title: 'Resistance is futile': Weaker selection for resistance during larger epidemics further increases prevalence and depresses host density

abstract: What determines how much resistance hosts evolve? One might intuit that hosts evolve higher resistance when parasites are more abundant. However, the opposite pattern can arise due to costs of resistance. Here we illustrate with mathematical, experimental, and field approaches how ecological context can increase parasite abundance and select for lower resistance.  Resistance is futile when all host genotypes become sufficiently infected. To make this argument, we first analyzed an eco-evolutionary model of parasites, hosts, and hosts resources. We determined eco-evolutionary outcomes for resistance (mathematically, transmission rate) and densities along gradients that drive epidemic size. When epidemic drivers are high, hosts evolve lower resistance, amplifying epidemics and decreasing host density. Experimental mesocosms qualitatively agreed. In the experiment, higher supply of nutrients drove larger epidemics of survival-reducing fungal parasites. Evolving zooplankton hosts were less resistant at high nutrients than at low. Less resistance, in turn, was associated with higher infection prevalence and lower host density. We also analyzed the size of naturally occurring epidemics, finding a broad, bimodal distribution of epidemic sizes consistent with the eco-evolutionary model. Together, our three approaches supported predictions that high epidemic drivers lead to evolution of lower resistance which drives higher prevalence and lower host density.

category: evolutionary biology


title: Parthenogenesis and the Evolution of Anisogamy

abstract: Recently, it was pointed out [1] that classic models for the evolution of anisogamy do not take into account the possibility of parthenogenetic reproduction, even though sex is facultative in many relevant taxa (e.g. algae) that harbour both anisogamous and isogamous species. Here we complement the analysis of [1] with an approach where we assume that the relationship between progeny size and its survival may differ between parthenogenetically and sexually produced progeny, favouring either the former or the latter. We show that the findings of [1], that parthenogenesis can stabilise isogamy relative to the obligate sex case, extend to our scenarios. We additionally investigate two different ways for one mating type to take over the entire population. First, parthenogenesis can lead to biased sex ratios that are sufficiently extreme that one type can displace the other, leading to de facto asexuality for the remaining type that now lacks partners to fuse with. This process involves positive feedback: microgametes, being numerous, lack opportunities for syngamy, and should they proliferate parthenogenetically, the next generation makes this asexual route even more prominent for microgametes. Second, we consider mutations to strict asexuality in producers of micro- or macrogametes, and show that the prospects of asexual invasion depend strongly on the mating type in which the mutation arises. Perhaps most interestingly, we also find scenarios in which parthenogens have an intrinsic survival advantage yet facultatively sexual isogamous populations are robust to the invasion of asexuals, despite us assuming no genetic benefits of recombination. Here equal contribution from both mating types to zygotes that are sufficiently well provisioned can outweigh the additional costs associated with syngamy.


title: Sexual selection in females across the animal tree of life

abstract: The pioneers of sexual selection theory proposed that males are generally  eager whereas females are rather  coy with respect to mating. This male-centred perspective on sexual selection continues to permeate our perception of sex differences across disciplines. Despite an increased awareness that females also compete for mating partners, we still tend to consider sexual selection in females a rare peculiarity. Here we present meta-analytic evidence from 72 species across a broad range of animal taxa to show that sexual selection in females is widespread and should be considered the norm rather than the exception. Thereby, our results extend our general understanding of sexual reproduction and may contribute to a more balanced perspective of how sexual selection operates in both males and females.


title: Increased biosynthesis of acetyl-CoA in the yeast Saccharomyces cerevisiae by overexpression of a deregulated pantothenate kinase gene

abstract:
Coenzyme A (CoA) and its derivatives such as acetyl-CoA are essential metabolites for several biosynthetic reactions. In the yeast S. cerevisiae, five enzymes (encoded by essential genes CAB1-CAB5; coenzyme A biosynthesis) are required to perform CoA biosynthesis from pantothenate, cysteine and ATP. Similar to enzymes from other eukaryotes, yeast pantothenate kinase (PanK, encoded by CAB1) turned out to be inhibited by acetyl-CoA. By genetic selection of intragenic suppressors of a temperature-sensitive cab1 mutant combined with rationale mutagenesis of the presumed acetyl-CoA binding site within PanK, we were able to identify the variant CAB1 W331R, encoding a hyperactive PanK completely insensitive to inhibition by acetyl-CoA. Using a versatile gene integration cassette containing the TPI1 promoter, we constructed strains overexpressing CAB1 W331R in combination with additional genes of CoA biosynthesis (CAB2, CAB3, HAL3, CAB4 and CAB5). In these strains, the level of CoA nucleotides was 15-fold increased, compared to a reference strain without additional CAB genes. Overexpression of wild-type CAB1 instead of CAB1 W331R turned out as substantially less effective (4-fold increase of CoA nucleotides). Supplementation of overproducing strains with additional pantothenate could further elevate the level of CoA (2.3-fold). Minor increases were observed after overexpression of FEN2 (encoding a pantothenate permease) and deletion of PCD1 (CoA-specific phosphatase). We conclude that the strategy described in this work may improve the efficiency of biotechnological applications depending on acetyl-CoA.

Key pointsO_LIA gene encoding a hyperactive yeast pantothenate kinase (PanK) was constructed.
C_LIO_LIOverexpression of CoA biosynthetic genes elevated CoA nucleotides 15-fold.
C_LIO_LISupplementation with pantothenate further increased the level of CoA nucleotides.
C_LI

category: bioengineering


title: Correcting differential gene expression analysis for cyto-architectural alterations in substantia nigra of Parkinson's disease patients reveals known and potential novel disease-associated genes and pathways

abstract:
Several studies have analyzed gene expression profiles in the substantia nigra to better understand the pathological mechanisms causing Parkinsons disease (PD). However, the concordance between the identified gene signatures in these individual studies was generally low. This might be caused by a change in cell type composition as loss of dopaminergic neurons in the substantia nigra pars compacta is a hallmark of PD. Through an extensive meta-analysis of nine previously published microarray studies, we demonstrated that a big proportion of the detected differentially expressed genes was indeed caused by cyto-architectural alterations due to the heterogeneity in the neurodegenerative stage and/or technical artifacts. After correcting for cell composition, we identified a common signature that deregulated the previously unreported ammonium transport, as well as known biological processes including bioenergetic pathways, response to proteotoxic stress, and immune response. By integrating with protein-interaction data, we shortlisted a set of key genes, such as LRRK2, PINK1, and PRKN known to be related to PD; others with compelling evidence for their role in neurodegeneration, such as GSK3{beta}, WWOX, and VPC; as well as novel potential players in the PD pathogenesis, including NTRK1, TRIM25, ELAVL1. Together, these data showed the importance of accounting for cyto-architecture in these analyses and highlight the contribution of multiple cell types and novel processes to PD pathology providing potential new targets for drug development.

Significance StatementThe exploration of the transcriptomic landscape in PD is pivotal for the understanding of the pathological mechanisms of this disease. Nonetheless, little attention has been paid to the influence of cell composition on the transcriptome even though it is known that cyto-architecture undergoes major alterations in neurodegenerative diseases such as PD. Our study signifies that changes in cellular architecture of human substantia nigra in PD have a strong effect on the set of detected differentially expressed genes. By reanalyzing the data and accounting for cell composition, we provide an updated description of deregulated biological processes in PD and nominate a shortlist of PD-associated genes for further investigations.

category: bioinformatics


title: spatzie: An R package for identifying significant transcription factor motif co-enrichment from enhancer-promoter interactions

abstract: Genomic interactions provide important context to our understanding of the state of the genome. One question is whether specific transcription factor interactions give rise to genome organization. We introduce spatzie, an R package and a website that implements statistical tests for significant transcription factor motif cooperativity between enhancer-promoter interactions. We conducted controlled experiments under realistic simulated data from ChIP-seq to confirm spatzie is capable of discovering co-enriched motif interactions even in noisy conditions. We then use spatzie to investigate cell type specific transcription factor cooperativity within recent human ChIA-PET enhancer-promoter interaction data. The method is available online at https://spatzie.mit.edu.


title: Oxytocin modulates neurocomputational mechanisms underlying prosocial reinforcement learning

abstract: Humans often act in the best interests of others. However, how we learn which actions result in good outcomes for other people and the neurochemical systems that support this  prosocial learning remain poorly understood. Using computational models of reinforcement learning, functional magnetic resonance imaging and dynamic causal modelling, we examined how different doses of intranasal oxytocin, a neuropeptide linked to social cognition, impact how people learn to benefit others (prosocial learning) and whether this influence could be dissociated from how we learn to benefit ourselves (self-oriented learning). We show that a low dose of oxytocin prevented decreases in prosocial performance over time, despite no impact on self-oriented learning. Critically, oxytocin produced dose-dependent changes in the encoding of prediction errors (PE) in the midbrain-subgenual anterior cingulate cortex (sgACC) pathway specifically during prosocial learning. Our findings reveal a new role of oxytocin in prosocial learning by modulating computations of PEs in the midbrain-sgACC pathway.

category: neuroscience


title: Topographical relocation of adolescent sleep spindles reveals a new maturational pattern of the human brain

abstract: Current theories of human neural development emphasize the posterior-to-anterior pattern of brain maturation. However, this scenario leaves out significant brain areas not directly involved with sensory input and behavioral control. Suggesting the relevance of cortical activity unrelated to sensory stimulation, such as sleep, we investigated adolescent transformations in the topography of sleep spindles. Sleep spindles are known to be involved in neural plasticity and in adults have a bimodal topography: slow spindles are frontally dominant, while fast spindles have a parietal/precuneal origin. The late functional segregation of the precuneus from the frontoparietal network during adolescence suggests that spindle topography might approach the adult state relatively late in development, and it may not be a result of the posterior-to-anterior maturational pattern. We analyzed the topographical distribution of spindle parameters in HD-EEG polysomnographic sleep recordings of adolescents and found that slow spindle duration maxima traveled from central to anterior brain regions, while fast spindle density, amplitude and frequency peaks traveled from central to more posterior brain regions. These results provide evidence for the gradual posteriorization of the anatomical localization of fast sleep spindles during adolescence and indicate the existence of an anterior-to posterior pattern of human brain maturation.


title: Magnetic Field Mapping and Correction for Moving OP-MEG

abstract:
BackgroundOptically pumped magnetometers (OPMs) have made moving, wearable magnetoencephalography (MEG) possible. The OPMs typically used for MEG require a low background magnetic field to operate, which is achieved using both passive and active magnetic shielding. However, the background magnetic field is never truly zero Tesla, and so the field at each of the OPMs changes as the participant moves. This leads to position and orientation dependent changes in the measurements, which manifest as low frequency artefacts in MEG data.

