title: A comprehensive neural simulation of slow-wave sleep and highly responsive wakefulness dynamics

abstract: Hallmarks of neural dynamics during healthy human brain states span spatial scales from neuromodulators acting on microscopic ion channels to macroscopic changes in communication between brain regions. Developing a scale-integrated understanding of neural dynamics has therefore remained challenging. Here, we perform the integration across scales using mean-field modeling of Adaptive Exponential (AdEx) neurons, explicitly incorporating intrinsic properties of excitatory and inhibitory neurons. We report that when AdEx mean-field neural populations are connected via structural tracts defined by the human connectome, macroscopic dynamics resembling human brain activity emerge. Importantly, the model can qualitatively and quantitatively account for properties of empirical spontaneous and stimulus-evoked dynamics in the space, time, phase, and frequency domains. Remarkably, the model also reproduces brain-wide enhanced responsiveness and capacity to encode information particularly during wake-like states, as quantified using the perturbational complexity index. The model was run using The Virtual Brain (TVB) simulator, and is open-access in EBRAINS. This approach not only provides a scale-integrated understanding of brain states and their underlying mechanisms, but also open access tools to investigate brain responsiveness, toward producing a more unified, formal understanding of experimental data from conscious and unconscious states, as well as their associated pathologies.


title: The unfolded protein response triggers the ancestral immune deficiency pathway

abstract: The insect immune deficiency (IMD) pathway is a defense mechanism that senses and responds to Gram negative bacteria. Ticks lack genes encoding upstream components that initiate the IMD pathway. Despite this deficiency, core signaling molecules are present and functionally restrict tick-borne pathogens. The molecular events preceding activation remain undefined. Here, we show that the Unfolded Protein Response (UPR) initiates the IMD network in Ixodes scapularis ticks. The endoplasmic reticulum (ER) stress receptor, IRE1, is phosphorylated in response to tick-borne bacteria, but does not splice the mRNA encoding XBP1. Instead, through protein modeling and reciprocal pulldowns, we show that Ixodes IRE1 complexes with TRAF2. Disrupting IRE1-TRAF2 signaling blocks IMD pathway activation and diminishes the production of reactive oxygen species. Through in vitro, in vivo, and ex vivo techniques we demonstrate that the UPR-IMD pathway circuitry limits the Lyme disease-causing spirochete Borrelia burgdorferi and the rickettsial agents Anaplasma phagocytophilum and A. marginale (anaplasmosis). Altogether, our study uncovers a novel linkage between the UPR and the IMD pathway in ticks.

category: immunology


title: The unfolded protein response triggers the immune deficiency pathway in ticks


title: Leishmania parasite arginine deprivation response pathway influences the host macrophage lysosomal arginine sensing machinery

abstract:
Extensive interaction between the host and pathogen metabolic networks decidedly shapes the outcome of infection. Infection with Leishmania donovani, an intracellular protozoan parasite, leads to a competition for arginine between the host and the parasite. L. donovani transports arginine via a high-affinity transporter LdAAP3, encoded by the two genes LdAAP3.1 and LdAAP3.2. Earlier reports show that upon arginine starvation, cultured Leishmania parasites promptly activate an Arginine Deprivation Response (ADR) pathway, resulting in the stoichiometric up-regulation of LdAAP3.2 mRNA, protein and activity. Lysosomes, on the other hand, are known to employ a specific sensor and an arginine-activated amino acid transporter, solute carrier family 38 member 9 (SLC38A9) that monitors intra-lysosome arginine sufficiency and subsequently up-regulates cellular mTORkinase activity. The present study investigates the interaction between Leishmania and macrophage-lysosome arginine sensing machinery. We show that infection with L. donovani activates SLC38A9 arginine sensing in the human monocyte like-macrophage cell line (THP-1) when grown under physiological concentrations of arginine (0.1 mM). However, supplementing the macrophage growth medium with excess arginine (1.5 mM) followed by infection led to the down-regulation of SLC38A9. Similarly, THP-1 cells infected with LdAAP3.2 null mutants grown in 0.1 mM arginine resulted in reduced expression of SLC38A9 and mTOR. These results indicate that inside the host macrophage, Leishmania overcome low arginine levels by up-regulating the transport of arginine via LdAAP3 and SLC38A9 signalling. Furthermore, while LdAAP3.2 null mutants were impaired in their ability to develop inside THP-1 macrophages, their infectivity and intracellular growth were restored in SLC38A9 silenced macrophages. This study provides the first identification of regulatory role of SLC38A9 in the expression and role of LdAAP3.

Author SummaryLeishmania donovani, the causative agent of kala-azar, exhibits a digenetic life cycle. Following infection of the mammalian host, promastigotes differentiate into intracellular amastigotes within the phagolysosome of macrophages. Arginine is a central point of competition between the host and the pathogen. L. donovani senses lack of arginine in the surrounding micro-environment and activates a unique ADR pathway, thus upregulating the expression of the arginine transporter (LdAAP3). The arginine-activated amino acid transporter SLC38A9 localizes to the lysosome surface of mammalian cells and acts as a sensor that transmits information about arginine levels in the lysosome lumen to the mechanistic target of rapamycin (mTOR) kinase. In the present study, we identified the functional interaction of host SLC38A9 and parasite LdAAP3 in macrophages infected with L. donovani. We report that host SLC38A9 upregulation is critical for enhancing and maintaining high LdAAP3 levels in intracellular L. donovani. Our results decode crucial information regarding the molecular mechanism involved in the arginine sensing response in L. donovani-infected host cells. These findings increase our understanding of the interaction of signalling intermediates during Leishmania infection which may lead to the discovery of novel therapeutic interventions.

category: molecular biology


title: Distribution and habitat use of the Madagascar Peregrine Falcon: first estimates for area of habitat and population size

abstract: Accurately demarcating species distributions has long been at the core of ecology. Yet our understanding of the factors limiting species range limits is incomplete, especially for tropical species in the Global South. Human-driven threats to the survival of many taxa are increasing, particularly habitat loss and climate change. Identifying distributional range limits of at-risk and data-limited species using Species Distribution Models (SDMs) can thus inform spatial conservation planning to mitigate these threats. The Madagascar Peregrine Falcon (Falco peregrinus radama) is the resident sub-species of the Peregrine Falcon complex distributed across Madagascar, Mayotte, and the Comoros Islands. Currently, there are significant knowledge gaps regarding its distribution, habitat preferences and population size. Here, we use point process regression models and ordination to identify Madagascar Peregrine Falcon environmental range limits and propose a population size estimate based on inferred habitat. From our models, the core range of the Madagascar Peregrine Falcon extends across the central upland plateau of Madagascar with a patchier range across coastal and low-elevation areas. Range-wide habitat use indicated that the Madagascar Peregrine Falcon prefers areas of high elevation and aridity, coupled with high vegetation heterogeneity and > 95 % herbaceous landcover, but generally avoids areas of > 30 % cultivated land and > 10 % mosaic forest. Based on inferred high-class habitat, we estimate this habitat area could potentially support a population size ranging between 150-300 pairs. Following International Union for Conservation of Nature Red List guidelines, we recommend this sub-species be classed as Vulnerable, due to its small population size. Despite its potentially large range, the Madagascar Peregrine has specialized habitat requirements and would benefit from targeted conservation measures based on spatial models in order to maintain viable populations.

category: ecology


title: Alternate patterns of temperature variation bring about very different disease outcomes at different mean temperatures

abstract: The dynamics of host-parasite interactions are highly temperature-dependent and may be modified by increasing frequency and intensity of climate-driven heat events. Here, we show that altered patterns of temperature variance lead to an almost order-of-magnitude shift in thermal performance of host and pathogen life history traits over and above the effects of mean temperature and, moreover, that different temperature regimes affect these traits differently. We found that diurnal fluctuations of {+/-}3{degrees}C lowered infection rates and reduced spore burden compared to constant temperatures in our focal host Daphnia magna exposed to the microsporidium parasite Ordospora colligata. In contrast, a three-day heatwave (+6{degrees}C) did not affect infection rates, but increased spore burden (relative to constant temperatures with the same mean) at 16{degrees}C, while reducing burden at higher temperatures. We conclude that changing patterns of climate variation, superimposed on shifts in mean temperatures due to global warming, may have profound and unanticipated effects on disease dynamics.


title: Predation risk differentially affects aphid morphotypes: impacts on prey behavior, fecundity and transgenerational dispersal morphology

abstract: To avoid predation, prey initiate anti-predator defenses such as altered behavior, physiology and/or morphology. Prey trait changes in response to perceived predation risk can influence several aspects of prey biology that collectively contribute to individual success and thus population growth. However, studies often focus on single trait changes in a discrete life stage or morphotype. We assessed how predation risk by Harmonia axyridis affects several important traits in the aphid, Myzus persicae: host plant preference, fecundity and investment in dispersal. Importantly, we examined whether these traits changed in a similar way between winged (alate) and wingless (apterous) adult aphid morphotypes, which differ in morphology, but also in life-history characteristics important for reproduction and dispersal. Host plant preference was influenced by the presence of H.axyridis odors in choice tests; wingless aphids were deterred by the odor of plants with H.axyridis whereas winged aphids preferred plants with H.axyridis present. Wingless aphids reared in the presence of ladybeetle cues produced fewer offspring in the short-term, but significantly more when reared with exposure to predator cues for multiple generations. However, winged aphid fecundity was unaffected by H.axyridis cues. Lastly, transgenerational plasticity was demonstrated in response to predation risk via increased formation of winged aphid morphotypes in the offspring of predator cue-exposed wingless mothers. Importantly, we found that responses to risk differ across aphid polyphenism and that plasticity in aphid morphology occurs in response to predation risk. Together our results highlight the importance of considering how predation risk affects multiple life stages and morphotypes.


title: Robust, data-driven bioregionalizations emerge from diversity concordance

abstract:
AimDespite the increasing interest in developing new bioregionalizations and assessing the most widely accepted biogeographic frameworks, no study to date has sought to systematically define a system of small bioregions nested within larger ones that better reflect the distribution and patterns of biodiversity. Here, we examine how an algorithmic, data-driven model of diversity patterns can lead to an ecologically interpretable hierarchy of bioregions.

