation reflects a transient increase of priming following calcium-dependent transitions. iv. Backward transitions and recycling restore the resting state. v. Depression reflects backward transitions and slow recycling after intense release. Such finely-tuned kinetics offers a mechanism for collective non-linear transitional adaptations of a homogeneous vesicle pool to an ever-changing pattern of electrical activity.


title: Increased temporal discounting and reduced model-based control in problem gambling are not substantially modulated by exposure to virtual gambling environments.

abstract: High-performance virtual reality (VR) technology has opened new possibilities for the examination of the reactivity towards addiction-related cues (cue-reactivity) in addiction. In this preregistered study (https://osf.io/4mrta), we investigated the subjective, physiological, and behavioral effects of gambling-related VR environment exposure in participants reporting frequent or pathological gambling (n=31) as well as non-gambling controls (n=29). On two separate days, participants explored two rich and navigable VR-environments (neutral: cafe vs. gambling-related: casino/sports-betting facility), while electrodermal activity and heart rate were continuously measured using remote sensors. Within VR, participants performed a temporal discounting task and a sequential decision-making task designed to assess model-based and model-free contributions to behavior. Replicating previous findings, we found strong evidence for increased temporal discounting and reduced model-based control in participants reporting frequent or pathological gambling. Although VR gambling environment exposure increased subjective craving, there was if anything inconclusive evidence for further behavioral or physiological effects. Instead, VR exposure substantially increased physiological arousal (electrodermal activity), across groups and conditions. VR is a promising tool for the investigation of context effects in addiction, but some caution is warranted since effects of real gambling environments might not generally replicate in VR. Future studies should delineate how factors such as cognitive load and ecological validity could be balanced to create a more naturalistic VR experience.


title: An EEG study on the effect of being overweight on anticipatory and consummatory reward in response to pleasant taste stimuli

abstract: Two-thirds of adults in the United Kingdom currently suffer from overweight or obesity, making it one of the biggest contributors to health problems. Within the framework of the incentive sensitisation theory, it has been hypothesised that overweight people experience heightened reward anticipation when encountering cues that signal food, such as pictures and smells of food, but that they experience less reward from consuming food compared to normal-weight people. There is, however, little evidence for this prediction. Few studies test both anticipation and consumption in the same study, and even fewer with electroencephalography (EEG). This study sought to address this gap in the literature by measuring scalp activity when overweight and normal-weight people encountered cues signalling the imminent arrival of pleasant and neutral taste stimuli, and when they received these stimuli. The behavioural data showed that there was a smaller difference in valence ratings between the pleasant and neutral taste in the overweight than normal-weight group, in accordance with our hypothesis. However, contrary to our hypothesis, the groups did not differ in their electrophysiological response to taste stimuli. Instead, there was a reduction in N1 amplitude to both taste and picture cues in overweight relative to normal-weight participants. This suggests that reduced attention to cues may be a crucial factor in risk of overweight.


title: abmR: an R package for agent-based model analysis of large-scale movements across taxa

abstract:
O_LIAgent-based modeling (ABM) shows promise for animal movement studies. However, a robust, open-source, and spatially explicit ABM coding platform is currently lacking.
C_LIO_LIWe present abmR, an R package for conducting continental-scale ABM simulations across animal taxa. The package features two movement functions, each of which relies on the Ornstein-Uhlenbeck (OU) process.
C_LIO_LIThe theoretical background for abmR is discussed and the main functionalities are illustrated using two example populations.
C_LIO_LIPotential future additions to this open-source package may include the ability to specify multiple environmental variables or to model interactions between agents. Additionally, updates may offer opportunities for disease ecology and integration with other R movement modeling packages.
C_LI


title: Particle foraging strategies promote microbial diversity in marine environments

abstract: Microbial foraging in patchy environments, where resources are fragmented into particles or pockets embedded in a large matrix, plays a key role in natural environments. In the oceans and freshwater systems, particle-associated bacteria can interact with particle surfaces in different ways: some colonize only during short transients, while others form long-lived, stable colonies. We do not yet understand the ecological mechanisms by which both short-term and long-term colonizers can coexist. Here, we address this problem with a mathematical model that explains how marine populations with different detachment rates from particles can stably coexist. In our model, populations grow only while on particles, but also face the increased risk of mortality by predation and sinking. Key to coexistence is the idea that detachment from particles modulates both net growth and mortality, but in opposite directions, creating a trade-off between them. While slow-detaching populations show the highest growth return (i.e., produce more net offspring), they are more susceptible to suffer higher rates of mortality than fast-detaching populations. Surprisingly, fluctuating environments, manifesting as blooms of particles (favoring growth) and predators (favoring mortality) significantly expand the likelihood that populations with different detachment rates can coexist. Our study shows how the spatial ecology of microbes in the ocean can lead to a predictable diversification of foraging strategies and the coexistence of multiple taxa on a single growth-limiting resource.