ObjectiveWe modelled the spatial variation in the magnetic field and used the model to predict the movement artefact found in a dataset.

MethodsWe demonstrate a method for modelling this field with a triaxial magnetometer, then showed that we can use the same technique to predict the movement artefact in a real OPM-based MEG (OP-MEG) dataset.

ResultsUsing an 86-channel OP-MEG system, we found that this modelling method maximally reduced the power spectral density of the data by 26.2 {+/-} 0.6 dB at 0 Hz, when applied over 5 s non-overlapping windows.

ConclusionThe magnetic field inside our state-of-the art magnetically shielded room can be well described by low-order spherical harmonic functions. We achieved a large reduction in movement noise when we applied this model to OP-MEG data.

SignificanceReal-time implementation of this method could reduce passive shielding requirements for OP-MEG recording and allow the measurement of low-frequency brain activity during natural participant movement.


title: Single-cell transcriptome profiling reveals multicellular ecosystem of nucleus pulposus during degeneration progression

abstract: Degeneration of the nucleus pulposus (NP) is a major contributor to intervertebral disc degeneration (IVDD) and low back pain. However, the underlying molecular complexity and cellular heterogeneity remain poorly understood. Here, we first reported a comprehensive single-cell resolution transcriptional landscape of human NP. Six novel human nucleus pulposus cell (NPCs) populations were identified by distinct molecular signatures. The potential functional differences among NPC subpopulations were analyzed at the single-cell level. Predictive genes, transcriptional factors, and signal pathways with respect to degeneration grades were analyzed. We reported that fibroNPCs, one of our identified subpopulations, might be a population for NP regeneration. CD90+NPCs were observed to be progenitor cells in degenerative NP tissues. NP-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including granulocytic myeloid-derived suppressor cells (G-MDSCs). We uncovered CD11b, OLR1, and CD24 as surface markers of NP-derived G-MDSCs. The G-MDSCs were also found to be enriched in mildly degenerated (grade I and II) NP tissues compared to severely degenerated (grade III and IV) NP tissues. Their immunosuppressive function and protective effects for NPCs were revealed. Collectively, this study revealed the NPC type complexity and phenotypic characteristics in NP, providing new insights and clues for IVDD treatment.

category: cell biology


title: The measure of spatial position within groups that best predicts predation risk depends on group movement

abstract: Both empirical and theoretical studies show that an individuals spatial position within a group can impact the risk of being targeted by predators. Spatial positions can be quantified in numerous ways, but there are no direct comparisons of different spatial measures in predicting the risk of being targeted by real predators. Here we assess these spatial measures in groups of stationary and moving virtual prey being attacked by three-spined sticklebacks (Gasterosteus aculeatus). In stationary groups, the limited domain of danger best predicted the likelihood of attack. In moving groups, the number of near neighbours was the best predictor but only over a limited range of distances within which other prey were counted. Otherwise, measures of proximity to the groups edge outperformed measures of local crowding in moving groups. There was no evidence that predators preferentially attacked the front or back of the moving groups. Domains of danger without any limit, as originally used in the selfish herd model, were also a poor predictor of risk. These findings reveal that the collective properties of prey can influence how spatial position affects predation risk, via effects on predators targeting, hence selection may act differently on prey positioning behaviour depending on group movement.

category: animal behavior and cognition


title: Temporal Progression: A case study in Porcine Survivability through Hemostatic Nanoparticles

abstract: This paper focuses on the analysis of time series representation of blood loss and cytokines in animals experiencing trauma to understand the temporal progression of factors affecting survivability of the animal. Trauma related grave injuries cause exsanguination and lead to death. 50% of deaths especially in the armed forces are due to trauma injuries. Restricting blood loss usually requires the presence of first responders, which is not feasible in certain cases. Hemostatic nanoparticles have been developed to tackle these kinds of situations to help achieve efficient blood coagulation. Hemostatic nanoparticles were administered into trauma induced porcine animals (pigs) to observe impact on the cytokine and blood loss experienced by them. In this paper we present temporal models to study the impact of the hemostatic nanoparticles and provide snapshots about the trend in cytokines and blood loss in the porcine data to study their progression over time. We utilized Piecewise Aggregate Approximation, Similarity based Merging and clustering to evaluate the impact of the different hemostatic nanoparticles administered. In some cases the fluctuations in the cytokines may be too small. So in addition we highlight situations where temporal modelling that produces a smoothed time series may not be useful as it may remove out the noise and miss the overall fluctuations resulting from the nanoparticles. Our results indicate certain nanoparticles stand out and lead to novel hypothesis formation.


title: CoRe: A robustly benchmarked R package for the identification of core fitness genes in genome-wide pooled CRISPR knock-out screens

abstract: CRISPR-Cas9 genome-wide screens are being increasingly performed, allowing systematic explorations of cancer dependencies at unprecedented accuracy and scale. Identifying from these screens the genes that are essential for cell survival invariantly across tissues, conditions, and genomic-contexts (core-fitness genes), is of paramount importance to assess the safety profile of candidate therapeutic targets and for elucidating mechanisms involved in tissue-specific genetic diseases. We present CoRe: An R package implementing novel methods for identifying core-fitness genes from joint analyses of multiple CRISPR-Cas9 screens. We demonstrate that CoRe outperforms state-of-the-art tools, yielding more reliable sets of core-fitness genes than existing and widely used reference sets.


title: baredSC: Bayesian Approach to Retrieve Expression Distribution of Single-Cell

abstract: The number of studies using single-cell RNA sequencing (scRNA-seq) is constantly growing. This powerful technique provides a sampling of the whole transcriptome of a cell. However, the commonly used droplet-based method often produces very sparse samples. Sparsity can be a major hurdle when studying the distribution of the expression of a specific gene or the correlation between the expressions of two genes. We show that the main technical noise associated with these scRNA-seq experiments is due to the sampling (i.e. Poisson noise). We developed a new tool named baredSC, for Bayesian Approach to Retrieve Expression Distribution of Single-Cell, which infers the intrinsic expression distribution in single-cell data using a Gaussian mixture model (GMM). baredSC can be used to obtain the distribution in one dimension for individual genes and in two dimensions for pairs of genes, in particular to estimate the correlation in the two genes expressions. We apply baredSC to simulated scRNA-seq data and show that the algorithm is able to uncover the expression distribution used to simulate the data, even in multi-modal cases with very sparse data. We also apply baredSC to two real biological data sets. First, we use it to measure the anti-correlation between Hoxd13 and Hoxa11, two genes with known genetic interaction in embryonic limb. Then, we study the expression of Pitx1 in embryonic hindlimb, for which a trimodal distribution has been identified through flow cytometry. While other methods to analyze scRNA-seq are too sensitive to sampling noise, baredSC reveals this trimodal distribution.


title: Smell what you hardly see: Odors assist categorization in the human visual cortex

abstract: Visual categorization is the brain ability to rapidly and automatically respond to widely variable visual inputs in a category-selective manner (i.e., distinct responses between categories and similar responses within categories). Whether category-selective neural responses are purely visual or can be influenced by other sensory modalities remains unclear. Here, we test whether odors modulate visual categorization, expecting that odors facilitate the neural categorization of congruent visual objects, especially when the visual category is ambiguous. Scalp electroencephalogram (EEG) was recorded while natural images depicting various objects were displayed in rapid 12-Hz streams (i.e., 12 images / second) and variable exemplars of a target category (either human faces, cars, or facelike objects in dedicated sequences) were interleaved every 9th stimulus to tag category-selective responses at 12/9 = 1.33 Hz in the EEG frequency spectrum. During visual stimulation, participants (N = 26) were implicitly exposed to odor contexts (either body, gasoline or baseline odors) and performed an orthogonal cross-detection task. We identify clear category-selective responses to every category over the occipito-temporal cortex, with the largest response for human faces and the lowest for facelike objects. Critically, body odor boosts the response to the ambiguous facelike objects (i.e., either perceived as nonface objects or faces) over the right hemisphere, especially for participants reporting their presence post-stimulation. By contrast, odors do not significantly modulate other category-selective responses, nor the general visual response recorded at 12 Hz, revealing a specific influence on the categorization of congruent ambiguous stimuli. Overall, these findings support the view that the brain actively uses cues from the different senses to readily categorize visual inputs, and that olfaction, which is generally considered as poorly functional in humans, is well placed to disambiguate visual information.


title: The RIFF: an automated environment for studying the neural basis of auditory-guided complex behavior

abstract: Behavior consists of the interaction between an organism and its environment, and is controlled by the brain. Brain activity varies at sub-second time scales, but behavioral measures are usually coarse (often consisting of only binary trial outcomes). To overcome this mismatch, we developed the RIFF: a programmable interactive arena for freely-moving rats with multiple feeding areas, multiple sound sources, high-resolution behavioral tracking, and simultaneous electrophysiological recordings. We describe two complex tasks implemented in the RIFF. Rats quickly learned these tasks and developed anticipatory behavior. Neurons in auditory cortex and posterior insula showed sensitivity to non-auditory parameters such as location and pose. Our combination of wireless electrophysiology and detailed behavioral documentation in a controlled environment produces insights into the cognitive capabilities and learning mechanisms of rats and opens the way to a better understanding of how brains control behavior.