LocationAustralia.

Time periodPresent.

Major taxa studiedTerrestrial vertebrates and vascular plants.

MethodsWe compiled information on the biophysical characteristics and species occupancy of Australias geographic conservation units (bioregions). Then, using cluster analysis to identify groupings of bioregions representing optimal discrete-species areas, we evaluated what a hierarchical bioregionalization system would look like when based empirically on the within-and between-site diversity patterns across taxa. Within an information-analytical framework, we then assessed the degree to which the World Wildlife Funds (WWF) biomes and ecoregions and our suite of discrete-species areas are spatially associated and compared those results among bioregionalization scenarios.

ResultsInformation on biodiversity patterns captured was moderate for WWFs biomes (50- 58% for birds beta, and plants alpha and beta diversity, of optimal discrete areas, respectively) and ecoregions (additional 4-25%). Our plants and vertebrate optimal areas retained more information on alpha and beta diversity across taxa, with the two algorithmically derived biogeographic scenarios sharing 86.5% of their within- and between-site diversity information. Notably, discrete-species areas for beta diversity were parsimonious with respect to those for alpha diversity.

Main conclusionsNested systems of bioregions must systematically account for the variation of species diversity across taxa if biodiversity research and conservation action are to be most effective across multiple spatial or temporal planning scales. By demonstrating an algorithmic rather than subjective method for defining bioregionalizations using species-diversity concordances, which reliably reflects the distributional patterns of multiple taxa, this work offers a valuable new tool for systematic conservation planning.


title: Sexual morph specialisation in a trioecious nematode balances opposing selective forces.

abstract: The coexistence of different mating strategies, whereby a species can reproduce both by selfing and outcrossing, is an evolutionary enigma that has long intrigued biologists (Darwin, 1877). Theory predicts only two stable mating states : outcrossing with strong inbreeding depression or selfing with weak inbreeding depression. As these two mating strategies are subject to opposing selective forces, mixed breeding systems are thought to be a rare transitory state, yet they have been found to persist even after multiple speciation events. We hypothesise that if each mating strategy plays a distinctive role during the species life history, opposing selective pressures could be balanced, permitting the stable co-existence of selfing and outcrossing sexual morphs. In this scenario, we would expect each sexual morph to be specialised in their respective roles. Here we show, using a combination of behavioural, physiological and gene expression studies, that the selfing (hermaphrodite) and outcrossing (female) sexual morphs of the trioecious nematode Auanema freiburgensis have distinct adaptations optimised for their different roles during the life cycle. A. freiburgensis hermaphrodites are produced under stressful conditions, are specialised for dispersal to new habitat patches and exhibit metabolic and intestinal changes that enable them to meet the energetic cost of dispersal and reproduction. In contrast, A. freiburgensis females are produced in favourable conditions, facilitate rapid population growth and compensate for the lack of reproductive assurance by reallocating resources from intestinal development to robust mate-finding behaviour. The specialisation of each mating system for their role in the life cycle could balance opposing selective forces allowing the stable maintenance of both outcrossing and selfing mating systems in A. freiburgensis.

category: evolutionary biology


title: Non-additive QTL mapping of lactation traits in 124,000 sequence-imputed cattle reveals novel recessive loci

abstract: Deleterious recessive conditions have primarily been studied in a Mendelian disease context. Recently, several large effect, deleterious recessive mutations were discovered via non-additive GWAS of quantitative growth and developmental traits in cattle. This showed quantitative traits can be used as proxies of genetic disorders if they are indicative of whole animal health status and susceptible to underlying genetic conditions. Lactation traits might also reflect genetic disorders in cattle, given the increased energy demands of lactation and the substantial stresses imposed on the animal. Here, we report a screen of over 124,000 cows for recessive effects based on lactation traits. We discovered novel loci associated with five large recessive impacts on milk yield traits represented by missense variants (DOCK8, IL4R, KIAA0556, and SLC25A4) or premature stop variants (ITGAL, LRCH4, and RBM34) as candidate causal mutations. On milk composition traits, we identified several small effect dominance contributions to previously reported additive QTL. In contrasting analyses of milk yield and milk composition phenotypes, we note differing genetic architectures. Milk yield phenotypes presented lower heritabilities and fewer additive QTL, but higher non-additive genetic variance and a higher proportion of loci exhibiting dominance compared to milk composition phenotypes. Large-effect recessive QTL are segregating at surprisingly high frequencies in cattle. We speculate that the differences in genetic architecture between milk yield and milk composition phenotypes derive from underlying dissimilarities in the cellular and molecular representation of these traits. Lactation yields may act as a better proxy than milk composition traits for a wide range of underlying biological disorders affecting animal fitness

category: genetics


title: Temporal and sex-dependent gene expression patterns in a renal ischemia-reperfusion injury and recovery pig model

abstract:
Men are more prone to acute kidney injury (AKI) and chronic kidney disease (CKD), progressing to end-stage renal disease (ESRD) than women. Severity and capacity to regenerate after AKI are important determinants of CKD progression, and of patient morbidity and mortality in the hospital setting. To determine sex differences during injury and recovery we have generated a female and male renal ischemia/reperfusion injury (IRI) pig model, which represents a major cause of AKI. Although no differences were found in blood urea nitrogen (BUN) and serum creatinine (SCr) levels between both sexes, females exhibited higher mononuclear infiltrates at basal and recovery, while males showed more tubular damage at injury. Global transcriptomic analyses of kidney biopsies from our IRI pig model revealed a sexual dimorphism in the temporal regulation of genes and pathways relevant for kidney injury and repair, which was also detected in human samples. Enrichment analysis of gene sets revealed five temporal and four sexual patterns governing renal IRI and recovery. Overall, this study constitutes an extensive characterization of the time and sex differences occurring during renal IRI and recovery at gene expression level and offers a template of translational value for further study of sexual dimorphism in kidney diseases.

AUTHOR SUMMARYKidneys correct functioning is essential for optimal body homeostasis, being their basic functions blood filtration and excretion of wastes and toxins. Inherited or acquired conditions can cause renal dysfunction requiring renal replacement therapy, which will affect patients life quality and survival. A major cause of kidney failure is the renal ischemia/reperfusion injury (IRI), which occurs in many clinical situations like kidney transplantation or aortic aneurysm surgery. Interestingly, men are more susceptible to IRI than women, being women more protected against kidney injury. However, the genetics regulating these sex differences in injury and renal repair remained unknown.

Here, we provide a novel porcine model to study renal injury and recovery in both males and females. Using this model, we have identified the gene sets involved in renal injury and recovery processes. Moreover, global genetic analyses allowed us to discover the temporal and sex-dependent patterns that regulate those gene sets and, finally, kidney damage and repair. A relevant finding of our study is that males develop a feminized genetic profile during recovery, which may represent a survival mechanism to diminish the androgenic pro-damage effects on kidney cells. To sum up, our results provide novel sex-dependent targets to prevent renal injury and promote kidney recovery.

category: genomics


title: Diurnal activity budget of Hippopotamus amphibius at Bui National Park, Ghana

abstract: Animals apportion time for their daily behavioral activities. We studied the activity budget of Hippopotamus amphibius at the Black Volta River in the Bui National Park, Ghana. We performed instantaneous scan sample using ground count survey between August 2020 to July 2021. We observed that H. amphibius spent most of their day time resting (54.75 %), followed by feeding (22.93 %), walking (19.2 %) and touching (3.12 %). We found significant difference in the time spent between the daily activities (H = 41.67; p < 0.0001). Except activities involving touching, we found no significant seasonal differences in feeding, resting and walking activities by H. amphibius. Understanding the behavioral activities of H. amphibius will enhance management and conservation of the animals.

category: animal behavior and cognition


title: Diurnal activity budget and conservation implication of Hippopotamus amphibius at Bui National Park, Ghana


title: Mapping the Energy Landscape of PROTAC-Mediated Protein-protein Interactions

abstract: One of the principal difficulties in computational modeling of macromolecules is the vast conformational space that arises out of large numbers of atomic degrees of freedom. This problem is a familiar issue in the area of protein-protein docking, where models of protein complexes are generated from the monomeric subunits. Although restriction of molecular flexibility is a commonly used approximation that decreases the dimensionality of the problem, the seemingly endless number of possible ways two binding partners can interact generally necessitates the use of further approximations to explore the search space. Recently, growing interest in using computational tools to build predictive models of PROTAC-mediated complexes has led to the application of state-of-the-art protein-protein docking techniques to tackle this problem. Additionally, the atomic degrees of freedom introduced by flexibility of linkers used in the construction of PROTACs further expands the configurational search space, a problem that can be tackled with conformational sampling tools. However, repurposing existing tools to carry out protein-protein docking and linker conformer generation independently results in extensive sampling of structures incompatible with PROTAC-mediated complex formation. Here we show that it is possible to restrict the search to the space of protein-protein conformations that can be bridged by a PROTAC molecule with a given linker composition by using a cyclic coordinate descent algorithm to position PROTACs into complex-bound configurations. We use this methodology to construct a picture of the energy landscape of PROTAC-mediated interactions in a model test case, and show that the global minimum lies in the space of native-like conformations.

category: bioinformatics


title: BWA-MEME: BWA-MEM emulated with a machine learning approach

abstract:
MotivationThe growing use of next-generation sequencing and enlarged sequencing throughput require efficient short-read alignment, where seeding is one of the major performance bottlenecks. The key challenge in the seeding phase is searching for exact matches of substrings of short reads in the reference DNA sequence. Existing algorithms, however, present limitations in performance due to their frequent memory accesses.