title: Movement shapes the structure of fish communities along a cross-shore section in the California Current

abstract: Pelagic fish communities are shaped by bottom-up and top-down processes, transport by currents, and active swimming. However, the interaction of these processes remains poorly understood. Here, we use a regional implementation of the APex ECOSystem Model (APECOSM), a mechanistic model of the pelagic food web, to investigate these processes in the California Current, a highly productive upwelling system characterized by vigorous mesoscale circulation. The model is coupled with an eddy-resolving representation of ocean currents and lower trophic levels, and is tuned to reproduce observed fish biomass from fisheries independent trawls. Several emergent properties of the model compare realistically with observations. First, the epipelagic community accounts for one order of magnitude less biomass than the vertically migratory community, and is composed by smaller species. Second, the abundance of small fish decreases from the coast to the open ocean, while the abundance of large fish remains relatively uniform. This in turn leads to flattening of biomass size-spectra away from the coast for both communities. Third, the model reproduces a cross-shore succession of small to large sizes moving offshore, consistent with observations of species occurrence. These cross-shore variations emerge in the model from a combination of: (1) passive offshore advection by the mean current, (2) active swimming towards coastal productive regions to counterbalance this transport, and (3) mesoscale heterogeneity that reduces the ability of organisms to return to coastal waters. Our results highlight the importance of passive and active movement in structuring the pelagic food web, and suggest that a correct representation of these processes is needed for realistic simulations with marine ecosystem models.


title: The effect of mating complexity on gene drive dynamics

abstract: Gene drive technology promises to deliver on some of the global challenges humanity faces today in healthcare, agriculture and conservation. However, there is a limited understanding of the consequences of releasing self-perpetuating transgenic organisms into the wild populations under complex ecological conditions. In this study, we analyze the impact of three such complexities, mate-choice, mating systems and spatial mating network, on the population dynamics for two distinct classes of modification gene drive systems. All three factors had a high impact on the modelling outcome. First, we demonstrate that distortion based gene drives appear to be more robust against the mate-choice than viability-based gene drives. Second, we find that gene drive spread is much faster for higher degrees of polygamy. Including a fitness cost, the drive is fastest for intermediate levels of polygamy. Finally, the spread of gene drive is faster and more effective when the individuals have fewer connections in a spatial mating network. Our results highlight the need to include mating complexities while modelling the properties of gene drives such as release thresholds, timescales and population-level consequences. This inclusion will enable a more confident prediction of the dynamics of engineered gene drives and possibly even inform on the origin and evolution of natural gene drives.


title: 3D-imaging inspired improvements to hearing model in parasitoid fly Ormia ochracea

abstract:
This manuscript was compiled on October 5, 2021 Although most binaural organisms localize sound sources using neurological structures to amplify the sounds they hear, some animals use mechanically coupled hearing organs instead. One of these animals, the parasitoid fly Ormia ochracea, has astoundingly accurate sound localization abilities and can locate objects in the azimuthal plane with a precision of 2{degrees}, equal to that of humans. This is accomplished despite an intertympanal distance of only 0.5 mm, which is less than 1/100th of the wavelength of the sound emitted by the crickets that it parasitizes. In 1995, Miles et al. developed a model of hearing mechanics in O. ochracea, which works well for incoming sound angles of less than {+/-}30{degrees}, but suffers from reduced accuracy (up to 60% error) at higher angles. Even with this limitation, it has served as the basis for multiple bio-inspired microphone designs for decades. Here, we present critical improvements to the classic O. ochracea hearing model based on information from 3D reconstructions of O. ochraceas tympana. The 3D images reveal that the tympanal organ has curved lateral faces in addition to the flat front-facing prosternal membranes represented in the Miles model. To mimic these faces, we incorporated spatially-varying spring and damper coefficients that respond asymmetrically to incident sound waves, making a new quasi-two-dimensional (q2D) model. The q2D model has high accuracy (average errors of less than 10%) for the entire range of incoming sound angles. This improved biomechanical hearing model can inform the development of new technologies and may help to play a key role in developing improved hearing aids.

Significance StatementThe ability to identify the location of sound sources is critical to organismal survival and for technologies that minimize unwanted background noise, such as directional microphones for hearing aids. Because of its exceptional auditory system, the parasitoid fly Ormia ochracea has served as an important model for binaural hearing and a source of bioinspiration for building tiny directional microphones with outsized sound localization abilities. Here, we performed 3D imaging of the flys tympanal organs and used the morphological information to improve the current model for hearing in O. ochracea. This model greatly expands the range of biological accuracy from {+/-}30{degrees} to all incoming sound angles, providing a new avenue for studies of binaural hearing and further inspiration for fly-inspired technologies.