title: Segmental duplications and their variation in a complete human genome

abstract: Despite their importance in disease and evolution, highly identical segmental duplications (SDs) have been among the last regions of the human reference genome (GRCh38) to be finished. Based on a complete telomere-to-telomere human genome (T2T-CHM13), we present the first comprehensive view of human SD organization. SDs account for nearly one-third of the additional sequence increasing the genome-wide estimate from 5.4% to 7.0% (218 Mbp). An analysis of 266 human genomes shows that 91% of the new T2T-CHM13 SD sequence (68.3 Mbp) better represents human copy number. We find that SDs show increased single-nucleotide variation diversity when compared to unique regions; we characterize methylation signatures that correlate with duplicate gene transcription and predict 182 novel protein-coding gene candidates. We find that 63% (35.11/55.7 Mbp) of acrocentric chromosomes consist of SDs distinct from rDNA and satellite sequences. Acrocentric SDs are 1.75-fold longer (p=0.00034) than other SDs, are frequently shared with autosomal pericentromeric regions, and are heteromorphic among human chromosomes. Comparing long-read assemblies from other human (n=12) and nonhuman primate (n=5) genomes, we use the T2T-CHM13 genome to systematically reconstruct the evolution and structural haplotype diversity of biomedically relevant (LPA, SMN) and duplicated genes (TBC1D3, SRGAP2C, ARHGAP11B) important in the expansion of the human frontal cortex. The analysis reveals unprecedented patterns of structural heterozygosity and massive evolutionary differences in SD organization between humans and their closest living relatives.

category: genomics


title: Alternative Splicing Regulates the Physiological Adaptation of the Mouse Hind Limb Postural and Phasic Muscles to Microgravity

abstract: Muscle atrophy and fiber type alterations are well-characterized physiological adaptations to microgravity with both understood to be primarily regulated by differential gene expression (DGE). While microgravity-induced DGE has been extensively investigated, adaptations to microgravity due to alternative splicing (AS) have not been studied in a mammalian model. We sought to comprehensively elucidate the transcriptomic underpinnings of microgravity-induced muscle phenotypes in mice by evaluating both DGE and changes in AS due to extended spaceflight. Tissue sections and total RNA were isolated from the gastrocnemius and quadriceps, postural and phasic muscles of the hind limb, respectively, of 32-week-old female BALB/c mice exposed to microgravity or ground control conditions for nine weeks. Immunohistochemistry disclosed muscle type-specific physiological adaptations to microgravity that included i) a pronounced reduction in muscle fiber cross-sectional area in both muscles and ii) a prominent slow-to-fast fiber type transition in the gastrocnemius. RNA sequencing revealed that DGE and AS varied across postural and phasic muscle types with preferential employment of DGE in the gastrocnemius and AS in the quadriceps. Gene ontology analysis indicated that DGE and AS regulate distinct molecular processes. Various non-differentially expressed transcripts encoding musculoskeletal proteins (Tnnt3, Tnnt1, Neb, Ryr1, and Ttn) and muscle-specific RNA binding splicing regulators (Mbnl1 and Rbfox1) were found to have significant changes in AS that altered critical functional domains of their protein products. In striking contrast, microgravity-induced differentially expressed genes were associated with lipid metabolism and mitochondrial function. Our work serves as the first comprehensive investigation of coordinate changes in DGE and AS in large limb muscles across spaceflight. We propose that substantial remodeling of pre-mRNA by AS is a major component of transcriptomic adaptation of skeletal muscle to microgravity. The alternatively spliced genes identified here could be targeted by small molecule splicing regulator therapies to address microgravity-induced changes in muscle during spaceflight.


title: Fabrication and Characterization Methods for Investigating Cell-Matrix Interactions in Environments Possessing Spatial Orientation Heterogeneity

abstract: Fibrillar collagen is a ubiquitous structural protein that plays a significant role in determining the mechanical properties of various tissues. The constituent collagen architecture can give direct insight into the respective functional role of the tissue due to the strong structure-function relationship that is exhibited. In such tissues, matrix structure can vary across local subregions contributing to mechanical heterogeneity which can be implicated in tissue function or failure. The post-myocardial infarction scar environment is an example of note where mechanically insufficient collagen can result in impaired cardiac function and possibly tissue rupture due to post-MI cellular response and matrix interactions. In order to further develop the understanding of cell-matrix and cell-cell interactions within heterogeneous environments, we developed a method of heterogeneous collagen gel fabrication which produces a region of randomly oriented fibers directly adjacent to an interconnected region of anisotropic alignment. To fully capture and evaluate the degree of alignment and spatial orientation heterogeneity, several image processing and automated analysis methods were employed. Our analysis revealed the successful fabrication of an interconnected spatially heterogeneous collagen gel possessing distinct regions of random or preferential alignment. Additionally, embedded cell populations were observed to recognize and reorient with their underlying and surrounding architectures through our cell-centric analysis techniques.


title: Computational Design Map for Heterogeneous Experimental Studies

abstract: This paper focuses on the discovery of a computational design map of disparate heterogeneous outcomes from bioinformatics experiments in pig (porcine) studies to help identify key variables impacting the experiment outcomes. Specifically we aim to connect discoveries from disparate laboratory experimentation in the area of trauma, blood loss and blood clotting using data science methods in a collaborative ensemble setting. Trauma related grave injuries cause exsanguination and death, constituting up to 50% of deaths especially in the armed forces. Restricting blood loss in such scenarios usually requires the presence of first responders, which is not feasible in certain cases. Moreover, a traumatic event may lead to a cytokine storm, reflected in the cytokine variables. Hemostatic nanoparticles have been developed to tackle these kinds of situations of trauma and blood loss. This paper highlights a collaborative effort of using data science methods in evaluating the outcomes from a lab study to further understand the efficacy of the nanoparticles. An intravenous administration of hemostatic nanoparticles was executed in pigs that had to undergo hemorrhagic shock and blood loss and other immune response variables, cytokine response variables are measured. Thus, through various hemostatic nanoparticles used in the intervention, multiple data outcomes are produced and it becomes critical to understand which nanoparticles are critical and what variables are key to study further variations in the lab. We propose a collaborative data mining framework which combines the results from multiple data mining methods to discover impactful features. We used frequent patterns observed in the data from these experiments. We further validate the connections between these frequent rules by comparing the results with decision trees and feature ranking. Both the frequent patterns and the decision trees help us identify the critical variables that stand out in the lab studies and need further validation and follow up in future studies. The outcomes from the data mining methods help produce a computational design map of the experimental results. Our preliminary results from such a computational design map provided insights in determining which features can help in designing the most effective hemostatic nanoparticles.


title: Diffusion and interaction dynamics of the cytosolic peroxisomal import receptor PEX5

abstract:
Measuring diffusion dynamics in living cells is essential for the understanding of molecular interactions. While various techniques have been used to explore such characteristics in the plasma membrane, this is less developed for measurements inside the cytosol. An example of cytosolic action is the import of proteins into peroxisomes, via the peroxisomal import receptor PEX5. Here, we combined advanced microscopy and spectroscopy techniques such as fluorescence correlation spectroscopy (FCS) and super-resolution STED microscopy to present a detailed characterization of the diffusion and interaction dynamics of PEX5. Among other features, we disclose a slow diffusion of PEX5, independent of aggregation or target binding, but associated with cytosolic interaction partners via its N-terminal domain. This sheds new light on the functionality of the receptor in the cytosol. Besides specific insights, our study highlights the potential of using complementary microscopy tools to decipher molecular interactions in the cytosol via studying their diffusion dynamics.

SummaryThe peroxisomal import receptor PEX5 transports newly synthesized proteins from the cytosol to the peroxisomal matrix. Here the cytosolic diffusion and interaction dynamics of PEX5 are characterized by advanced microscopic spectroscopy methods, revealing a so far unknown interaction partner.

category: biophysics


title: Immune determinants of the association between tumor mutational burden and immunotherapy response across cancer types

abstract: The FDA has recently approved high tumor mutational burden (TMB), defined by [≥]10 mutations/Mb, as a biomarker for the treatment of solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies testify that high TMB levels are only able to stratify ICI responders in a subset of cancer types, where the mechanisms underlying this observation have remained unknown. We hypothesized that the tumor immune microenvironment (TME) may modulate the stratification power of TMB (termed TMB power) in a cancer type, leading to this observation. To systematically study this hypothesis, we analyzed TCGA expression data to infer the levels of 31 immune-related factors characteristic of the TME of different cancer types. We integrated this information with TMB and response data of 2,277 patients treated with anti-PD1 or anti-PD-L1 ICI to identify the key immune factors that can determine TMB power across 14 different cancer types. We find that high levels of M1 macrophages and low resting dendritic cells in the TME characterize cancer types with high TMB power. A model based on these two immune factors is strongly predictive of the TMB power in a given cancer type (Spearman Rho=0.76, P<3.6x10-04). Using this model, we provide predictions of the TMB power in nine additional cancer types, including rare cancers, for which TMB and ICI response data are not yet publicly available on a large scale. Our analysis indicates that TMB-High may be highly predictive of ICI response in cervical squamous cell carcinoma, suggesting that such a study should be prioritized.