ResultsThis paper presents BWA-MEME, the first full-fledged short read alignment software that leverages learned indices for solving the exact match search problem for efficient seeding. BWA-MEME is a practical and efficient seeding algorithm based on a suffix array search algorithm that solves the challenges in utilizing learned indices for SMEM search which is extensively used in the seeding phase. Our evaluation shows that BWA-MEME achieves up to 3.45x speedup in seeding throughput over BWA-MEM2 by reducing the number of instructions by 4.60x, memory accesses by 8.77x, and LLC misses by 2.21x, while ensuring the identical SAM output to BWA-MEM2.

AvailabilityThe source code and test scripts are available for academic use at https://github.com/kaist-ina/BWA-MEME/.

Contacttom418@kaist.ac.kr, dhan.ee@kaist.ac.kr


title: Free energy and stacking of eumelaninnanoaggregates

abstract: Eumelanin, a member of the melanin family, is a black-brown insoluble pigment. It possesses a broad range of properties such as antioxidation, free radical scavenging, photo-protection, and charge carrier transportation. Surprisingly, the exact molecular structure of eumelanin remains undefined. It is, however, generally considered to consist of two main building blocks, 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole carboxylic acid (DHICA). We focus on DHI and report, for the first time, a computational investigation of structural properties of DHI eumelanin aggregates in aqueous solutions. First, multi-microsecond molecular dynamics (MD) simulations at different concentrations were performed to investigate aggregation and ordering of tetrameric DHI-eumelanin protomolecules. This was followed by umbrella sampling (US) and density functional theory (DFT) calculations to study the physical mechanisms of stacking. Aggregation occurs through formation of nanoscale stacks and was observed in all systems. Further analyses showed that aggregation and coarsening of the domains is due to decrease in hydrogen bonds between the eumelanins and water; while domains exist, there is no long-range order. The results show non-covalent stacks with and interlayer distance between eumelanin protomolecules being less than 3.5 [A]. This is in good agreement with transmission electron microscopy data. Both free energy calculations and DFT revealed strong stacking interactions. The electrostatic potential map provides an explanation and a rationale for the slightly sheared relative orientations and, consequently, for the curved shapes of the nanoscale domains.

category: biophysics


title: IL1B loss is associated with increased AR activity in castration-resistant prostate cancer

abstract: Castration-resistant prostate cancer represents a continuum of phenotypes, including tumors with high levels of androgen receptor (AR) expression and activity and those which do not express AR and rely on alternative pathways for survival. The process by which AR-positive prostate cancer cells and tumors lose AR expression and acquire neuroendocrine features is referred to as neuroendocrine differentiation. Numerous therapies and exposures have been demonstrated to induce neuroendocrine differentiation in vitro, including the pro-inflammatory cytokine, interleukin 1 beta (IL-1{beta}), encoded by the gene IL1B. The purpose of our studies was to determine the relationship between the expression and activity of AR in relationship to IL-1{beta} and IL1B in prostate cancer. We performed analysis of de-identified human clinical data and generated prostate cancer cell lines with overexpression or knockout of IL1B. In primary prostate cancer, higher expression of IL1B predicts longer time to biochemical recurrence. In metastatic castration-resistant prostate cancer, IL1B expression is decreased and inversely correlates with AR and AR-target gene expression and AR activity, while positively correlating with the neuroendocrine prostate cancer (NEPC) score and neuroendocrine marker gene expression. In vitro, we report that AR-positive castration-resistant prostate cancer cells (C4-2B, 22Rv1) secrete IL-1{beta}, and knockout of IL1B in these cells results in increased AR activity, in the presence and absence of dihydrotestosterone (DHT). Importantly, knockout of IL1B prevented AR attrition during androgen-deprivation. Taken together, our studies demonstrate that loss of IL1B in AR-positive castration-resistant prostate cancer cells can increase and maintain AR activity in the absence of androgens, suggesting another potential mechanism of high AR activity in castration-resistant prostate cancer.

category: cancer biology


title: Mevastatin in colon cancer by spectroscopic and microscopic methods - Raman imaging and AFM studies

abstract: One of the most important areas of medical science is oncology, which is responsible for both the diagnostics and treatment of cancer diseases. Simultaneously one of the main challenges of oncology is the development of modern drugs effective in the fight against cancer. Statins are a group of biologically active compounds with the activity of 3-hydroxy-3-methyl glutaryl-CoA reductase inhibitors, an enzyme catalyzing the reduction of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) to mevalonic acid. By acting on this enzyme, statins inhibit the endogenous cholesterol synthesis which in turn causes the reduction of its systemic concentrations. However, in vitro and in vivo studies confirm also the cytostatic and cytotoxic effects of statins against various types of cancer cells including colon cancer. In the presented studies the influence of mevastatin on cancerous colon cells CaCo-2 by Raman spectroscopy and imaging is discussed and compared with biochemistry characteristic for normal colon cells CCD-18Co. Based on vibrational features of colon cells: normal cells CCD-18Co, cancerous cells CaCo-2 and cancerous cells CaCo-2 treated by mevastatin in different concentrations and incubation times we have confirm the influence of this statin on biochemistry composition of cancerous human colon cells. Moreover, the spectroscopic results for colon normal cells and cancerous cells based on data typical for nucleic acids, proteins, lipids have been compared. The cytotoxisity of mevastatin was determined by using XTT tests.


title: Dynamic analysis of lower leg muscles response to whole body vibration stimulation at different frequencies and postures: implications for training

abstract:
PurposeTo characterise the mechanical and neuromuscular response of lower limb muscles in subjects undergoing Whole Body Vibration (WBV) at different frequencies while holding two static postures.

MethodsTwenty-five participants underwent WBV at 15, 20, 25 and 30 Hz while holding a static  hack squat and on  fore feet posture. Surface electromyography (sEMG) and soft tissue accelerations were collected from Gastrocnemius Lateralis (GL), Soleus (SOL) and Tibialis Anterior (TA) muscles.

ResultsOnly specific WBV settings led to a significant increase in muscle contraction. Specifically, the WBV-induced activation of SOL and GL was maximal in fore-feet and in response to higher frequencies. Estimated displacement at muscle bellies revealed a resonant pattern never highlighted before. After stimulation starts, muscle oscillation reaches a peak followed by a drop and a further stabilisation (few seconds after the peak) that suggests the occurrence of a neuromuscular activation to reduce the vibration-induced oscillation.

ConclusionLower leg muscles need a response time to tune to a vibratory stimulation, which discourages the use of dynamic exercises on vibrating platforms. To maximize calf muscle response to WBVs, a stimulation frequency in the range of 25-30 Hz and an  on fore feet posture are recommended.

category: physiology


title: Integration of genome-wide association studies and gene coexpression networks unveils promising soybean resistance genes against five common fungal pathogens

abstract: Soybean is one of the most important legume crops worldwide. However, soybean yield is dramatically affected by fungal diseases, leading to economic losses of billions of dollars yearly. Here, we integrated publicly available genome-wide association studies and transcriptomic data to prioritize candidate genes associated with resistance to Cadophora gregata, Fusarium graminearum, Fusarium virguliforme, Macrophomina phaseolina, and Phakopsora pachyrhizi. We identified 188, 56, 11, 8, and 3 high-confidence candidates for resistance to F. virguliforme, F. graminearum, C. gregata, M. phaseolina and P. pachyrhizi, respectively. The prioritized candidate genes are highly conserved in the pangenome of cultivated soybeans and are heavily biased towards fungal species-specific defense response. The vast majority of the prioritized candidate resistance genes are related to plant immunity processes, such as recognition, signaling, oxidative stress, systemic acquired resistance, and physical defense. Based on the number of resistance alleles, we selected the five most resistant accessions against each fungal species in the soybean USDA germplasm. Interestingly, the most resistant accessions do not reach the maximum theoretical resistance potential. Hence, they can be further improved to increase resistance in breeding programs or through genetic engineering. Finally, the coexpression network generated here is available in a user-friendly web application (https://soyfungigcn.venanciogroup.uenf.br/) and an R/Shiny package (https://github.com/almeidasilvaf/SoyFungiGCN) that serve as a public resource to explore soybean-pathogenic fungi interactions at the transcriptional level.

category: plant biology


title: Spatial and Texture Analysis of Root System Architecture with Earth Mover's Distance

abstract:
PurposeRoot system architectures are complex, multidimensional, and challenging to characterize effectively for agronomic and ecological discovery.

MethodsWe propose a new method, Spatial and Texture Analysis of Root SystEm distribution with Earth movers Distance (STARSEED), for comparing root system distributions that incorporates spatial information through a novel application of the Earth Movers Distance (EMD).

ResultsWe illustrate that the approach captures the response of sesame root systems for different genotypes and soil moisture levels. STARSEED provides quantitative and visual insights into changes that occur in root architectures across experimental treatments.

ConclusionSTARSEED can be generalized to other plants and provides insight into root system architecture development and response to varying growth conditions not captured by existing root architecture metrics and models. The code and data for our experiments are publicly available: https://github.com/GatorSense/STARSEED.


title: Spatial and Texture Analysis of Root System Distribution with Earth Mover's Distance (STARSEED)


title: Tomato leaves under stress: A comparison of stress response to mild abiotic stress between a cultivated and a wild tomato species

abstract:
Tomato is one of the most produced crop plants on earth and growing in the fields and greenhouses all over the world. Breeding with known traits of wild species can enhance stress tolerance of cultivated crops. In this study, we investigated responses of the transcriptome as well as primary and secondary metabolites in leaves of a cultivated and a wild tomato to several abiotic stresses such as nitrogen deficiency, chilling or warmer temperatures, elevated light intensities and combinations thereof.

