bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of human behavior on the evolution of viral strains during an epidemic
Authors: Azizi Asma , Komarova Natalia L. , Wodarz Dominik
Published: September 2021

It is well known in the literature that human behavior can change as a reaction to disease observed in others, and that such behavioral changes can be an important factor in the spread of an epidemic. It has been noted that human behavioral traits in disease avoidance are under selection in the presence of infectious diseases. Here we explore a complimentary trend: the pathogen itself might experience a force of selection to become less “visible”, or less “symptomatic”, in the presence of such human behavioral trends. Using a stochastic SIR agent-based model, we investigated the co-evolution of two viral strains with cross-immunity, where the resident strain is symptomatic while the mutant strain is asymptomatic. We assumed that individuals exercised self-regulated social distancing (SD) behavior if one of their neighbors was infected with a symptomatic strain. We observed that the proportion of asymptomatic carriers increased over time with a stronger effect corresponding to higher levels of self-regulated SD. Adding mandated SD made the effect more significant, while the existence of a time-delay between the onset of infection and the change of behavior reduced the advantage of the asymptomatic strain. These results were consistent under random geometric networks, scale-free networks, and a synthetic network that represented the social behavior of the residents of New Orleans.
Benchmarking feature quality assurance strategies for non-targeted metabolomics
Authors: El Abiead Yasin , Milford Maximilian , Schoeny Harald , Rusz Mate , Salek Reza M , Koellensperger Gunda
Published: September 2021

Automated data pre-processing (DPP) forms the basis of any liquid chromatography-high resolution mass spectrometry-driven non-targeted metabolomics experiment. However, current strategies for quality control of this important step have rarely been investigated or even discussed. We exemplified how reliable benchmark peak lists could be generated for eleven publicly available datasets acquired across different instrumental platforms. Moreover, we demonstrated how these benchmarks can be utilized to derive performance metrics for DPP and tested whether these metrics can be generalized for entire datasets. Relying on this principle, we cross-validated different strategies for quality assurance of DPP, including manual parameter adjustment, variance of replicate injection-based metrics, unsupervised clustering performance, automated parameter optimization, and deep learning-based classification of chromatographic peaks. Overall, we want to highlight the importance of assessing DPP performance on a regular basis.
Reconstruction of the binding pathway of an anti-HIV drug, Indinavir, in complex with the HTLV-1 protease by Unaggregated Unbiased Molecular Dynamics simulation
Authors: Sohraby Farzin , Aryapour Hassan
Published: September 2021

Retroviruses are a growing concern for the health of human beings, and one of the dangerous members of this family is the Human T-cell Leukemia Virus 1 (HTLV-1) virus. It has affected more than 20 million people so far, and since there are no registered treatments against it yet, urgent treatment solutions are needed. One of the most promising drug targets to fight this virus is the protease enzyme of the virus’s protein machinery. In this study, by utilizing a computational method called Unaggregated Unbiased Molecular Dynamics (UUMD), we reconstructed the binding pathway of a HTLV-1 protease inhibitor, Indinavir, to find the details of the binding pathway, the influential residues, and also the stable states of the binding pathway. We achieved the native conformation of the inhibitor in 6 rounds, 360 replicas by performing over 4 micro-seconds of UMD simulations. We found 3 Intermediate states between the solvated state and the native conformation state in the binding pathway. We also discovered that aromatic residues such as Trp98 and Trp98′, catalytic residues Asp32 and Asp32′, and the flap region’s residues have the most influential roles in the binding pathway and also have the most contribution to the total interaction energies. We believe that the details found in this study would be a great guide for developing new treatment solutions against the HTLV-1 virus by inhibiting the HTLV-1 protease.
Reassortment Network of Influenza A Virus
Authors: Gong Xingfei , Hu Mingda , Chen Wei , Yang Haoyi , Wang Boqian , Yue Junjie , Jin Yuan , Liang Long , Ren Hongguang
Published: September 2021

Influenza A virus (IAV) genomes are composed of eight single-stranded RNA segments. Genetic exchange through reassortment of the segmented genomes often endows IAVs with new genetic characteristics, which may affect transmissibility and pathogenicity of the viruses. However, a comprehensive understanding of the reassortment history of IAVs remains lacking. To this end, we assembled 40296 whole-genome sequences of IAVs for analysis. Using a new clustering method based on Mean Pairwise Distances in the phylogenetic trees, we classified each segment of IAVs into clades. Correspondingly, reassortment events among IAVs were detected by checking the segment clade compositions of related genomes under specific environment factors and time period. We systematically identified 1927 possible reassortment events of IAVs and constructed their reassortment network. Interestingly, minimum spanning tree of the reassortment network reproved that swine act as an intermediate host in the reassortment history of IAVs between avian species and human. Moreover, reassortment patterns among related subtypes constructed in this study are consistent with previous studies. Taken together, our genome-wide reassorment analysis of all the IAVs offers an overview of the leaping evolution of the virus and a comprehensive network representing the relationships of IAVs.