category: cancer biology


title: A Neuroscience-Inspired Spiking Neural Network for Auditory Spatial Attention Detection Using Single-Trial EEG

abstract: Recently, studies have shown that the alpha band (8-13 Hz) EEG signals enable the decoding of auditory spatial attention. However, deep learning methods typically requires a large amount of training data. Inspired by "sparse coding" in cortical neurons, we propose a spiking neural network model for auditory spatial attention detection. The model is composed of three neural layers, two of them are spiking neurons. We formulate a new learning rule that is based on firing rate of pre-synaptic and post-synaptic neurons in the first layer and the second layer of spiking neurons. The third layer consists of 10 spiking neurons that the pattern of their firing rate after training is used in test phase of the method. The proposed method extracts the patterns of recorded EEG of leftward and rightward attention, independently, and uses them to train network to detect the auditory spatial attention. In addition, a computational approach is presented to find the best single-trial EEG data as training samples of leftward and rightward attention EEG. In this model, the role of using low connectivity rate of the layers and specific range of learning parameters in sparse coding is studied. Importantly, unlike most prior model, our method requires 10% of EEG data as training data and has shown 90% accuracy in average. This study suggests new insights into the role of sparse coding in both biological networks and brain-inspired machine learning.


title: Spatio-temporal Coordination of Transcription During the Cell Growth Cycle in Budding Yeast.

abstract: Metabolic oscillation percolate throughout cellular physiology. The transcriptome oscillates between gene cohorts encoding for biosynthesis and growth, and for catabolism and stress response. However, long protein half-lives dampen effects on protein abundance, and the function of periodic transcription remains elusive. To test three prevailing hypotheses, we performed RNA-seq analysis during a dynamic state of the system, just preceding a bifurcation of system dynamics to a longer period. A few enzymes with short protein half-live and high transcript abundance amplitude could play a direct role in metabolic dynamics (hypothesis H1), e.g., carbonic anhydrase, sulfate uptake and the glyoxylate cycle. Substantial changes in the relative duration of expression of the antagonistic cohorts precede the bifurcation, supporting the idea of a function in cellular resource allocation (H2). The pulse-width modulation model, a mathematical formulation of this idea, explains the dependence of the cycle period on the culture growth rate. This pulse-like model of cell growth provides a first theoretical framework, where the phenomenon is understood as a mechanism of cellular resource allocation and protein homeostasis. The universal temporal program of transcription encodes the spatial structure of the cell, and we further suggest a function in pattern formation of the growing cell (H3).


title: The cell growth cycle in budding yeast: testing hypotheses.


title: The cell growth cycle: resource allocation and subcellular pattern formation in budding yeast.


title: On Periodic Gene Expression in Budding Yeast


title: Adaptive phenotypic plasticity stabilizes evolution in fluctuating environments

abstract: Fluctuating environmental conditions are ubiquitous in natural systems, and populations have evolved various strategies to cope with such fluctuations. The particular mechanisms that evolve profoundly influence subsequent evolutionary dynamics. One such mechanism is phenotypic plasticity, which is the ability of a single genotype to produce alternate phenotypes in an environmentally dependent context. Here, we use digital organisms (self-replicating computer programs) to investigate how adaptive phenotypic plasticity alters evolutionary dynamics and influences evolutionary outcomes in cyclically changing environments. Specifically, we examined the evolutionary histories of both plastic populations and non-plastic populations to ask: (1) Does adaptive plasticity promote or constrain evolutionary change? (2) Are plastic populations better able to evolve and then maintain novel traits? And (3), how does adaptive plasticity affect the potential for maladaptive alleles to accumulate in evolving genomes? We find that populations with adaptive phenotypic plasticity undergo less evolutionary change than non-plastic populations, which must rely on genetic variation from de novo mutations to continuously readapt to environmental fluctuations. Indeed, the non-plastic populations undergo more frequent selective sweeps and accumulate many more genetic changes. We find that the repeated selective sweeps in non-plastic populations drive the loss of beneficial traits and accumulation of maladaptive alleles via deleterious hitchhiking, whereas phenotypic plasticity can stabilize populations against environmental fluctuations. This stabilization allows plastic populations to more easily retain novel adaptive traits than their non-plastic counterparts. In general, the evolution of adaptive phenotypic plasticity shifted evolutionary dynamics to be more similar to that of populations evolving in a static environment than to non-plastic populations evolving in an identical fluctuating environment. All natural environments subject populations to some form of change; our findings suggest that the stabilizing effect of phenotypic plasticity plays an important role in subsequent adaptive evolution.


title: No general shift in spring migration phenology by eastern North American birds since 1970

abstract: We studied the phenology of spring bird migration from eBird and EPOQ checklist programs South of 49{degrees}N in the province of Quebec, Canada, between 1970 and 2020. 152 species were grouped into Arctic, long-distance, and short-distance migrants. Among those species, 75 significantly changed their migration dates, after accounting for temporal variability in observation effort, species abundance, and latitude. But in contrast to most studies on the subject, we found no general advance in spring migration dates, with 36 species advancing and 39 species delaying their migration. Several early-migrant species associated to open water advanced their spring migration, possibly due to decreasing early-spring ice cover in the Great Lakes and the St-Lawrence river since 1970. Arctic breeders and short-distance migrants advanced their first arrival dates more than long-distance migrants not breeding in the arctic. However, there was no difference among migrant groups when median arrival dates were considered. We conclude that general claims about advances in spring migration dates in eastern North America are misleading due to large taxonomic variation.

category: ecology


title: Short single-stranded DNA with putative non-canonical structures comprises a novel class of plasma cell-free DNA

abstract: Cell-free DNA (cfDNA) in human blood is currently investigated as a minimally invasive, highly informative biomarker. Here, we aimed to investigate the existence of the shorter cfDNA fragments in the blood. Using an improved cfDNA purification protocol and a 3'-end-labeling method, we found DNA fragments of approximately 50 nucleotides in human plasma, present at a molar concentration comparable to that of the nucleosome-sized fragments. These short fragments cannot be recovered by widely used cfDNA isolation methods, and are composed of single-stranded DNA (ssDNA), thus escaping detection in previous studies. We established a library-preparation protocol based on our unique ssDNA ligation technique and applied it to the isolated cfDNA. Deep sequencing of these libraries revealed that the short fragments are derived from hundreds of thousands of genomic sites in open chromatin regions and enriched with transcription factor-binding sites. Remarkably, antisense strands of putative G-quadruplex motifs occupy as much as one-third of peaks called with these short fragments. Hence, we propose a novel class of plasma cfDNA composed of short single-stranded fragments that potentially form non-canonical DNA structures.


title: Velodrome: Out-of-Distribution Generalization from Labeled and Unlabeled Gene Expression Data for Drug Response Prediction

abstract: Data discrepancy between preclinical and clinical datasets poses a major challenge for accurate drug response prediction based on gene expression data. Different methods of transfer learning have been proposed to address this data discrepancy. These methods generally use cell lines as source domains and patients, patient-derived xenografts, or other cell lines as target domains. However, they assume that they have access to the target domain during training or fine-tuning and they can only take labeled source domains as input. The former is a strong assumption that is not satisfied during deployment of these models in the clinic. The latter means these methods rely on labeled source domains which are of limited size. To avoid these assumptions, we formulate drug response prediction as an out-of-distribution generalization problem which does not assume that the target domain is accessible during training. Moreover, to exploit unlabeled source domain data, which tends to be much more plentiful than labeled data, we adopt a semi-supervised approach. We propose Velodrome, a semi-supervised method of out-of-distribution generalization that takes labeled and unlabeled data from different resources as input and makes generalizable predictions. Velodrome achieves this goal by introducing an objective function that combines a supervised loss for accurate prediction, an alignment loss for generalization, and a consistency loss to incorporate unlabeled samples. Our experimental results demonstrate that Velodrome outperforms state-of-the-art pharmacogenomics and transfer learning baselines on cell lines, patient-derived xenografts, and patients. Finally, we showed that Velodrome models generalize to different tissue types that were well-represented, under-represented, or completely absent in the training data. Overall, our results suggest that Velodrome may guide precision oncology more accurately.


title: Out-of-Distribution Generalization from Labeled and Unlabeled Gene Expression Data for Drug Response Prediction


title: Towards increased shading potential: a combined phenotypic and genetic analysis of rice shoot architecture

abstract:
Rice feeds more than half of the worlds human population. In modern rice farming, a major constraint for productivity is weed proliferation and the ecological impact of herbicide application. Increased weed competitiveness of commercial rice varieties requires enhanced shade casting to limit growth of shade-sensitive weeds and the need for herbicide. We aimed to identify traits that enhance rice shading capacity based on the canopy architecture and the underlying genetic components. We performed a phenotypic screen of a rice diversity panel comprised of 344 varieties, examining 13 canopy architecture traits linked with shading capacity in 4-week-old plants. The analysis revealed a vast range of phenotypic variation across the diversity panel. We used trait correlation and clustering to identify core traits that define shading capacity to be shoot area, number of leaves, culm and solidity (the compactness of the shoot). To simplify the complex canopy architecture, these traits were combined into a Shading Rank metric that is indicative of a plants ability to cast shade. Genome wide association study (GWAS) revealed genetic loci underlying canopy architecture traits, out of which five loci were substantially contributing to shading potential. Subsequent haplotype analysis further explored allelic variation and identified seven haplotypes associated with increased shading. Identification of traits contributing to shading capacity and underlying allelic variation presented in this study will serve future genomic assisted breeding programmes. The investigated diversity panel, including widely grown varieties, shows that there is big potential and genetic resources for improvement of elite breeding lines. Implementing increased shading in rice breeding will make its farming less dependent on herbicides and contribute towards more environmentally sustainable agriculture.