The wild species responded different to varied temperature conditions compared to the cultivated tomato. Nitrogen deficiency caused the strongest responses and induced in particular the secondary metabolism in both species but to much higher extent in the cultivated tomato. Our study supports the potential of a targeted induction of valuable secondary metabolites in green residues of horticultural production, that will otherwise only be composted after fruit harvest. In particular, the cultivated tomato showed a strong induction in the group of mono caffeoylquinic acids in response to nitrogen deficiency. In addition, the observed differences in stress responses between cultivated and wild tomato can lead to new breeding targets for better stress tolerance.


title: An Arabidopsis root phloem pole cell atlas reveals PINEAPPLE genes as transitioners to autotrophy

abstract:
Single cell sequencing has recently allowed the generation of exhaustive root cell atlases. However, some cell types are elusive and remain underrepresented. Here, we use a second- generation single cell approach, where we zoom in on the root transcriptome sorting with specific markers to profile the phloem poles at an unprecedented resolution. Our data highlight the similarities among the developmental trajectories and gene regulatory networks communal to protophloem sieve element (PSE) adjacent lineages in relation to PSE enucleation, a key event in phloem biology.

As a signature for early PSE-adjacent lineages, we have identified a set of DNA-binding with one finger (DOF) transcription factors, the PINEAPPLEs (PAPL), that act downstream of PHLOEM EARLY DOF (PEAR) genes, and are important to guarantee a proper root nutrition in the transition to autotrophy.

Our data provide a holistic view of the phloem poles that act as a functional unit in root development.


title: Mutually Antagonistic Protein Pairs of Cancer

abstract: Switch-like behavior of tumorigenesis could be governed by antagonistic gene and protein pairs with mutual inhibition. Unlike extensive analysis of gene expression, search for protein level antagonistic pairs has been limited. Here, potential cancer type specific antagonist protein pairs with mutual inhibition were obtained from large scale datasets. Cancer samples or cancer types were compared to retrieve potential protein pairs with contrasting differential expression patterns. Analysis of two different protein expression datasets showed that a few proteins participate in most of the mutually antagonistic relationships. Some proteins with highly antagonistic profile were identified, which could not be attained from a differential expression or a correlation based analysis. The antagonistic protein pairs are sparsely connected by molecular interactions. Glioma, melanoma, and cervical cancer, are more frequently associated with antagonistic proteins than most of the other cancer types. Integrative analysis of mutually antagonist protein pairs contributes to our understanding of systems level changes of cancer.

category: systems biology


title: Two microRNA regulatory circuits set start and end times for dendritic arborization of a nociceptive neuron

abstract: Choreographic dendritic arborization takes place within a defined time frame, but the timing mechanism is currently not known. Here, we report that a precisely timed lin-4-lin-14 regulatory circuit triggers an initial dendritic growth activity whereas a precisely timed let-7-lin-41 regulatory circuit signals a subsequent developmental decline in dendritic growth ability, hence restricting dendritic arborization within a defined time frame. Loss-of-function mutations in the lin-4 microRNA gene cause limited dendritic outgrowth whereas loss-of-function mutations in its direct target, the lin-14 transcription factor gene, cause precocious and excessive outgrowth. In contrast, loss-of-function mutations in the let-7 microRNA gene prevent a developmental decline in dendritic growth ability whereas loss-of-function mutations in its direct target, the lin-41 tripartite motif protein gene, cause further decline. lin-4 and let-7 regulatory circuits are expressed at the right place and the right time to set start and end times for PVD dendritic arborization. Replacing the endogenous lin-4 promoter at the lin-4 locus with a late-onset let-7 promoter delays PVD dendrite arborization whereas replacing the endogenous let-7 promoter at the let-7 locus with an early-onset lin-4 promoter causes precocious decline in dendritic growth ability in PVD neurons. We further find that lin-28 acts upstream of let-7 in regulating developmental decline in dendritic growth ability. Our results indicate that the lin-4-lin-14 and the lin-28-let-7-lin-41 regulatory circuits control the timing of PVD dendrite arborization through antagonistic regulation of the DMA-1 receptor level on PVD dendrites.

category: neuroscience


title: SMN controls neuromuscular junction integrity through U7 snRNP

abstract: The neuromuscular junction (NMJ) is an essential synapse for animal survival whose loss is a key hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). While insights into the function of the causative genes implicate RNA dysregulation in NMJ pathogenesis, the RNA-mediated mechanisms controlling the biology of this specialized synapse that go awry in disease remain elusive. Here, we show that activity of the SMA-determining SMN protein in the assembly of U7 small nuclear ribonucleoprotein (snRNP), which functions in the 3-end processing of replication-dependent histone mRNAs, is required for NMJ integrity. AAV9-mediated gene delivery of U7-specific Lsm10 and Lsm11 proteins selectively enhances U7 snRNP assembly, corrects histone mRNA processing defects, and rescues key structural and functional abnormalities of neuromuscular pathology in SMA mice - including NMJ denervation, reduced synaptic transmission, and skeletal muscle atrophy. Furthermore, U7 snRNP dysfunction induced by SMN deficiency drives selective loss of the synaptic organizing protein Agrin at NMJs innervating vulnerable axial muscles of SMA mice, revealing an unanticipated link between U7-dependent histone mRNA processing and motor neuron-derived expression of an essential factor for NMJ biology. Together, these findings establish a direct contribution of U7 snRNP dysfunction to the neuromuscular phenotype in SMA and the requirement of RNA-mediated histone gene regulation for maintaining functional synaptic connections between motor neurons and muscles.


title: Disentangling the flow of signals between populations of neurons

abstract: Technological advances now allow us to record from large populations of neurons across multiple brain areas. These recordings may illuminate how communication between areas contributes to brain function, yet a substantial barrier remains: How do we disentangle the concurrent, bidirectional flow of signals between populations of neurons? We therefore propose here a novel dimensionality reduction framework: Delayed Latents Across Groups (DLAG). DLAG disentangles signals relayed in each direction, identifies how these signals are represented by each population, and characterizes how they evolve within and across trials. We demonstrate that DLAG performs well on synthetic datasets similar in scale to current neurophysiological recordings. Then we study simultaneously recorded populations in primate visual areas V1 and V2, where DLAG reveals signatures of bidirectional yet selective communication. Our framework lays a foundation for dissecting the intricate flow of signals across populations of neurons, and how this signaling contributes to cortical computation.


title: Weakly activated core inflammation pathways were identified as a central signaling mechanism contributing to the chronic neurodegeneration in Alzheimer's disease

abstract: Neuro-inflammation signaling has been identified as an important hallmark of Alzheimers disease (AD) in addition to amyloid {beta} plaques (A{beta}) and neurofibrillary tangles (NFTs). However, our knowledge of neuro-inflammation is very limited; and the core signaling pathways associated with neuro-inflammation are missing. From a novel perspective, i.e., investigating weakly activated molecular signals (rather than the strongly activated molecular signals), in this study, we uncovered the core neuro-inflammation signaling pathways in AD. Our novel hypothesis is that weakly activated neuro-inflammation signaling pathways can cause neuro-degeneration in a chronic process; whereas, strongly activated neuro-inflammation often cause acute disease progression like in COVID-19. Using the two large-scale genomics datasets, i.e., Mayo Clinic (77 control and 81 AD samples) and RosMap (97 control and 260 AD samples), our analysis identified 7 categories of signaling pathways implicated on AD and related to virus infection: immune response, x-core signaling, apoptosis, lipid dysfunctional, biosynthesis and metabolism, and mineral absorption signaling pathways. More interestingly, most of genes in the virus infection, immune response and x-core signaling pathways, are associated with inflammation molecular functions. Specifically, the x-core signaling pathways were defined as a group of 9 signaling proteins: MAPK, Rap1, NF-kappa B, HIF-1, PI3K-Akt, Wnt, TGF-beta, Hippo and TNF, which indicated the core neuro-inflammation signaling pathways responding to the low-level and weakly activated inflammation and hypoxia, and leading to the chronic neuro-degeneration. The core neuro-inflammation signaling pathways can be used as novel therapeutic targets for effective AD treatment and prevention.


title: Explainable Machine Learning Analysis Reveals Gender Differences in the Phenotypic and Neurobiological Markers of Cannabis Use Disorder

abstract:
BackgroundCannabis Use Disorder (CUD) has been linked to environmental, personality, mental health, neurocognitive and neurobiological risk factors. While many studies have revealed gender differences in CUD, the relative importance of these complex factors by gender has not been described.

MethodsWe conducted a data-driven examination of gender differences in CUD in a community sample of young adults (Human Connectome Project [HCP]; n = 1204, 54% female). We employed state-of-the-art machine learning methods [gradient tree boosting, XGBoost] in combination with novel factor ranking tools [SHapleys Additive exPlanations (SHAP)] as an  explainable machine learning approach in the multimodal data collected by the HCP (phenotypic and brain data).

ResultsWe were able to successfully classify both cannabis dependence and cannabis use levels. Previously identified environmental, personality, mental health, neurocognitive, and brain factors highly contributed to the classification. Predominantly-male risk factors included personality (high openness), mental health (high externalizing, high childhood conduct disorder, high fear somaticism), neurocognitive (impulsive delay discounting, slow working memory performance) and brain (low hippocampal volume) factors. Conversely, predominantly-female risk factors included environmental (low education level, low instrumental support) factors.