Availability

Source code freely available for download at https://github.com/ElevenStr/IAVreassortment, implemented in python.

Lead Contact

bioren@163.com
Transcriptional networks underpinning ploidy related increased leaf potassium in neo-tetraploids
Authors: Fischer Sina , Flis Paulina , Zhao Fang-Jie , Salt David E.
Published: September 2021

Neo-tetraploid Arabidopsis thaliana have elevated leaf potassium (K) driven by processes within the root. The root transcriptome of neo-tetraploids is distinct from diploids, with evidence of altered K homeostasis. Mutational analysis revealed that the canonical K-uptake transporters AKT1 and HAK5 are not required for this elevated leaf K in neo-tetraploids, while the endodermis, root hairs, and SOS signaling are. Contrasting the root transcriptomes of neo-tetraploids and diploids of mutants that block the neo-tetraploid K phenotype, allowed us to identify 91 differentially expressed genes associated with elevated leaf K in neo-tetraploids. This set of genes connects WGD to elevated leaf K, and is enriched in functions such as cell wall and Casparian strip development, and ion-transport, in the endodermis, root hairs, and procambium. This gene set provides tools to test the intriguing idea of recreating the physiological effects of WGD within a diploid genome.
Evolutionary innovations through gain and loss of genes in the ectomycorrhizal Boletales
Authors: Wu Gang , Miyauchi Shingo , Morin Emmanuelle , Kuo Alan , Drula Elodie , Varga Torda , Kohler Annegret , Feng Bang , Cao Yang , Lipzen Anna , Daum Christopher , Hundley Hope , Pangilinan Jasmyn , Johnson Jenifer , Barry Kerrie , LaButti Kurt , Ng Vivian , Ahrendt Steven , Min Byoungnam , Choi In-Geol , Park Hongjae , Plett Jonathan M. , Magnuson Jon , Spatafora Joseph W. , Nagy László G. , Henrissat Bernard , Grigoriev Igor V. , Yang Zhu-Liang , Xu Jianping , Martin Francis M.
Published: September 2021

In this study, we aim to identify genomic traits of the transitions to the ectomycorrhizal ecology within the Boletales, one of the most diverse lineages of symbiotrophic fungi.

We sequenced the genomes and compared the gene repertoires of symbiotrophic Boletales species to their saprotrophic brown-rot relatives. We also reconstructed gene duplication/loss histories along a time-calibrated phylogeny.

We showed that the rate of gene duplication is constant along the backbone of Boletales phylogeny with large loss events in lineages leading to several families. The rate of gene family expansion sharply increased in the late Miocene and mostly took place in Boletaceae.

Most of the ectomycorrhizal Boletales are characterized by a large genome size due to transposable element (TE) expansions and a reduction in the diversity of plant cell wall degrading enzymes (PCWDEs) compared to their brown-rot relatives. However, several species in the Boletaceae, Paxillaceae and Boletinellaceae have kept a substantial set of endoglucanases and LPMOs acting on cellulose/hemicellulose and fungal polysaccharides suggesting that they may partly decompose organic matter by a combined activity of oxidative and hydrolytic enzymes.

The present study provides novel insights on our understanding of the mechanisms that influence the evolutionary diversification of boletes and symbiosis evolution.
Overriding defective FPR chemotaxis signaling in diabetic neutrophil stimulates infection control in diabetic wound
Authors: Roy Ruchi , Zayas Janet , Wood Stephen J. , Mohamed Mohamed F. , Frausto Dulce M. , Estupinian Ricardo , Giurini Eileena F. , Kuzel Timothy M. , Zloza Andrew , Reiser Jochen , Shafikhani Sasha H.
Published: September 2021

Infection is a major co-morbidity that contributes to impaired healing in diabetic wounds. Although impairments in diabetic neutrophils have been blamed for this co-morbidity, what causes these impairments and whether they can be overcome, remain largely unclear. Diabetic neutrophils, extracted from diabetic individuals, exhibit chemotaxis impairment but this peculiar functional impairment has been largely ignored because it appears to contradict the clinical findings which blame excessive neutrophil influx (neutrophilia) as a major impediment to healing in chronic diabetic ulcers. Here, we report that exposure to glucose in diabetic range results in impaired chemotaxis signaling through the FPR1 chemokine receptor in neutrophils, culminating in reduced chemotaxis and delayed neutrophil trafficking in wound in diabetic animals, and rendering diabetic wound vulnerable to infection. We further show that at least some auxiliary chemokine receptors remain functional under diabetic conditions and their engagement by the pro-inflammatory cytokine CCL3, overrides the requirement for FPR1 signaling and substantially improves infection control by jumpstarting the neutrophil response toward infection, and stimulates healing in diabetic wound. We posit that CCL3 may have real therapeutic potential for the treatment of diabetic foot ulcers if it is applied topically after the surgical debridement process which is intended to reset chronic ulcers into acute fresh wounds.
Laminar microcircuitry of visual cortex producing attention-associated electric fields
Authors: Westerberg Jacob A. , Schall Michelle S. , Maier Alexander , Woodman Geoffrey F. , Schall Jeffrey D.
Published: September 2021