One sentence summaryThrough screening a rice diversity panel for variation in shoot architecture, we identified traits corresponding to plant shading potential and their genetic constituents.

category: plant biology


title: Midfrontal theta tACS facilitates motor coordination in dyadic human-avatar motor interactions

abstract: Synchronous interpersonal motor interactions require moment-to-moment predictions and proactive monitoring of the partners actions. Neurophysiologically, this is highlighted by an enhancement of midfrontal theta activity. In the present study we explored the causal role of midfrontal theta for interpersonal motor interactions employing transcranial alternating current stimulation (tACS). We implemented a realistic human-avatar interaction task in immersive virtual reality (IVR) where participants controlled a virtual arm and hand to press a button synchronously with a virtual partner. Participants completed the task while receiving theta (Experiment 1) or beta (control frequency, Experiment 2) EEG-informed tACS over the frontal midline, as well as sham stimulation as a control. Results showed that frontal theta tACS significantly improved behavioural performance (by reducing interpersonal asynchrony) and participants motor strategies (by increasing movement times and reducing reaction times), while beta tACS had no effect on these measures. These results suggest that theta tACS over frontal areas facilitates action monitoring and motor abilities supporting interpersonal interactions.


title: Linking the brain with behaviour: the neural dynamics of success and failure in goal-directed behaviour

abstract:
The human brain is extremely flexible and capable of rapidly selecting relevant information in accordance with task goals. Regions of frontoparietal cortex flexibly represent relevant task information such as task rules and stimulus features when participants perform tasks successfully, but less is known about how information processing breaks down when participants make mistakes. This is important for understanding whether and when information coding recorded with neuroimaging is directly meaningful for behaviour. Here, we used magnetoencephalography (MEG) to assess the temporal dynamics of information processing, and linked neural responses with goal-directed behaviour by analysing how they changed on behavioural error. Participants performed a difficult stimulus-response task using two stimulus-response mapping rules. We used time-resolved multivariate pattern analysis to characterise the progression of information coding from perceptual information about the stimulus, cue and rule coding, and finally, motor response. Response-aligned analyses revealed a ramping up of perceptual information prior to a correct response, suggestive of internal evidence accumulation. Strikingly, when participants made a stimulus-related error, and not when they made other types of errors, patterns of activity initially reflected the stimulus presented, but later reversed, and accumulated towards a representation of the incorrect stimulus. This suggests that the patterns recorded at later timepoints reflect an internally generated stimulus representation that was used to make the (incorrect) decision.

These results illustrate the orderly and overlapping temporal dynamics of information coding in perceptual decision-making and show a clear link between neural patterns in the late stages of processing and behaviour.


title: Single-cell RNA-sequencing reveals thoracolumbar vertebra heterogeneity and rib-genesis in pigs

abstract: Thoracolumbar vertebra (TLV) and rib primordium (RP) development is a common evolutionary feature across vertebrates although whole-organism analysis of TLV and RP gene expression dynamics has been lacking. Here we investigated the single-cell transcriptomic landscape of thoracic vertebra (TV), lumbar vertebra (LV), and RP cells from a pig embryo at 27 days post-fertilization (dpf) and identified six cell types with distinct gene-expression signatures. In-depth dissection of the gene-expression dynamics and RNA velocity revealed a coupled process of osteogenesis and angiogenesis during TLV and rib development. Further analysis of cell-type-specific and strand-specific expression uncovered the extremely high levels of HOXA10 3-UTR sequence specific to osteoblast of LV cells, which may function as anti-HOXA10-antisense by counteracting the HOXA10-antisense effect to determine TLV transition. Thus, this work provides a valuable resource for understanding embryonic osteogenesis and angiogenesis underlying vertebrate TLV and RP development at the cell-type-specific resolution, which serves as a comprehensive view on the transcriptional profile of animal embryo development.

category: developmental biology


title: Extraordinarily precise nematode sex ratios: Adaptive responses to vanishingly rare mating options

abstract: Sex ratio theory predicts both mean sex ratio and variance under a range of population structures. Here, we compare two genera of phoretic nematodes (Parasitodiplogaster and Ficophagus spp.) associated with twelve fig-pollinating wasp species in Panama. The host wasps exhibit classic Local Mate Competition: only inseminated females disperse from natal figs, and their offspring form mating pools that consist of scores of the adult offspring contributed by one or a few foundress mothers. In contrast, in both nematode genera, only sexually undifferentiated juveniles disperse, and their mating pools routinely consist of eight or fewer adults. Across all mating pool sizes, the sex ratios observed in both nematode genera are consistently female-biased (~0.34 males), which is markedly less female-biased than is often observed in the host wasps (~0.10 males). In further contrast with their hosts, variances in nematode sex ratios are also consistently precise (significantly less than binomial). The constraints associated with predictably small mating pools within highly subdivided populations appear to select for precise sex ratios that contribute both to the reproductive success of individual nematodes, and to the evolutionary persistence of nematode species. We suggest that some form of environmental sex determination underlies these precise sex ratios.


title: Sexual selection for rare beneficial mutations promotes the evolution of sexual reproduction and adaptation

abstract: Sexual selection is the process by which traits providing a mating advantage are favoured. Theoretical treatments of the evolution of sex by sexual selection propose that it operates by reducing the load of deleterious mutations. Here, we postulate instead that sexual selection primarily acts through females preferentially mating with males carrying beneficial mutations. We used simulation and analytical modelling to investigate the evolutionary dynamics of beneficial mutations in the presence of sexual selection. We found that female choice for males with beneficial mutations had a much greater impact on genetic quality than choice for males with low mutational load. We also relaxed the typical assumption of a fixed mutation rate. For deleterious mutations, mutation rate should always be minimized, but when rare beneficial mutations can occur, female choice for males with those rare beneficial mutations could overcome a decline in average fitness and allow an increase in mutation rate. We propose that sexual selection for beneficial mutations could overcome the  two-fold cost of sex much more readily than choice for males with low mutational load and may therefore be a more powerful explanation for the prevalence of sexual reproduction than the existing theory. If sexual selection results in higher fitness at higher mutation rates and if the variability produced by mutation itself promotes sexual selection, then a feedback loop between these two factors could have had a decisive role in driving adaptation.


title: Sexual selection for males with beneficial mutations


title: Comparative Transcriptomics Identifies Potential Stemness-Related Markers for Mesenchymal Stromal/Stem Cells

abstract: Mesenchymal stromal/stem cells (MSCs) are multipotent cells residing in multiple tissues with the capacity for self-renewal and differentiation into various cell types. These properties make them promising candidates for regenerative therapies. MSC identification is critical in yielding pure populations for successful therapeutic applications; however, the criteria for MSC identification proposed by the International Society for Cellular Therapy (ISCT) is inconsistent across different tissue sources. In this study, we aimed to identify potential markers to be used together with the ISCTs criteria to provide a more accurate means of MSC identification. Thus, we carried out a comparative analysis of the expression of human and mouse MSCs derived from multiple tissues to identify the common differentially expressed genes. We show that six members of the proteasome degradation system are similarly expressed across MSCs derived from bone marrow, adipose tissue, amnion, and umbilical cord. Also, with the help of predictive models, we found that these genes successfully identified MSCs across all the tissue sources tested. Moreover, using genetic interaction networks, we showed a possible link between these genes and antioxidant enzymes in the MSC antioxidant defense system, thereby pointing to their potential role in prolonging the life span of MSCs. Our results suggest that these genes can be used as stemness-related markers.


title: Precise genotyping of circular mobile elements uncovers human associated plasmids with surprisingly recent common ancestors

abstract: Mobile genetic elements with circular genomes play a key role in the evolution of microbial communities. These circular genomes correspond to cyclic paths in metagenome graphs, and yet, assemblies derived from natural microbial communities produce graphs riddled with spurious cycles, complicating the accurate reconstruction of circular genomes. We present an algorithm that reconstructs true circular genomes based on the identification of so-called  dominant cycles. Our algorithm leverages paired reads to bridge gaps between assembly contigs and scrutinizes cycles through a nucleotide-level analysis, making the approach robust to mis-assembly artifacts. We validated the approach using simulated and reference data. Application of this approach to 32 publicly available DNA shotgun sequence data sets from diverse natural environments led to the reconstruction of hundreds of circular mobile genomes. Clustering revealed 20 clusters of cryptic, prevalent, and abundant plasmids that have clonal population structures with surprisingly recent common ancestors. This work enables the robust study of evolution and spread of mobile elements in natural settings.


title: A comparison of shear- and compression-induced mechanotransduction in SW1353 chondrocytes

abstract: Mechanotransduction is a biological phenomenon where mechanical stimuli are converted to biochemical responses. A model system for studying mechanotransduction are the chondrocytes of articular cartilage. Breakdown of this tissue results in decreased mobility, increased pain, and reduced quality of life. Either disuse or overloading can disrupt cartilage homeostasis, but physiological cyclical loading promotes cartilage homeostasis. To model this, we exposed SW1353 cells to cyclical mechanical stimuli, shear and compression, for different durations of time (15 and 30 min). By utilizing liquid chromatography-mass spectroscopy (LC-MS), metabolomic profiles were generated detailing metabolite features and biological pathways that are altered in response to mechanical stimulation. In total, 1,457 metabolite features were detected. Statistical analyses identified several pathways of interest. Taken together, differences between experimental groups were associated with inflammatory pathways, lipid metabolism, beta-oxidation, central energy metabolism, and amino acid production. These findings expand our understanding of chondrocyte mechanotransduction under varying loading conditions and time periods.


title: Comparative transcriptome analysis of noble crayfish and marbled crayfish immune response to Aphanomyces astaci  challenges

abstract:
Introduction of invasive North American crayfish species and their pathogen Aphanomyces astaci has significantly contributed to the decline of European freshwater crayfish populations. In this study, noble crayfish, a susceptible native European species, and marbled crayfish, an invasive disease-resistant species, were challenged with haplogroup A (low virulence) and haplogroup B (high virulence) strain of A. astaci. Hepatopancreatic tissue was isolated 3 and 21 days post-challenge. Our results revealed strong up-regulation in expression levels of the prophenoloxidase cascade immune-related genes in the haplogroup B challenged noble crayfish 3 days post-challenge. In the marbled crayfish, we observed an up-regulation of immune system relevant genes (DSCAM, AP, ALFs, CTLs and hemocyanin) 3 days post-challenge. This response highlights the marbled crayfish capability of building the immune tolerance. Furthermore, we successfully characterised several novel immune related gene groups in both crayfish species, contributing to our current understanding of crayfish immune related genes landscape.