ConclusionsOur data-driven analysis of gender differences in the multimodal risk factors underlying cannabis dependence and use levels demonstrate that environmental factors contribute more strongly to CUD in women, whereas individual factors such as personality, mental health and neurocognitive factors have a larger importance in men. This warrants further investigations, and suggests the importance of understanding how these differences relate to the development of effective treatment approaches.


title: Programming isotype specific plasma cell differentiation

abstract: Antibodies are produced across multiple isotypes with distinct properties that coordinate initial antigen clearance and confer long-term antigen-specific immune protection. Here, we interrogate the molecular programs of isotype-specific murine plasma cells (PC) following helper T cell dependent immunization and within established steady-state immunity. Using integrated single cell strategies, we reveal conserved and divergent components of the rapid effector phase of antigen-specific IgM+ versus inflammation modulating programs dictated by IgG2a/b+ PC differentiation. During antibody affinity maturation, the germinal center (GC) cycle imparts separable programs for post-GC inhibitory IgG1+ and inflammatory IgG2a/b+ PC to direct long-term cellular function. In the steady-state, two subsets of IgM+ and separate IgG2b+ PC programs clearly segregate from splenic IgA+ PC programs that emphasize mucosal barrier protection. These diverse isotype-specific molecular pathways of PC differentiation control complementary modules of antigen clearance and immune protection that could be selectively targeted for immunotherapeutic applications and vaccine design.


title: Cell size matters: nano- and micro-plastics preferentially drive declines of large marine phytoplankton due to co-aggregation

abstract: Marine plastic pollution represents a key environmental concern. Whilst ecotoxicological data for plastic is increasingly available, its impact upon marine phytoplankton remains unclear. Owing to their predicted abundance in the marine environment and likely interactions with phytoplankton, here we focus on the smaller fraction of plastic particles ([~]50 nm and [~]2 {micro}m polystyrene spheres). Exposure of natural phytoplankton communities and laboratory cultures revealed that plastic exposure does not follow traditional trends in ecotoxicological research, since large phytoplankton appear particularly susceptible towards plastics exposure despite their higher surface-to-volume ratios. Cell declines appear driven by hetero-aggregation and co-sedimentation of cells with plastic particles, recorded visually and demonstrated using confocal microscopy. As a consequence, plastic exposure also caused disruption to photosynthetic functioning, as determined by both photosynthetic efficiency and high throughput proteomics. Negative effects upon phytoplankton are recorded at concentrations orders of magnitude above those estimated in the environment. Hence, it is likely that impacts of NPs and MPs are exacerbated at the high concentrations typically used in ecotoxicological research (i.e., mg L-1).


title: Population assessment and habitat associations of the Visayan Hornbill Penelopides panini in Northwest Panay, Philippines

abstract:
BackgroundSeven out of 10 hornbill species in the Philippines are threatened with extinction. Among these is the Endangered Visayan hornbill Penelopides panini, found on Panay and Negros islands. Threatened by habitat loss and hunting, its population size is thought to have declined from 1,800 individuals 20 years ago to less than 1,000. However, a recent study on Negros estimated 3,564 individuals across three core forest blocks. This study aims to quantify the Visayan hornbill population size in and around the Northwest Panay Peninsula Natural Park (NWPPNP) on Panay, the largest contiguous low-elevation forest landscape remaining across its range, and its broad habitat associations across a gradient of environmental degradation.

MethodsHornbills were surveyed using 10-minute Distance sampling point counts (n = 362) along transects (average length 1.1 km). Habitat variables were recorded, while habitat was classified into: primary forest, secondary forest, plantation or open habitat. Using Distance software, population densities were estimated for, and post-stratified by habitat, with the overall population estimate taken as a mean of habitat density estimates weighted by habitat area. Using logistic binary regression, hornbill occurrence was modelled against reduced habitat factors extracted from factor analysis of the habitat data.

ResultsSurveys covered 204.4 km2 of the 374.8 km2 Northwest Panay Peninsula. Hornbills were not recorded in plantation or open habitats. The estimated density of hornbills was significantly higher in primary forest (17.7 individuals km-2 {+/-} 29.7% CV) than in secondary forest (5.0 individuals km-2 {+/-} 36.7 %CV; z = 9.538, P < 0.001). The overall population estimate is 2,231 individuals {+/-} 24.4 %CV for the NWPPNP and environs, and 2,949 individuals {+/-} 23.1 %CV for the entire Northwest Panay Peninsula. One habitat factor, described by increasing numbers of large trees, elevation and distance from the Parks boundary, had a significant positive effect in explaining hornbill occurrence, with hornbills significantly more likely to occur in primary forest than the other habitat types.

ConclusionsOur study demonstrates the habitat preference of the Visayan hornbill, highlights the importance of the NWPPNP for the species conservation, and provides strong evidence for re-assessing the global population size.


title: Evaluating host to host transplants as a method to study plant bacterial assembly

abstract: The ability to predict plant microbiome assembly will enable new bacterial-based technologies for agriculture. A major step towards this is quantifying the roles of ecological processes on community assembly. This is challenging, in part because individual plants are colonised by different communities of soil bacteria and it is difficult to estimate if the absence of a given species was a) because it was not present in the soil to colonise a given plant or b) it went locally extinct from competition, predation or similar. To minimise this uncertainty, the authors develop a mesocosm system to study bacterial communities of individual plants by replicated transplantation to a recipient host plant population, ensuring new hosts receive a homogenous species pool for colonisation. We sought to understand which factors affected the transplant and, what the main drivers of variation in the model communities were. A nested factorial design was used to investigate the transplantation of cultured or total, root or leaf associated bacterial communities from donor host species to surrogate host species. Specific metrics were developed to quantify colonisation efficiency of communities. The results show the root communities were more effectively transplanted than leaf communities, with leaf communities more susceptible to contamination. For root communities the strongest driver of beta diversity was the donor host species, and for leaves it was the surrogate host species. Overall, the results reveal that root, but not leaf communities are amenable to transplant reflecting their differing ecological drivers. This work provides the basis to develop a plant microbiome transplant system.


title: Efficient ancestry and mutation simulation with msprime 1.0

abstract: Stochastic simulation is a key tool in population genetics, since the models involved are often analytically intractable and simulation is usually the only way of obtaining ground-truth data to evaluate inferences. Because of this necessity, a large number of specialised simulation programs have been developed, each filling a particular niche, but with largely overlapping functionality and a substantial duplication of effort. Here, we introduce msprime version 1.0, which efficiently implements ancestry and mutation simulations based on the succinct tree sequence data structure and tskit library. We summarise msprimes many features, and show that its performance is excellent, often many times faster and more memory efficient than specialised alternatives. These high-performance features have been thoroughly tested and validated, and built using a collaborative, open source development model, which reduces duplication of effort and promotes software quality via community engagement.


title: Dominating Lengthscales of Zebrafish Collective Behaviour

abstract: Collective behaviour in living systems is observed across many scales, from bacteria to insects, to fish shoals. Zebrafish have emerged as a model system amenable to laboratory study. Here we report a three-dimensional study of the collective dynamics of fifty Zebrafish. We observed the emergence of collective behaviour changing between polarised to randomised, upon adaption to new environmental conditions. We quantify the spatial and temporal correlation functions of the fish and identify two length scales, the persistence length and the nearest neighbour distance, that capture the essence of the behavioural changes. The ratio of the two length scales correlates robustly with the polarisation of collective motion that we explain with a reductionist model of self-propelled particles with alignment interactions.


title: Effect of Vinyl Chloride Exposure on Cardiometabolic Toxicity

abstract: Vinyl chloride is an organochlorine mainly used to manufacture its polymer polyvinyl chloride, which is extensively used in the manufacturing of consumer products. Recent studies suggest that chronic low dose vinyl chloride exposure affects glucose homeostasis in high fat diet-fed mice. Our data suggest that even in the absence of high fat diet, exposure to vinyl chloride (0.8 ppm, 6h/day, 5day/week, for 12 weeks) induces glucose intolerance (1.0 g/kg, i.p) in male C57BL/6 mice. This was accompanied with the depletion of hepatic glutathione and a modest increase in lung interstitial macrophages. Vinyl chloride exposure did not affect the levels of circulating immune cells, endothelial progenitor cells, platelet-immune cell aggregates, and cytokines and chemokines. The acute challenge of vinyl chloride-exposed mice with LPS did not affect lung immune cell composition or plasma IL-6. To examine the effect of vinyl chloride exposure on vascular inflammation and atherosclerosis, LDL receptor-KO mice on C57BL/6 background maintained on western diet were exposed to vinyl chloride for 12 weeks (0.8 ppm, 6h/day, 5day/week). Unlike the WT C57BL/6 mice, vinyl chloride exposure did not affect glucose tolerance in the LDL receptor-KO mice. Plasma cytokines, lesion area in the aortic valve, and markers of lesional inflammation in vinyl chloride-exposed LDL receptor-KO mice were comparable with the air-exposed controls. Collectively, despite impaired glucose tolerance and modest pulmonary inflammation, chronic low dose vinyl chloride exposure does not affect surrogate markers of cardiovascular injury, LPS-induced acute inflammation in C57BL/6 mice, and chronic inflammation and atherosclerosis in the LDL receptor-KO mice.

category: pharmacology and toxicology


title: Only females show a stable association between neuroticism and microstructural asymmetry of the cingulum across childhood and adolescence: A longitudinal DTI study

abstract:
Neuroticism is characterized by a tendency to experience negative and anxious emotions. This personality trait is linked to an increased risk of anxiety and mood disorders. In a cross-sectional 3T diffusion tensor imaging (DTI) study in children and adolescents, we found an association between neuroticism and a relative imbalance between left and right (i.e., asymmetry) fractional anisotropy (FA) in the cingulum and white matter underlying the ventromedial prefrontal cortex with opposite directions in females and males. Here we analyzed the longitudinal follow-up DTI data, which was acquired in 76 typically-developing 7- to 18-year-olds, including up to 11 scans per subject. Neuroticism was assessed up to four times. Our longitudinal DTI measurements substantiate robust associations between higher neuroticism scores and increased left relative to right cingulum FA in females and decreased left relative to right cingulum FA in males. In females, the association was already present in late childhood and with a stable expression across childhood and adolescence. In males, the association gradually emerged during adolescence. Future longitudinal studies should clarify which neurobiological factors (e.g., genetic variation, prenatal stress, sex hormones) contribute to the sex-specific associations in the relationship between neuroticism and interhemispheric microstructural asymmetry of the cingulum.