title: A biologically accurate model of directional hearing in the parasitoid fly Ormia ochracea


title: Long-term Motor Learning in the Wild with High Volume Video Game Data

abstract: Motor learning occurs over long periods of practice during which motor acuity - the ability to execute actions more accurately, precisely, and within a shorter amount of time - improves. Laboratory-based motor learning studies are typically limited to a small number of participants and a time frame of minutes to several hours per participant. Thus, there is a need to assess the generalizability of theories and findings from lab-based motor learning studies on much larger samples across longer time scales. In addition, laboratory-based studies of motor learning use relatively simple motor tasks which participants are unlikely to be intrinsically motivated to learn, limiting the interpretation of their findings in more ecologically valid settings. We studied the acquisition and longitudinal refinement of a complex sensorimotor skill embodied in a first-person shooter video game scenario, with a large sample size (N = 7174 participants, 682,564 repeats of the 60 sec game) over a period of months. Participants voluntarily practiced the gaming scenario for as much as several hours per day up to 100 days. We found improvement in performance accuracy (quantified as hit rate) was modest over time but motor acuity (quantified as hits per second) improved considerably, with 40-60% retention from one day to the next. We observed steady improvements in motor acuity across multiple days of video game practice, unlike most motor learning tasks studied in the lab that hit a performance ceiling rather quickly. Learning rate was a nonlinear function of baseline performance level, amount of daily practice, and to a lesser extent, number of days between practice sessions. In addition, we found that the benefit of additional practice on any given day was non-monotonic; the greatest improvements in motor acuity were evident with about an hour of practice and 90% of the learning benefit was achieved by practicing 30 minutes per day. Taken together, these results provide a proof-of-concept in studying motor skill acquisition outside the confines of the traditional laboratory and provide new insights into how a complex motor skill is acquired in an ecologically valid setting and refined across much longer time scales than typically explored.


title: Quantifying the impact of gut microbiota on inflammation and hypertensive organ damage

abstract:
AimsHypertension (HTN) can lead to heart and kidney damage. The gut microbiota has been linked to HTN, although it is difficult to estimate its significance due to the variety of other features known to influence HTN. In the present study, we used germ-free (GF) and colonized (COL) littermate mice to quantify the impact of microbial colonization on organ damage in HTN.

Methods and resultsFour-week-old male GF C57BL/6J littermates were randomized to remain GF or receive microbial colonization. HTN was induced by subcutaneous infusion with angiotensin (Ang) II (1.44mg/kg/d) and 1% NaCl in the drinking water; sham-treated mice served as control. Renal damage was exacerbated in GF mice, whereas cardiac damage was more comparable between COL and GF, suggesting that the kidney is more sensitive to microbial influence. Multivariate analysis revealed a larger effect of HTN in GF mice. Serum metabolomics demonstrated that the colonization status influences circulating metabolites relevant to HTN. Importantly, GF mice were deficient in anti-inflammatory fecal short-chain fatty acids (SCFA). Flow cytometry showed that the microbiome has an impact on the induction of anti-hypertensive myeloid-derived suppressor cells and pro-inflammatory Th17 cells in HTN. In vitro inducibility of Th17 cells was significantly higher for cells isolated from GF than conventionally raised mice.

ConclusionsMicrobial colonization status of mice had potent effects on their phenotypic response to a hypertensive stimulus, and the kidney is a highly microbiota-susceptible target organ in HTN. The magnitude of the pathogenic response in GF mice underscores the role of the microbiome in mediating inflammation in HTN.

Translation PerspectiveTo assess the potential of microbiota-targeted interventions to prevent organ damage in hypertension, an accurate quantification of microbial influence is necessary. We provide evidence that the development of hypertensive organ damage is dependent on colonization status and suggest that a healthy microbiota provides anti-hypertensive immune and metabolic signals to the host. In the absence of normal symbiotic host-microbiome interactions, hypertensive damage to the kidney in particular is exacerbated. We suggest that hypertensive patients experiencing perturbations to the microbiota, which are common in CVD, may be at a greater risk for target-organ damage than those with a healthy microbiome.


title: Zoonotic potential of a novel bat morbillivirus

abstract: Bats are significant reservoir hosts for many viruses with zoonotic potential1. SARS-CoV-2, Ebola virus, and Nipah virus are examples of such viruses that have caused deadly epidemics and pandemics when spilled over from bats into human and animal populations2,3. Careful surveillance of viruses in bats is critical for identifying potential zoonotic pathogens. However, metagenomic surveys in bats often do not result in full-length viral sequences that can be used to regenerate such viruses for targeted characterization4. Here, we identify and characterize a novel morbillivirus from a vespertilionid bat species (Myotis riparius) in Brazil, which we term myotis bat morbillivirus (MBaMV). There are 7 species of morbilliviruses including measles virus (MeV), canine distemper virus (CDV) and rinderpest virus (RPV)5. All morbilliviruses cause severe disease in their natural hosts6-10, and pathogenicity is largely determined by species specific expression of canonical morbillivirus receptors, CD150/SLAMF111 and NECTIN412. MBaMV used Myotis spp CD150 much better than human and dog CD150 in fusion assays. We confirmed this using live MBaMV that was rescued by reverse genetics. Surprisingly, MBaMV replicated efficiently in primary human myeloid but not lymphoid cells. Furthermore, MBaMV replicated in human epithelial cells and used human NECTIN4 almost as well as MeV. Our results demonstrate the unusual ability of MBaMV to infect and replicate in some human cells that are critical for MeV pathogenesis and transmission. This raises the specter of zoonotic transmission of a bat morbillivirus.