Graphical abstracta) Study species noble crayfish (Astacus astacus) in purple and marbled crayfish (Procambarus virginalis) in green challenged with the pathogen Aphanomyces astaci haplogroup A (Hap A) strain of low virulence and haplogroup B (Hap B) strain of high virulence. b) Sampling scheme of the infection experiment: 5 individuals were taken from the experiment three- and 21-days post-challenge. From each individual, a hepatopancreas sample was taken, followed by RNA isolation and sequencing. c) De novo transcriptome assembly and annotation were conducted for each species. d) Differential gene expression analysis revealed the distinct immune response in the noble crayfish 3 days post-challenge with the Hap B strain of A. astaci and marbled crayfish 3 days post-challenge with the Hap A strain of A. astaci. Immune related DEGs were not present in either species 21 days post-challenge with A. astaci. e) Noble crayfish challenged with the Hap B strain of A. astaci were acutely infected and ultimately moribund, while the A. astaci Hap A challenged marbled crayfish showed high resistance to the pathogen, resulting infected without any mortality.

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title: Mechanical counterbalance of kinesin and dynein motors in microtubular network regulates cell mechanics, 3D architecture, and mechanosensing

abstract: Microtubules (MTs) and MT motor proteins form active 3D networks made of unstretchable cables with rod-like bending mechanics that provide cells with a dynamically changing structural scaffold. In this study, we report an antagonistic mechanical balance within the dynein-kinesin microtubular motor system. Dynein activity drives microtubular network inward compaction, while isolated activity of kinesins bundles and expands MTs into giant circular bands that deform the cell cortex into discoids. Furthermore, we show that dyneins recruit MTs to sites of cell adhesion increasing topographic contact guidance of cells, while kinesins antagonize it via retraction of MTs from sites of cell adhesion. Actin-to-microtubules translocation of septin-9 enhances kinesins-MTs interactions, outbalances activity of kinesins over dyneins and induces discoid architecture of cells. These orthogonal mechanisms of MT network reorganization highlight the existence of an intricate mechanical balance between motor activities of kinesins and dyneins that controls cell 3D architecture, mechanics, and cell-microenvironment interactions.


title: On the inference of positive and negative species associations and their relation to abundance

abstract: The prevalence of rare species in ecosystems begs the question of how they persist. In a recent paper, Calatayuda et al. (CEA) provided a new hypothesis that rare species, in contrast to common species, share unique microhabitats and/or preferentially engage in mutualistic interactions. CEA support this hypotheses by reconstructing association networks from spatially replicated abundance data finding that rare species are over-representing in positive association networks while common species are over-representing in negative association networks. However, the use of abundance and co-occurrence data to infer true species associations is difficult and often inaccurate. Here, I show that the finding of rare species being more represented in positive association networks can be explained by statistical artifacts in the inference of species associations from abundance data. I caution against the inference of ecological association networks from abundance data alone.


title: Fibronectin meshwork controls epithelial stem cell fate

abstract: Adult stem cell fate is tightly balanced by the local microenvironment called niche and sustain tissue regeneration1-4. How niche signals are integrated and regulate regeneration remains largely unexplored. The extracellular matrix and integrin ligand fibronectin is a crucial and well-characterized wound healing actor that has never been involved in skin regeneration. Here, we show that fibronectin displays a highly specific enrichment in hair follicle stem cells (HFSC) at the onset of regeneration. Conditional deletion of fibronectin in HFSC compartment (Lrig1, K19) leads to hair regeneration blockade, impaired stem cell location and fate. Dermal injection of exogenous fibronectin rescues these phenotypes. To elucidate molecular mechanism underlying fibronectin function, we used conditional deletion models of SLC3A2, the main integrin coreceptor. We show that, via its role in integrin-dependent assembly of fibronectin matrix, SLC3A2 acts as molecular relay of niche signals. Thus, fibronectin-integrin-SLC3A2 cascade finely tunes HFSC fate and tissue regenerative power.

category: physiology


title: Convolutional neural networks trained with a developmental sequence of blurry to clear images reveal core differences between face and object processing

abstract: Although convolutional neural networks (CNNs) provide a promising model for understanding human vision, most CNNs lack robustness to challenging viewing conditions such as image blur, whereas human vision is much more reliable. Might robustness to blur be attributable to vision during infancy, given that acuity is initially poor but improves considerably over the first several months of life? Here, we evaluated the potential consequences of such early experiences by training CNN models on face and object recognition tasks while gradually reducing the amount of blur applied to the training images. For CNNs trained on blurry to clear faces, we observed sustained robustness to blur, consistent with a recent report by Vogelsang and colleagues (2018). By contrast, CNNs trained with blurry to clear objects failed to retain robustness to blur. Further analyses revealed that the spatial frequency tuning of the two CNNs was profoundly different. The blurry to clear face-trained network successfully retained a preference for low spatial frequencies, whereas the blurry to clear object-trained CNN exhibited a progressive shift toward higher spatial frequencies. Our findings provide novel computational evidence showing how face recognition, unlike object recognition, allows for more holistic processing. Moreover, our results suggest that blurry vision during infancy is insufficient to account for the robustness of adult vision to blurry objects.


title: APOE4 genotype increases neuronal calcium signals and decreases pial arteriole responsivity and vasomotion in visual cortex of awake mice

abstract:
Vascular dysfunction is an early feature of late onset Alzheimers disease (AD), preceding classic AD pathology such as beta amyloid accumulation and formation of hyperphosphorylated tau. Such vascular dysfunction may promote classic AD pathology by decreasing blood flow, impairing brain oxygenation and clearance of molecules such as beta amyloid. The main genetic risk factor for AD is the {varepsilon}4 allele of APOE, which has been found to increase blood brain barrier permeability and decrease vascular density, as well as decrease blood flow and functional hyperaemia in anaesthetised mice undergoing acute surgery. These results suggest that APOE4 may confer AD risk via its effects on the vasculature. However, the responses of neurons and individual vessels have not been studied, so neurovascular relationships are unknown, and no previous studies have looked at awake mice.

We therefore measured neurovascular responses at rest and in response to visual stimulation using 2 photon imaging of awake APOE3 and APOE4 targeted-replacement (APOE TR) mice that expressed the calcium indicator GCaMP6f in excitatory neurons, while labelling the vascular lumen with Texas Red dextran. In parallel, we measured cerebral blood flow, blood oxygenation and cerebral blood volume using combined laser Doppler flowmetry and haemoglobin spectrometry. Measurements were performed in mice aged between 3-4 months to 12-13 months.

We found a milder vascular deficit in awake mice than previous studies that used an acute surgical preparation: capillary responses to visual stimulation were the same in APOE3 and APOE4 TR mice, leading to unimpaired functional hyperaemia. However, neuronal calcium signals during visual stimulation were significantly enhanced in APOE4 mice, while there was a marked decrease in pial arteriole responsiveness and vasomotion. This pattern of results was unaffected by age, suggesting that APOE4 expression creates a stable, but mildly altered neurovascular state that does not itself cause degeneration. However, these changes likely make the system more sensitive to subsequent insults; for example, weaker vasomotion could impair clearance of beta amyloid as it starts to accumulate, and therefore may help explain how APOE4 expression increases risk of developing AD.


title: Brain capillary obstruction as a novel mechanism of anti-CD19 CAR T cell neurotoxicity

abstract: Immunotherapy for hematologic malignancies with CD19-directed CAR T cells is associated with neurotoxicity in about 40% of patients. Systemic cytokine release syndrome, endothelial activation, and disruption of endothelial integrity have all been associated with neurotoxicity, but it remains unclear how these mechanisms interact and how they lead to neurologic dysfunction. We developed a syngeneic mouse model which manifests systemic cytokine release and behavioral abnormalities within 3-5 days after infusion of high-dose murine CD19-CAR T cells. Histologic examination revealed widespread brain hemorrhages, diffuse extravascular IgG deposition, loss of capillary pericyte coverage and increased prevalence of string capillaries. In vivo two-photon imaging of blood flow revealed plugging of >10% of capillaries by leukocytes, associated with regions of localized hypoxia. These data reveal capillary obstruction and associated brain hypoxia and microvascular decline as a potential basis for neurotoxicity during CD19-CAR T cell treatment in humans, which may be amenable to therapeutic interventions.


title: Neural coding of visual objects rapidly reconfigures to reflect sub-trial shifts in attentional focus

abstract: Every day, we respond to the dynamic world around us by flexibly choosing actions to meet our goals. This constant problem solving, in familiar settings and in novel tasks, is a defining feature of human behaviour. Flexible neural populations are thought to support this process by adapting to prioritise task-relevant information, driving coding in specialised brain regions toward stimuli and actions that are important for our goal. Accordingly, human fMRI shows that activity patterns in frontoparietal cortex contain more information about visual features when they are task-relevant. However, if this preferential coding drives momentary focus, for example to solve each part of a task, it must reconfigure more quickly than we can observe with fMRI. Here we used MVPA with MEG to test for rapid reconfiguration of stimulus information when a new feature becomes relevant within a trial. Participants saw two displays on each trial. They attended to the shape of a first target then the colour of a second, or vice versa, and reported the attended features at a choice display. We found evidence of preferential coding for the relevant features in both trial phases, even as participants shifted attention mid-trial, commensurate with fast sub-trial reconfiguration. However, we only found this pattern of results when the task was difficult, and the stimulus displays contained multiple objects, and not in a simpler task with the same structure. The data suggest that adaptive coding in humans can operate on a fast, sub-trial timescale, suitable for supporting periods of momentary focus when complex tasks are broken down into simpler ones, but may not always do so.


title: Sex Differences in Functional Topography of Association Networks

abstract:
Prior work has shown that there is substantial interindividual variation in the spatial distribution of functional networks across the cerebral cortex, or functional topography. However, it remains unknown whether there are sex differences in the topography of individualized networks in youth. Here we leveraged an advanced machine learning method (sparsity-regularized nonnegative matrix factorization) to define individualized functional networks in 693 youth (ages 8-23 years) who underwent functional magnetic resonance imaging as part of the Philadelphia Neurodevelopmental Cohort. Multivariate pattern analysis using support vector machines classified participant sex based on functional topography with 83% accuracy (p<0.0001). Brain regions most effective in classifying participant sex belonged to association networks, including the ventral attention and default mode networks. Mass-univariate analyses using generalized additive models with penalized splines provided convergent results. Comparative analysis using transcriptomic data from the Allen Human Brain Atlas revealed that sex differences in multivariate patterns of functional topography correlated with the expression of genes on the X-chromosome. These results identify normative developmental sex differences in the functional topography of association networks and highlight the role of sex as a biological variable in shaping brain development in youth.