HighlightO_LIWe analyzed a unique longitudinal DTI dataset covering late childhood and adolescence.
C_LIO_LIIn the cingulum, left-right fractional anisotropy (FA) asymmetry scaled with neuroticism.
C_LIO_LIFemales displayed a stable association of neuroticism with increased cingulum asymmetry.
C_LIO_LIMales showed an association between neuroticism and decreased cingulum FA asymmetry.
C_LIO_LIThe association in males became more accentuated during adolescence
C_LI


title: Pre- and postsynaptically expressed spike-timing-dependent plasticity contribute differentially to neuronal learning

abstract:
A plethora of experimental studies have shown that long-term synaptic plasticity can be expressed pre- or postsynaptically depending on a range of factors such as developmental stage, synapse type, and activity patterns. The functional consequences of this diversity are not clear, although it is understood that whereas postsynaptic expression of plasticity predominantly affects synaptic response amplitude, presynaptic expression alters both synaptic response amplitude and short-term dynamics. In most models of neuronal learning, long-term synaptic plasticity is implemented as changes in connective weights. The consideration of long-term plasticity as a fixed change in amplitude corresponds more closely to post-than to presynaptic expression, which means theoretical outcomes based on this choice of implementation may have a postsynaptic bias. To explore the functional implications of the diversity of expression of long-term synaptic plasticity, we adapted a model of long-term plasticity, more specifically spike-timing-dependent plasticity (STDP), such that it was expressed either independently pre- or postsynaptically, or in a mixture of both ways. We compared pair-based standard STDP models and a biologically tuned triplet STDP model, and investigated the outcomes in a minimal setting, using two different learning schemes: in the first, inputs were triggered at different latencies, and in the second a subset of inputs were temporally correlated. We found that presynaptic changes adjusted the speed of learning, while postsynaptic expression was more efficient at regulating spike timing and frequency. When combining both expression loci, postsynaptic changes amplified the response range, while presynaptic plasticity allowed control over postsynaptic firing rates, potentially providing a form of activity homeostasis. Our findings highlight how the seemingly innocuous choice of implementing synaptic plasticity by single weight modification may unwittingly introduce a postsynaptic bias in modelling outcomes. We conclude that pre- and postsynaptically expressed plasticity are not interchangeable, but enable complimentary functions.

Author summaryDifferences between functional properties of pre- or postsynaptically expressed long-term plasticity have not yet been explored in much detail. In this paper, we used minimalist models of STDP with different expression loci, in search of fundamental functional consequences. Biologically, presynaptic expression acts mostly on neurotransmitter release, thereby altering short-term synaptic dynamics, whereas postsynaptic expression affects mainly synaptic gain. We compared models where plasticity was expressed only presynaptically or postsynaptically, or in both ways. We found that postsynaptic plasticity had a bigger impact over response times, while both pre- and postsynaptic plasticity were similarly capable of detecting correlated inputs. A model with biologically tuned expression of plasticity also completed these tasks over a range of frequencies. Also, postsynaptic spiking frequency was not directly affected by presynaptic plasticity of short-term plasticity alone, however in combination with a postsynaptic component, it helped restrain positive feedback, contributing to activity homeostasis. In conclusion, expression locus may determine affinity for distinct coding schemes while also contributing to keep activity within bounds. Our findings highlight the importance of carefully implementing expression of plasticity in biological modelling, since the locus of expression may affect functional outcomes in simulations.


title: Protein disulphide isomerase (PDI) is protective against several types of DNA damage, including that induced by amyotrophic lateral sclerosis-associated mutant TDP-43 in neuronal cells/ in vitro models

abstract: Protein disulphide isomerase (PDI) is a chaperone that catalyses the formation of thiol-disulphide bonds during protein folding. Whilst up-regulation of PDI is a protective mechanism to regulate protein folding, an increasingly wide range of cellular functions have been ascribed to PDI. Originally identified in the endoplasmic reticulum (ER), PDI has now been detected in many cellular locations, including the nucleus. However, its role in this cellular compartment remains undefined. PDI is implicated in multiple diseases, including amyotrophic lateral sclerosis (ALS), a fatal and rapidly progressing neurodegenerative condition affecting motor neurons. Loss of essential proteins from the nucleus is an important feature of ALS. This includes TAR DNA-binding protein-43 (TDP-43), a DNA/RNA binding protein present in a pathological form in the cytoplasm in almost all (97%) ALS cases, that is also mutated in a proportion of familial cases. PDI is protective against disease-relevant phenotypes associated with dysregulation of protein homeostasis (proteostasis) in ALS. DNA damage is also increasingly linked to ALS, which is induced by pathological forms of TDP-43 by impairment of its normal function in the non-homologous end-joining (NHEJ) mechanism of DNA repair. However, it remains unclear whether PDI is protective against DNA damage in ALS. In this study we demonstrate that PDI was protective against several types of DNA damage, induced by either etoposide, hydrogen peroxide (H2O2), or ALS-associated mutant TDP-43M337V in neuronal cells. This was demonstrated using widely used DNA damage markers, phosphorylated H2AX and 53BP1, which is specific for NHEJ. Moreover, we also show that PDI translocates into the nucleus following DNA damage. Here PDI is recruited directly to sites of DNA damage, implying that it has a direct role in DNA repair. This study therefore identifies a novel role of PDI in the nucleus in preventing DNA damage.


title: Neck motor unit activity displays neural signatures of temporal control during sequential saccade planning

abstract: Goal-directed behavior involves the transformation of neural movement plans into appropriate muscle activity patterns. Studies involving single saccades have shown that a rapid, direct pathway links saccade planning in frontal eye fields (FEF) to neck muscle activity. It is unknown if the rapid connection between FEF and neck muscle is maintained during sequential saccade planning. We show that sequence planning signals in the FEF are preserved in the neck EMG, although the activity is delayed specifically for the second saccade. Our results suggest that while the direct link between FEF and neck muscle facilitates downstream continuation of FEF response patterns, an indirect route exists through an inhibitory control center like the basal ganglia, limiting the information flow during processing of saccade sequences. Thus, the indirect and direct pathways from the FEF may function together to enable rapid synchronous, but controlled eye-head responses to sequential gaze shifts.


title: Sequential Transmission of Task-Relevant Information in Cortical Neuronal Networks

abstract: During auditory task performance, cortical processing of task-relevant information enables mammals to recognize sensory input and flexibly select behavioral responses. In mouse auditory cortex, small neuronal networks encode behavioral choice during a pure-tone detection task, but it is poorly understood how neuronal networks encode behavioral choice during a pure-tone discrimination task where tones have to be categorized into targets and non-targets. While the interactions between networked neurons are thought to encode behavioral choice, it remains unclear how patterns of neuronal network activity indicate the transmission of task-relevant information within the network. To this end, we trained mice to behaviorally discriminate target vs. non-target pure-tones while we used in vivo 2-photon imaging to record neuronal population activity in primary auditory cortex layer 2/3. We found that during task performance, a specialized subset of neurons transiently encoded intersection information, i.e., sensory information that was used to inform behavioral choice. Granger causality analysis showed that these neurons formed functional networks in which task-relevant information was transmitted sequentially between neurons. Differences in network structure between target and non-target sounds encoded behavioral choice. Correct behavioral choices were associated with shorter timescale communication between neurons. In summary, we find that specialized neuronal populations in auditory cortex form functional networks during auditory task performance whose structures depend on both sensory input and behavioral choice.


title: Stability of spectral estimates in resting-state magnetoencephalography: recommendations for minimal data duration with neuroanatomical specificity

abstract: The principle of resting-state paradigms is appealing and practical for collecting data from impaired patients and special populations, especially if data collection times can be minimized. To achieve this goal, researchers need to ensure estimated signal features of interest are robust. In electro- and magnetoencephalography (EEG, MEG) we are not aware of studies of the minimal length of recording required to yield a robust one-session snapshot of the frequency-spectrum derivatives that are typically used to characterize the complex dynamics of the brains resting-state. We aimed to fill this knowledge gap by studying the stability of common spectral measures of resting-state MEG source time series obtained from large samples of single-session recordings from shared data repositories featuring different recording conditions and instrument technologies (OMEGA: N = 107; Cam-CAN: N = 50). We discovered that the rhythmic and arrhythmic spectral properties of intrinsic brain activity can be robustly estimated in most cortical regions when derived from relatively short recordings of 30-s to 120-s of resting-state data, regardless of instrument technology and resting-state paradigm. Using an adapted leave-one-out approach and Bayesian analysis, we also provide evidence that the stability of spectral features over time is unaffected by age, sex, handedness, and general cognitive function. In summary, short MEG sessions are sufficient to yield robust estimates of frequency-defined brain activity during resting-state. This study may help guide future empirical designs in the field, particularly when recording times need to be minimized, such as with patient or special populations.


title: Awake perception is associated with dedicated neuronal assemblies in cerebral cortex

abstract:
Neural activity in sensory cortex combines stimulus responses and ongoing activity, but it remains unclear whether they reflect the same underlying dynamics or separate processes. Here we show that during wakefulness, the neuronal assemblies evoked by sounds in the auditory cortex and thalamus are specific to the stimulus and distinct from the assemblies observed in ongoing activity. In contrast, during anesthesia, evoked assemblies are indistinguishable from ongoing assemblies in cortex, while they remain distinct in the thalamus. A strong remapping of sensory responses accompanies this dynamical state change produced by anesthesia. Together, these results show that the awake cortex engages dedicated neuronal assemblies in response to sensory inputs, which we suggest is a network correlate of sensory perception.