Cognitive operations are widely studied by measuring electric fields through EEG and ECoG. However, despite their widespread use, the component neural circuitry giving rise to these signals remains unknown. Specifically, the functional architecture of cortical columns which results in attention-associated electric fields has not been explored. Here we detail the laminar cortical circuitry underlying an attention-associated electric field often measured over posterior regions of the brain in humans and monkeys. First, we identified visual cortical area V4 as one plausible contributor to this attention-associated electric field through inverse modeling of cranial EEG in macaque monkeys performing a visual attention task. Next, we performed laminar neurophysiological recordings on the prelunate gyrus and identified the electric-field-producing dipoles as synaptic activity in distinct cortical layers of area V4. Specifically, activation in the extragranular layers of cortex resulted in the generation of the attention-associated dipole. Feature selectivity of a given cortical column determined the overall contribution to this electric field. Columns selective for the attended feature contributed more to the electric field than columns selective for a different feature. Lastly, the laminar profile of synaptic activity generated by V4 was sufficient to produce an attention-associated signal measurable outside of the column. These findings suggest that the top-down recipient cortical layers produce an attention-associated electric field capable of being measured extracranially and the relative contribution of each column depends upon the underlying functional architecture.
Reach-dependent reorientation of rotational dynamics in motor cortex
Authors: Sabatini David A. , Kaufman Matthew T.
Published: September 2021

During reaching, neurons in motor cortex exhibit complex, time-varying activity patterns. Though single-neuron activity correlates with movement parameters, movement correlations explain neural activity only partially. Neural responses also reflect population-level dynamics thought to generate outputs. These dynamics have previously been described as “rotational”, such that activity orbits in neural state space. Here, we find two essential features previously missed. First, the planes in which rotations occur differ for different reaches. Second, this variation in planes reflects the overall location of activity in neural state space. Our “location-dependent rotations” model fits nearly all motor cortex activity during reaching and enables higher-quality decoding of reach kinematics from single-trial spiking. Varying rotational planes allows motor cortex to more simply produce richer outputs than possible under previous models. Finally, our model links representational and dynamical ideas: a representation-like signal is present as the state space location, which dynamics then convert into time-varying command signals.
Effects of vestibular stimulation on gait stability when walking at different step widths
Authors: Magnani Rina M. , van Dieën Jaap H. , Bruijn Sjoerd M.
Published: September 2021

Vestibular information modulates muscle activity during gait, presumably to contribute to stability. If this is the case, stronger effects of perturbing vestibular information on local dynamic stability of gait, a measure of the locomotor system’s response to small, naturally occurring perturbations, can be expected for narrow-base walking (which needs more control) than for normal walking and smaller effects for wide-base walking (which needs less control). An important mechanism to stabilize gait is to coordinate foot placement to center of mass (CoM) state. Vestibular information most likely contributes to sensing this CoM state. We, therefore, expected that stochastic electrical vestibular stimulation (EVS) would decrease the correlation between foot placement and CoM state during the preceding swing phase. In fourteen healthy participants, we measured the kinematics of the trunk (as a proxy of the CoM), and feet, while they walked on a treadmill in six conditions: control (usual step width), narrow-base, and wide-base, each with and without stochastic EVS (peak amplitude of 5 mA; RMS of ~ 1.2 mA; frequency band from 0 to 25 Hz). Stochastic EVS decreased local dynamic stability irrespective of step width. Foot placement correlated stronger with trunk motion during walking with EVS than without in the control condition. However, residual variance in foot placement was increased when walking with EVS, indicating less precise foot placement. Thus, a vestibular error signal leads to a decrease in gait stability and precision of foot placement but these effects are not consistently modulated by step width.
Structured random receptive fields enable informative sensory encodings
Authors: Pandey Biraj , Pachitariu Marius , Brunton Bingni W. , Harris Kameron Decker
Published: September 2021