SIGNIFICANCE STATEMENTWe identify normative developmental sex differences in the functional topography of personalized association networks including the ventral attention network and default mode network. Furthermore, chromosomal enrichment analyses revealed that sex differences in multivariate patterns of functional topography were spatially coupled to the expression of X-linked genes as well as astrocytic and excitatory neuronal cell-type signatures. These results highlight the role of sex as a biological variable in shaping functional brain development in youth.


title: Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence

abstract: SARS-CoV-2 has infected over 200 million and caused more than 4 million deaths to date. Most individuals (>80%) have mild symptoms and recover in the outpatient setting, but detailed studies of immune responses have focused primarily on moderate to severe COVID-19. We deeply profiled the longitudinal immune response in individuals with mild COVID-19 beginning with early time points post-infection (1-15 days) and proceeding through convalescence to >100 days after symptom onset. We correlated data from single cell analyses of peripheral blood cells, serum proteomics, virus-specific cellular and humoral immune responses, and clinical metadata. Acute infection was characterized by vigorous coordinated innate and adaptive immune activation that differed in character by age (young vs. old). We then characterized signals associated with recovery and convalescence to define and validate a new signature of inflammatory cytokines, gene expression, and chromatin accessibility that persists in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC).

category: immunology


title: Impaired function and delayed regeneration of dendritic cells in COVID-19

abstract: Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DC) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute disease to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage- HLADR+ cells lacking DC markers. Increased frequency of the recently discovered CD163+ CD14+ DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of PD-L1 in conventional DC (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naive CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.


title: Identifying dysregulated immune cell subsets following critical volumetric muscle loss with pseudo-time trajectories

abstract: Volumetric muscle loss (VML) results in permanent functional deficits and remains a substantial regenerative medicine challenge. A coordinated immune response is crucial for timely myofiber regeneration, however the immune response following VML has yet to be fully characterized. Here, we leveraged dimensionality reduction and pseudo-time analysis techniques to elucidate the cellular players underlying a functional or pathological outcome as a result of subcritical or critical VML in the murine quadriceps, respectively. We found that critical VML presented with a sustained presence of M2-like and CD206hiLy6Chi  hybrid macrophages whereas subcritical defects resolved these populations. These macrophage subsets may contribute to fibrogenesis in critical VML, especially in the presence of TGF-{beta}. Furthermore, several T cell populations were significantly elevated in critical VML compared to subcritical injuries. Specifically, there was a significant increase of CD127+ T cells at days 3 and 7, and upregulated CD127 expression may indicate aberrant IL-7 signaling in critical VML. These results demonstrate a dysregulated immune response in critical VML that is unable to resolve the chronic inflammatory state and transition to a pro-regenerative microenvironment. These data provide important insights into potential therapeutic strategies which could reduce the immune cell burden and pro-fibrotic signaling characteristic of VML.


title: Effective prophylaxis of COVID-19 in rhesus macaques using a combination of two parentally-administered SARS-CoV-2 neutralizing antibodies

abstract: SARS-CoV-2 is a respiratory borne pathogenic beta coronavirus that is the source of a worldwide pandemic and the cause of multiple pathologies in man. The rhesus macaque model of COVID-19 was utilized to test the added benefit of combinatory parenteral administration of two high-affinity anti-SARS-CoV-2 monoclonal antibodies (mAbs; C144-LS and C135-LS) expressly developed to neutralize the virus and modified to extend their pharmacokinetics. After completion of kinetics study of mAbs in the primate, combination treatment was administered prophylactically to mucosal viral challenge. Results showed near complete virus neutralization evidenced by no measurable titer in mucosal tissue swabs, muting of cytokine/chemokine response, and lack of any discernable pathologic sequalae. Blocking infection was a dose-related effect, cohorts receiving lower doses (6, 2 mg/kg) resulted in low grade viral infection in various mucosal sites compared to that of a fully protective dose (20 mg/kg). A subset of animals within this cohort whose infectious challenge was delayed 75 days later after mAb administration were still protected from disease. Results indicate this combination mAb effectively blocks development of COVID-19 in the rhesus disease model and accelerates the prospect of clinical studies with this effective antibody combination.

category: microbiology


title: Molecular programming in utero modulates hepatic lipid metabolism and adult metabolic risk in obese mother offspring in a sex-specific manner

abstract: Male and female offspring of obese mothers are known to differ significantly in their metabolic adaptation and later development of complications. We investigated the sex-dependent responses in obese offspring of mice with maternal obesity, focusing on changes in liver glucose and lipid metabolism. Maternal obesity prior to and during gestation led to hepatic insulin resistance and inflammation in male offspring, while female offspring were protected. These sex differences were explained by more efficient transcriptional and posttranscriptional reprogramming of metabolic pathways to prevent the damaging effects of maternal obesity in females compared to males. These differences were sustained later in life, resulting in a better metabolic balance in female offspring. In conclusion, sex and maternal obesity drive transcriptional and posttranscriptional regulation of major metabolic processes in offspring liver differently, explaining the sexual dimorphism in obesity-associated metabolic risk.


title: Bi-phasic effect of gelatin in myogenesis and skeletal muscle regeneration

abstract: Skeletal muscle regeneration requires extracellular matrix (ECM) remodeling including an acute and transient breakdown of collagen that produces gelatin. However, the physiological function of such a remodeling process on muscle tissue repair is unclear. Here we elaborate on a bi-phasic effect of gelatin in skeletal muscle regeneration, mediated by hormetic effects of reactive oxygen species (ROS). Low-dose gelatin stimulates ROS production from NADPH oxidase 2 (NOX2) and simultaneously upregulates antioxidant system for cellular defense, reminiscent of the adaptive compensatory process during mild stress. This response triggers the release of myokine IL-6 which stimulates myogenesis and facilitates muscle regeneration. By contrast, high-dose gelatin stimulates ROS overproduction from NOX2 and mitochondrial chain complex, and ROS accumulation by suppressing antioxidant system, triggering release of TNF, which inhibits myogenesis and regeneration. Our findings reveal gelatin-ROS-IL-6/TNF signaling cascades underlying a hormetic response of myogenic cells to gelatin.


title: Attentional brain rhythms during prolonged cognitive activity

abstract: As routine and lower demand cognitive tasks are taken over by automated assistive systems, human operators are increasingly required to sustain cognitive demand over long periods of time. This has been reported to have long term adverse effects on cardiovascular and mental health. However, it remains unclear whether prolonged cognitive activity results in a monotonic decrease in the efficiency of the recruited brain processes, or whether the brain is able to sustain functions over time spans of one hour and more. Here, we show that during working sessions of one hour or more, contrary to the prediction of a monotonic decline, behavioral performance in both humans and non-human primates consistently fluctuates between periods of optimal and suboptimal performance at a very slow rhythm of circa 5 cycles per hour. These fluctuations are observed in both high attentional (in non-human primates) and low attentional (in humans) demand conditions. They coincide with fluctuations in pupil diameter, indicating underlying changes in arousal and information-processing load. Accordingly, we show that these rhythmic behavioral fluctuations correlate, at the neurophysiological level, with fluctuations in the informational attention orientation and perception processing capacity of prefrontal neuronal populations. We further identify specific markers of these fluctuations in LFP power, LFP coherence and spike-field coherence, pointing towards long-range rhythmic modulatory inputs to the prefrontal cortex rather than a local prefrontal origin. These results shed light on the resilience of brain mechanisms to sustained effort and have direct implications on how to optimize high cognitive demand working and learning environments.


title: Evidence of neutralizing antibodies against SARS-CoV-2 in domestic cats living with owners with a history of COVID-19 in Lima, Peru

abstract: SARS-CoV-2 can infect a variety of wild and domestic animals worldwide. Of these, domestic cats are highly susceptible species and potential viral reservoirs. As such, it is important to investigate disease exposure in areas with active community transmission and high disease prevalence. In this report we demonstrate the presence of serum neutralizing antibodies against the receptor binding-domain (RBD) of the SARS-CoV-2 in cats whose owners had been infected with SARS-CoV-2 in Lima, Peru, using a commercial competitive ELISA SARS-CoV-2 Surrogate Virus Neutralization Test. Out of 41 samples, 17.1% (7/41) and 31.7% (13/41) were positive, using the cut-off inhibition value of 30% and 20%, respectively. Not all cats living in a single house had detectable neutralizing antibodies showing that heterogenous exposure and immune among cohabiting animals. This is the first report of SARS-COV-2 exposure of domestic cats in Lima, Peru. Further studies are required to ascertain the prevalence of SARS-COV-2 exposure among domestic cats of Lima, Peru.