One-Sentence SummarySensory responses in the awake cortex engage specific neuronal assemblies that disappear under anesthesia.


title: Age differences in aperiodic neural activity measured with resting EEG

abstract: Previous research using electroencephalography (EEG) and magnetoencephalography (MEG) has shown that neural oscillatory activity within the alpha band (8-12 Hz) becomes slower and lower in amplitude with advanced age. However, most studies have focused on quantifying age-related differences in periodic oscillatory activity with little consideration of the influence of aperiodic activity on these measures. The aim of this study was to investigate age differences in aperiodic activity inherent in the resting EEG signal. We assessed aperiodic activity in 85 healthy younger adults (mean age: 22.2 years, SD: 3.9, age range: 18-35, 37 male) and 92 healthy older adults (mean age: 66.1 years, SD: 8.2, age range 50-86, 53 male) by fitting the 1/f-like background activity evident in EEG power spectra using the fitting oscillations & one over f (FOOOF) toolbox. Across the scalp, the aperiodic exponent and offset were smaller in older compared to younger participants, reflecting a flatter 1/f-like slope and a downward broadband shift in the power spectra with age. Before correcting for aperiodic activity, older adults showed slower peak alpha frequency and reduced peak alpha power relative to younger adults. After correcting for aperiodic activity, peak alpha frequency remained slower in older adults; however, peak alpha power no longer differed statistically between age groups. The large sample size utilized in this study, as well as the depth of analysis, provides further evidence that the aperiodic component of the resting EEG signal is altered with aging and should be considered when investigating neural oscillatory activity.


title: VaxArray Immunoassay for the Multiplexed Quantification of Poliovirus D-Antigen

abstract: Next generation poliovirus vaccines are critical to reaching global poliovirus eradication goals. Recent efforts have focused on creating inactivated vaccines using attenuated Sabin strains that maintain patient safety benefits and immunogenicity of conventional inactivated vaccines while increasing manufacturing safety and lowering production costs, and on developing novel oral vaccines using modified Sabin strains that provide critical mucosal immunity but are further attenuated to minimize risk of reversion to neurovirulence. In addition, there is a push to improve the analytical tools for poliovirus vaccine characterization. Conventional and Sabin inactivated poliovirus vaccines typically rely on standard plate-based ELISA as in vitro D-antigen potency assays in combination with WHO international standards as calibrants. While widely utilized, the current D-antigen ELISA assays have a long time to result (up to 72 hours), can suffer from lab-to-lab inconsistency due to non-standardized protocols and reagents, and are inherently singleplex. For D-antigen quantitation, we have developed the VaxArray Polio Assay Kit, a multiplexed, microarray-based immunoassay that uses poliovirus-specific human monoclonal antibodies currently under consideration as standardized reagents for characterizing inactivated Sabin and Salk vaccines. The VaxArray assay can simultaneously quantify all 3 poliovirus serotypes with a time to result of less than 3 hours. Here we demonstrate that the assay has limits of quantification suitable for both bioprocess samples and final vaccines, excellent reproducibility and precision, and improved accuracy over an analogous plate-based ELISA. The assay is suitable for adjuvanted combination vaccines, as common vaccine additives and crude matrices do not interfere with quantification, and is intended as a high throughput, standardized quantitation tool to aid inactivated poliovirus vaccine manufacturers in streamlining vaccine development and manufacturing, aiding the global polio eradication effort.


title: The Correlation Between Cell and Nucleus Size is Explained by an Eukaryotic Cell Growth Model

abstract:
In eukaryotes, the cell volume is observed to be strongly correlated with the nuclear volume. The slope of this correlation depends on the cell type, growth condition, and the physical environment of the cell. We develop a computational model of cell growth and proteome increase, incorporating the kinetics of amino acid import, protein/ribosome synthesis and degradation, and active transport of proteins between the cytoplasm and the nucleoplasm. We also include a simple model of ribosome biogenesis and assembly. Results show that the cell volume is tightly correlated with the nuclear volume, and the cytoplasm-nucleoplasm transport rates strongly influences the cell growth rate as well as the cytoplasm/nucleoplasm ratio. Ribosome assembly and the ratio of ribosomal proteins to mature ribosomes also influence the cell volume and the cell growth rate. We find that in order to regulate the cell growth rate and the cytoplasm/nucleoplasm ratio, the cell must optimally control groups of kinetic parameters together, which could explain the quantitative roles of canonical growth pathways. Finally, using an extension of our model and single cell RNAseq data, it is possible to construct a detailed proteome distribution, provided that a quantitative cell division mechanism is known.

Author summaryWe develop computational model of cell proteome increase and cell growth to compute the cell volume to nuclear volume ratio. The model incorporates essential kinetics of protein and ribosome synthesis/degradation, and their transport across the nuclear envelope. The model also incorporates ribosome biogenesis and assembly. The model identifies the most important parameters in determining the cell growth rate and the nucleoplasm/cytoplasm ratio, and provides a computational starting point to construct the cell proteome based on the RNAseq data.

category: cell biology


title: Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis

abstract:
Amino acid metabolism in vascular endothelium is important for sprouting angiogenesis. SLC38A5 (solute carrier family 38 member 5), an amino acid (AA) transporter, shuttles neutral AAs across cell membrane, including glutamine, which may serve as metabolic fuel for proliferating endothelial cells (ECs) to promote angiogenesis. Here we found that Slc38a5 is highly enriched in normal retinal vascular endothelium, and more specifically in pathological sprouting neovessels. Slc38a5 is suppressed in retinal blood vessels from Lrp5-/- and Ndpy/- mice, both genetic models of defective retinal vascular development with Wnt signaling mutations. Additionally, Slc38a5 transcription is directly regulated by Wnt/{beta}-catenin signaling. Genetic deficiency of Slc38a5 in mice substantially delays retinal vascular development and suppresses pathological neovascularization in oxygen-induced retinopathy modeling ischemic proliferative retinopathies. Inhibition of SLC38A5 in retinal vascular ECs impairs EC proliferation and angiogenic function, suppresses glutamine uptake, and dampens vascular endothelial growth factor receptor 2 (VEGFR2). Together these findings suggest that SLC38A5 is a new metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in ECs.

Significance StatementAmino acid metabolism in vascular endothelium is important for angiogenesis. SLC38A5 (solute carrier family 38 member 5) is an amino acid (AA) transporter for shuttling neutral AAs such as glutamine across cell membrane. Our work demonstrate that Slc38a5 is highly enriched in retinal vascular endothelium. SLC38A5 regulates endothelial cell glutamine uptake and vascular growth factor receptors to impact blood vessels growth in retinal development and in retinopathies. This work uncovered a novel role of SLC38A5 as a metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in blood vessel endothelium. Findings from this study also suggest that targeting SLC38A5 or relevant AAs can be a new way to protect against retinopathy.

category: developmental biology


title: Chronic Benzene Exposure Aggravates Pressure Overload-Induced Cardiac Dysfunction

abstract: Benzene is a ubiquitous environmental pollutant abundant in household products, petrochemicals and cigarette smoke. Benzene is a well-known carcinogen in humans and experimental animals; however, little is known about the cardiovascular toxicity of benzene. Recent population-based studies indicate that benzene exposure is associated with an increased risk for heart failure. Nonetheless, it is unclear whether benzene exposure is sufficient to induce and/or exacerbate heart failure. We examined the effects of benzene (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on transverse aortic constriction (TAC)-induced pressure overload in male C57BL/6J mice. Our data show that benzene exposure had no effect on cardiac function in the Sham group; however, it significantly compromised cardiac function as depicted by a significant decrease in fractional shortening and ejection fraction, as compared with TAC/Air-exposed mice. RNA-seq analysis of the cardiac tissue from the TAC/benzene-exposed mice showed a significant increase in several genes associated with adhesion molecules, cell-cell adhesion, inflammation, and stress response. In particular, neutrophils were implicated in our unbiased analyses. Indeed, immunofluorescence studies showed that TAC/benzene exposure promotes infiltration of CD11b+/S100A8+/myeloperoxidase+-positive neutrophils in the hearts by 3-fold. In vitro, the benzene metabolites, hydroquinone and catechol, induced the expression of P-selectin in cardiac microvascular endothelial cells by 5-fold and increased the adhesion of neutrophils to these endothelial cells by 1.5-2.0-fold. Benzene metabolite-induced adhesion of neutrophils to the endothelial cells was attenuated by anti-P-selectin antibody. Together, these data suggest that benzene exacerbates heart failure by promoting endothelial activation and neutrophil recruitment.


title: Analysis of changes occurring in Codon Positions due to mutations through the cellular automata transition rules

abstract: Variation in the nucleotides of a codon may cause variations in the evolutionary patterns of a DNA or amino acid sequence. To address the capability of each position of a codon to have non-synonymous mutations, the concept of degree of mutation has been introduced. The degree of mutation of a particular position of codon defines the number of non-synonymous mutations occurring for the substitution of nucleotides at each position of a codon, when other two positions of that codon remain unaltered. A Cellular Automaton (CA), is used as a tool to model the mutations of any one of the four DNA bases A, C, T and G at a time where the DNA bases correspond to the states of the CA cells. Point mutation (substitution type) of a codon which characterizes changes in the amino acids, have been associated with local transition rules of a CA. Though there can be [Formula] transitions of a 4-state CA with 3-neighbourhood cells, here it has been possible to represent all possible point mutations of a codon in terms of combinations of 16 local transition functions of the CA. Further these rules are divided into 4 classes of equivalence. Also, according to the nature of mutations, the 16 local CA rules of substitutions are classified into 3 sets namely,  No Mutation,  Transition and  Transversion. The experiment has been carried out with three sets of single nucleotide variations(SNVs) of three different viruses but the symptoms of the diseases caused by them are to some extent similar to each other. They are SARS-CoV-1, SARS-CoV-2 and H1N1 Type A viruses. The aim is to understand the impact of nucleotide substitutions at different positions of a codon with respect to a particular disease phenotype.


title: DNA as a Recyclable Natural Polymer

abstract: Nature has the ability of circularly re-using its components to produce molecules and materials it needs. An example is the ability of most living organisms of digesting proteins they feed off into amino acids and then using such amino acids in the ribosomal synthesis of new proteins. Recently, we have shown that such recycling of proteins can be reproduced outside living organisms. The key proteins feature that allows for this type of recycling is their being sequence-defined polymers. Arguably, Natures most famous sequence-defined polymer is DNA. Here we show that it is possible starting from sheared calf-DNA to obtain all the four nucleotides as monophosphate-nucleotides (dNMPs). These dNMPs were phosphorylated in a one-pot, multi-enzymes, phosphorylation reaction to generate triphosphate-nucleotides (dNTPs). Finally, we used the dNTPs so achieved (with a global yield of [~]60%) as reagents for PCR (polymerase chain reaction) to produce target DNA strands, and for the diagnose of targeted DNA by quantitative PCR (qPCR). This approach is an efficient, convenient, and environmentally friendly way to produce dNTPs and DNA through recycling according to the paradigm of circular economy.

category: biochemistry


title: An integrated pipeline and multi-model graphical user interface for accurate nano-dosimetry

abstract: Accurate dosing of nanoparticles is crucial for risk assessment and for their safe use in medical and other applications. Although it is well-known that nanoparticles sediment, diffuse and aggregate as they move through a fluid, and that therefore the effective dose perceived by cells may not necessarily be that initially administered, dose quantification remains a challenge. This is because to date, methods for accurate dose estimation are difficult to implement, involving precise characterization of the nanomaterial and the exposure system as well as complex mathematical operations. Here we present a pipeline for accurate nano-dosimetry of engineered nanoparticles on cell monolayers, based on an easy-to-use graphical software - DosiGUI - which integrates two well-established particokinetic and particodynamic models. DosiGUI is an open source tool which was developed to facilitate nano-dosimetrics. The pipeline includes methods for determining the stickiness index which describes the affinity between nanoparticles and cells. Our results show that accurate estimations of the effective dose cannot prescind from rigorous characterization of the stickiness index, which depends on both nanoparticle characteristics and cell type.


title: Cell types and clonal relations in the mouse brain revealed by single-cell and spatial transcriptomics

abstract: The mammalian brain contains a large number of specialized cells that develop from a thin sheet of neuroepithelial progenitor cells1,2. Recently, high throughput single-cell technologies have been used to define the molecular diversity of hundreds of cell types in the nervous system3,4. However, the lineage relationships between mature brain cells and progenitor cells are not well understood, because transcriptomic studies do not allow insights into clonal relationships and classical fate-mapping techniques are not scalable5,6. Here we show in vivo barcoding of early progenitor cells that enables simultaneous profiling of cell phenotypes and clonal relations in the mouse brain using single-cell and spatial transcriptomics. We reconstructed thousands of clones to uncover the existence of fate-restricted progenitor cells in the mouse hippocampal neuroepithelium and show that microglia are derived from few primitive myeloid precursors that massively expand to generate widely dispersed progeny. By coupling spatial transcriptomics with clonal barcoding, we disentangle migration patterns of clonally related cells in densely labelled tissue sections. Compared to classical fate mapping, our approach enables high-throughput dense reconstruction of cell phenotypes and clonal relations at the single-cell and tissue level in individual animals and provides an integrated approach for understanding tissue architecture.


title: Scale Invariance in fNIRS as a Measurement of Cognitive Load

abstract:
Scale invariant neural dynamics are a relatively new but effective means of measuring changes in brain states as a result of varied cognitive load and task difficulty. This study is the first to test whether scale invariance (as measured by the Hurst exponent, H) can be used with functional near-infrared spectroscopy (fNIRS) to quantify cognitive load. We analyzed H extracted from the fNIRS time series while participants completed an N-back working memory task. Consistent with what has been demonstrated in fMRI, the current results showed that scale-invariance analysis significantly differentiated between task and rest periods as calculated from both oxy- (HbO) and deoxy-hemoglobin (HbR) concentration changes. Results from both channel-averaged H and a multivariate partial least squares approach (Task PLS) demonstrated higher H during the 1-back task than the 2-back task. These results were stronger for H derived from HbR than from HbO. As fNIRS is relatively portable and robust to motion-related artifacts, these preliminary results shed light on the promising future of measuring cognitive load in real life settings.

Author SummaryScale invariance reflects a pattern of self-similarity (or fractalness) across a time series of brain data. In human neuroscience studies using EEG and fMRI, higher scale invariance has been associated with individuals being in a state of minimal cognitive effort or while performing a relatively easy task compared to doing something more challenging. Functional near-infrared spectroscopy (fNIRS) is a flexible neuroimaging technique that can be used in naturalistic settings and measures the same underlying biological signal as fMRI. We expected that, if scale invariant brain states are indeed robust indicators of cognitive load or task difficulty, we should be able to replicate previous findings in fNIRS. Consistent with this hypothesis, we find that more scale invariant brain states are indeed associated with less cognitively demanding and more restful brain states in fNIRS data. This finding opens up a wide array of potential applications for monitoring cognitive load and fatigue in real-life settings, such as during driving, learning in schools, or during interpersonal interactions.


title: Refining epileptogenic high-frequency oscillations using deep learning: a reverse engineering approach

abstract:
Intracranially-recorded interictal high-frequency oscillations (HFOs) have been proposed as a promising spatial biomarker of the epileptogenic zone. However, visual verification of HFOs is time-consuming and exhibits poor inter-rater reliability. Furthermore, no method is currently available to distinguish HFOs generated from the epileptogenic zone (epileptogenic HFOs: eHFOs) from those generated from other areas (non-epileptogenic HFOs: non-eHFOs). To address these issues, we constructed a deep learning (DL)-based algorithm using HFO events from chronic intracranial electroencephalogram (iEEG) data via subdural grids from 19 children with medication-resistant neocortical epilepsy to: 1) replicate human expert annotation of artifacts and HFOs with or without spikes, and 2) discover eHFOs by designing a novel weakly supervised model (HFOs from the resected brain regions are initially labeled as eHFOs, and those from the preserved brain regions as non-eHFOs). The "purification power" of DL is then used to automatically relabel the HFOs to distill eHFOs. Using 12,958 annotated HFO events from 19 patients, the model achieved 96.3% accuracy on artifact detection (F1 score = 96.8%) and 86.5% accuracy on classifying HFOs with or without spikes (F1 score = 80.8%) using patient-wise cross-validation. Based on the DL-based algorithm trained from 84,602 HFO events from nine patients who achieved seizure-freedom after resection, the majority of such DL-discovered eHFOs were found to be HFOs with spikes (78.6%, p < 0.001). While the resection ratio of detected HFOs (number of resected HFOs/number of detected HFOs) did not correlate significantly with post-operative seizure freedom (the area under the curve [AUC]=0.76, p=0.06), the resection ratio of eHFOs positively correlated with post-operative seizure freedom (AUC=0.87, p=0.01). We discovered that the eHFOs had a higher signal intensity associated with ripple (80-250 Hz) and fast ripple (250-500 Hz) bands at the HFO onset and with a lower frequency band throughout the event time window (the inverted T-shaped), compared to non-eHFOs. We then designed perturbations on the input of the trained model for non-eHFOs to determine the models decision-making logic. The model probability significantly increased towards eHFOs by the artificial introduction of signals in the inverted T-shaped frequency bands (mean probability increase: 0.285, p < 0.001), and by the artificial insertion of spike-like signals into the time domain (mean probability increase: 0.452, p < 0.001). With this DL-based framework, we reliably replicated HFO classification tasks by human experts. Using a reverse engineering technique, we distinguished eHFOs from others and identified salient features of eHFOs that aligned with current knowledge.

Graphical abstract

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title: Early post-infection treatment of SARS-CoV-2 infected macaques with human convalescent plasma with high neutralizing activity reduces lung inflammation

abstract:
Early in the SARS-CoV-2 pandemic, there was a high level of optimism based on observational studies and small controlled trials that treating hospitalized patients with convalescent plasma from COVID-19 survivors (CCP) would be an important immunotherapy. However, as more data from controlled trials became available, the results became disappointing, with at best moderate evidence of efficacy when CCP with high titers of neutralizing antibodies was used early in infection. To better understand the potential therapeutic efficacy of CCP, and to further validate SARS-CoV-2 infection of macaques as a reliable animal model for testing such strategies, we inoculated 12 adult rhesus macaques with SARS-CoV-2 by intratracheal and intranasal routes. One day later, 8 animals were infused with pooled human CCP with a high titer of neutralizing antibodies (RVPN NT50 value of 3,003), while 4 control animals received normal human plasma. Animals were monitored for 7 days. Animals treated with CCP had detectable levels of antiviral antibodies after infusion. In comparison to the control animals, they had similar levels of virus replication in the upper and lower respiratory tract, but had significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. By highlighting strengths and weaknesses, data of this study can help to further optimize nonhuman primate models to provide proof-of-concept of intervention strategies, and guide the future use of convalescent plasma against SARS-CoV-2 and potentially other newly emerging respiratory viruses.

Author summaryThe results of treating SARS-CoV-2 infected hospitalized patients with COVID-19 convalescent plasma (CCP), collected from survivors of natural infection, have been disappointing. The available data from various studies indicate at best moderate clinical benefits only when CCP with high titer of neutralizing antibodies was infused early in infection. The macaque model of SARS-CoV-2 infection can be useful to gain further insights in the value of CCP therapy. In this study, animals were infected with SARS-CoV-2 and the next day, were infused with pooled human convalescent plasma, selected to have a very high titer of neutralizing antibodies. While administration of CCP did not result in a detectable reduction in virus replication in the respiratory tract, it significantly reduced lung inflammation. These data, combined with the results of monoclonal antibody studies, emphasize the need to use products with high titers of neutralizing antibodies, and guide the future development of CCP-based therapies.

category: immunology