title: SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation

abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-{kappa}B activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-{kappa}B signaling. Nsp14 caused the nuclear translocation of NF-{kappa}B p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5-monophosphate dehydrogenase 2 (IMPDH2) protein, which is known to regulate NF-{kappa}B signaling. We confirmed the Nsp14-IMPDH2 protein interaction and found that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14-mediated NF-{kappa}B activation and cytokine induction. Furthermore, IMDPH2 inhibitors (RIB, MPA) efficiently blocked SARS-CoV-2 infection, indicating that IMDPH2, and possibly NF-{kappa}B signaling, is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in causing the activation of NF-{kappa}B.


title: Complex structure of the Bacillus subtilis CdaA c-di-AMP cyclase domain and the phosphoglucomutase GlmM

abstract: Cyclic-di-adenosine monophosphate (c-di-AMP) is an important nucleotide signalling molecule, which plays a key role in osmotic regulation in bacteria. Cellular c-di-AMP levels are tightly regulated, as both high and low levels have a negative impact on bacterial growth. Here, we investigated how the activity of the main Bacillus subtilis c-di-AMP cyclase CdaA is regulated by the phosphoglucomutase GlmM. c-di-AMP is produced from two molecules of ATP by proteins containing a deadenylate cyclase (DAC) domain. CdaA is a membrane-linked cyclase with an N-terminal transmembrane domain followed by the cytoplasmic DAC domain. Here we show, using the soluble catalytic B. subtilis CdaACD domain and purified full-length GlmM or the GlmMF369 variant lacking the C-terminal flexible domain 4, that the cyclase and phosphoglucomutase form a stable complex in vitro and that GlmM is a potent cyclase inhibitor. We determined the crystal structure of the individual B. subtilis CdaACD and GlmM proteins, both of which form dimers in the structures, and of the CdaACD:GlmMF369 complex. In the complex structure, a CdaACD dimer is bound to a GlmMF369 dimer in such a manner that GlmM blocks the oligomerization of CdaACD and formation of active head-to-head cyclase oligomers, thus providing molecular details on how GlmM acts as cyclase inhibitor. The function of a key amino acid residue in CdaACD in complex formation was confirmed by mutagenesis analysis. As the amino acids at the CdaACD:GlmM interphase are conserved, we propose that the observed inhibition mechanism of CdaA by GlmM is conserved among Firmicutes.


title: Structural basis for the inhibition of the Bacillus subtilis c-di-AMP cyclase CdaA by the phosphoglucomutase GlmM


title: aCPSF1 in synergy with terminator U-tract dictates archaeal transcription termination efficiency via the KH domains recognizing U-tract

abstract: Recently, aCPSF1 was reported to function as the long-sought global transcription termination factor of archaea, while the working mechanism remains elusive. This work, through analyzing transcript-3'end-sequencing data of Methanococcus maripaludis, found positive correlations of both the terminator uridine(U)-tract and aCPSF1 with hierarchical transcription termination efficiencies (TTEs) at the genome-wide level. In vitro assays determined that aCPSF1 specifically binds to the terminator U-tract with U-tract number-related binding abilities, and in vivo assays demonstrated the two are indispensable in dictating high TTEs, revealing that aCPSF1 and the terminator U-tract in synergy determine high TTEs. The N-terminal KH domains equip aCPSF1 of specific binding to terminator U-tract and the in vivo aCPSF1-terminator U-tract synergism; aCPSF1s nuclease activity was also required for TTEs. aCPSF1 also functioned as back-up termination for transcripts with weak intrinsic terminator signals. aCPSF1 orthologs from Lokiarchaeota and Thaumarchaeota exhibited similar U-tract synergy in dictating TTEs. Therefore, aCPSF1 and the intrinsic U-rich terminator could work in a noteworthy two-in-one termination mode in Archaea, which could be widely employed by archaeal phyla; using one factor recognizing U-rich terminator signal and cleaving transcript 3'-end, the archaeal aCPSF1-dependent transcription termination could display a simplified archetypal mode of the eukaryotic RNA polymerase II termination machinery.


title: Systemic infection with highly pathogenic H5N8 of avian origin produces encephalitis and mortality in wild mammals at a UK rehabilitation centre

abstract: Europe has experienced extensive outbreaks of highly pathogenic avian influenza (HPAI) during the autumn/winter 2020/21 season. These avian influenza A viruses are highly transmissible and have infected over 1000 commercial and backyard poultry premises in Europe in this period causing high mortality. The impact on wild bird populations has also been significant, with over 400 detections in at least 47 different species reported across Europe as being positive with the H5N8 virus. Although different H5Nx combinations within the H5 clade 2.3.4.4b have been detected, the H5N8 subtype has predominated both in wild birds and domestic poultry outbreaks. In the UK there have been 22 outbreaks of H5N8 in domestic poultry and captive birds and more than 300 wild bird detections involving H5N8 over the autumn/winter 2020/21 period to April 2021. Here we detail the series of events surrounding the detection of an H5N8 influenza A virus of avian origin in five swans, a fox and three seals in a wildlife rehabilitation centre.


title: Extracellular electron transfer increases fermentation in lactic acid bacteria via a hybrid metabolism

abstract: Energy conservation in microorganisms is classically categorized into respiration and fermentation, however recent work shows some species can use mixed or alternative bioenergetic strategies. We explored the utility of a flavin-based extracellular electron transport (FLEET) system for energy conservation within diverse lactic acid bacteria (LAB), microorganisms that mainly rely on fermentative metabolism and are important in food fermentations. The LAB Lactiplantibacillus plantarum uses extracellular electron transfer to increase its NAD+/NADH ratio, generate more ATP through substrate-level phosphorylation and accumulate biomass more rapidly. This novel, hybrid metabolism was dependent on a type-II NADH dehydrogenase (Ndh2) and conditionally required a flavin-binding extracellular lipoprotein (PplA) in the FLEET system to confer increased fermentation yield, metabolic flux, and environmental acidification in both laboratory media and food fermentation. The discovery of a single pathway that blends features of fermentation and respiration expands our knowledge of energy conservation metabolism and provides immediate biotechnology applications.


title: Abundant and rare bacterial taxa structuring differently in sediment and water in thermokarst lakes in the Yellow River Source area, Qinghai-Tibet Plateau

abstract: Thermokarst lakes are forming from permafrost thaw and severely affected by accelerating climate change. Sediment and water in these lakes are distinct habitats but closely connected. However, our understanding of the differences and linkages between sediment and water in thermokarst lakes remain largely unknow, especially from the perspective of community assembly mechanisms. Here, we examined bacterial communities in sediment and water in thermokarst lakes in the Yellow River Source area, Qinghai-Tibet Plateau. Bacterial taxa were divided to abundant and rare according to their relative abundance, and the Sorensen dissimilarity ({beta}sor) was partitioned into turnover ({beta}turn) and nestedness ({beta}nest). The whole bacterial communities as well as the abundant and rare subcommunities differed substantially between sediment and water, in terms of taxonomical composition, -diversity, and {beta}-diversity. Sediment had significantly lower -diversity indexes but higher {beta}-diversity than water. Abundant taxa had significantly higher relative abundances but lower -diversity and {beta}-diversity than rare taxa. Moreover, bacterial communities are predominantly governed by strong turnover processes ({beta}turn/{beta}sor ratio of 0.925). Abundant subcommunities were significantly lower in {beta}turn/{beta}sor ratio compared to rare subcommunities. Bacterial communities in sediment had a significantly higher {beta}turn/{beta}sor ratio than in water. The results suggest that the bacterial communities of thermokarst lakes, especially rare subcommunities or particularly in sediment, might be strongly structured by environmental filtering and geographical isolation, leading to compositional distinct. This integral study increased our current knowledge of thermokarst lakes, enhancing our understanding of the community assembly rules and ecosystem structures and processes of these rapid changing and vulnerable ecosystems.


title: Variable Induction of Pro-inflammatory Cytokines by Commercial SARS CoV-2 Spike Protein Reagents: Potential Impacts of LPS on In Vitro Modeling and Pathogenic Mechanisms In Vivo

abstract: Proinflammatory cytokine production following infection with severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is associated with poor clinical outcomes. Like SARS CoV-1, SARS CoV-2 enters host cells via its spike protein, which attaches to angiotensin-converting enzyme 2 (ACE2). As SARS CoV-1 spike protein is reported to induce cytokine production, we hypothesized that this pathway could be a shared mechanism underlying pathogenic immune responses. We herein compared the capabilities of Middle East Respiratory Syndrome (MERS), SARS CoV-1 and SARS CoV-2 spike proteins to induce cytokine expression in human peripheral blood mononuclear cells (PBMC). We observed that only specific commercial lots of SARS CoV-2 induce cytokine production. Surprisingly, recombinant SARS CoV-2 spike proteins from different vendors and batches exhibited different patterns of cytokine induction, and these activities were not inhibited by blockade of spike protein-ACE2 binding using either soluble ACE2 or neutralizing anti-S1 antibody. Moreover, commercial spike protein reagents contained varying levels of endotoxin, which correlated directly with their abilities to induce cytokine production. The lipopolysaccharide (LPS) inhibitor, polymyxin B, blocked this cytokine induction activity. In addition, SARS CoV-2 spike protein avidly bound soluble LPS in vitro, rendering it a cytokine inducer. These results not only suggest caution in monitoring the purity of SARS CoV-2 spike protein reagents, but they indicate the possibility that interactions of SARS CoV-2 spike protein with LPS from commensal bacteria in virally infected mucosal tissues could promote pathogenic inflammatory cytokine production.