Brains must represent the outside world so that animals survive and thrive. In early sensory systems, neural populations have diverse receptive fields structured to detect important features in inputs, yet significant variability has been ignored in classical models of sensory neurons. We model neuronal receptive fields as random, variable samples from parameterized distributions and demonstrate this model in two sensory modalities using data from insect mechanosensors and mammalian primary visual cortex. Our approach leads to a significant theoretical connection between the foundational concepts of receptive fields and random features, a leading theory for understanding artificial neural networks. The modeled neurons perform a randomized wavelet transform on inputs, which removes high frequency noise and boosts the signal. Further, these random feature neurons enable learning from fewer training samples and with smaller networks in artificial tasks. This structured random model of receptive fields provides a unifying, mathematically tractable framework to understand sensory encodings across both spatial and temporal domains.
A linear neural circuit for light avoidance in Drosophila larvae
Authors: Sorkaç Altar , Savva Yiannis A. , Savaş Doruk , Talay Mustafa , Barnea Gilad
Published: September 2021

Understanding how neural circuits underlie behaviour is challenging even in the era of the connectome because it requires a combined approach encompassing anatomical and functional analyses. This is exemplified in studying the circuit underlying the light-avoidance behaviour displayed by the larvae of the fruit fly Drosophila melanogaster. While this behaviour is robust and the nervous system relatively simple, only bits and pieces of the circuit have been delineated1. Indeed, some studies resulted in contradicting conclusions regarding the contributions of various neuronal types to this behaviour2,3. Here we devise trans-Tango MkII, a new version of the transsynaptic circuit tracing and manipulation tool trans-Tango4. We implement trans-Tango MkII in anatomical tracing and combine it with circuit epistasis analysis. We use neuronal inhibition to test necessity of particular neuronal types for light-avoidance. We complement these experiments by selective neuronal activation to examine sufficiency in rescuing light-avoidance deficiencies exhibited by photoreceptor mutants. Together, our studies reveal a four-order, linear circuit for light-avoidance behaviour connecting the light-detecting photoreceptors with a pair of neuroendocrine cells via two types of clock neurons. Our combined approach could be readily expanded to other larval circuits. Further, this strategy provides the framework for studying more complex nervous systems and behaviours.
ON/OFF domains shape receptive fields in mouse visual cortex
Authors: Tring Elaine , Duan Konnie , Ringach Dario L.
Published: September 2021

In higher mammals, thalamic afferents to primary visual cortex (area V1) segregate according to their responses to increases (ON) or decreases (OFF) in luminance1–4. This organization induces columnar, ON/OFF domains postulated to provide a scaffold for the emergence of orientation tuning2,5–15. To further test this idea, we asked whether ON/OFF domains exist in mouse V1 – a species containing orientation tuned, simple cells, like those found in other mammals16–19. Here we show that mouse V1 is indeed parceled into ON/OFF domains. Revealingly, fluctuations in the relative density ON/OFF neurons on the cortical surface mirror fluctuations in the relative density of ON/OFF receptive field centers on the visual field. In each cortical volume examined, the average of simple-cell receptive fields correlates with the difference between the average of ON and OFF receptive fields7. Moreover, the local diversity of simple-cell receptive fields is explained by a model in which neurons linearly combine a small number of ON and OFF signals available in their cortical neighborhoods15,20. Altogether, these findings indicate that ON/OFF domains originate in fluctuations of the spatial density of ON/OFF inputs on the visual field which, in turn, shapes the structure of receptive fields10–13,21–23.
Chromosome-scale genome assembly of Eustoma grandiflorum, the first complete genome sequence in family Gentianaceae
Authors: Shirasawa Kenta , Arimoto Ryohei , Hirakawa Hideki , Ishimorai Motoyuki , Ghelfi Andrea , Miyasaka Masami , Endo Makoto , Kawabata Saneyuki , Isobe Sachiko
Published: September 2021

Eustoma grandiflorum (Raf.) Shinn., is an annual herbaceous plant native to the southern United States, Mexico, and the Greater Antilles. It has a large flower with a variety of colors and an important flower crop. In this study, we established a chromosome-scale de novo assembly of E. grandiflorum by integrating four genomic and genetic approaches: (1) Pacific Biosciences (PacBio) Sequel deep sequencing, (2) error correction of the assembly by Illumina short reads, (3) scaffolding by chromatin conformation capture sequencing (Hi-C), and (4) genetic linkage maps derived from an F2 mapping population. The 36 pseudomolecules and unplaced 64 scaffolds were created with total length of 1,324.8 Mb. Full-length transcript sequencing was obtained by PacBio Iso-Seq sequencing for gene prediction on the assembled genome, Egra_v1. A total of 36,619 genes were predicted on the genome as high confidence HC) genes. Of the 36,619, 25,936 were annotated functions by ZenAnnotation. Genetic diversity analysis was also performed for nine commercial E. grandiflorum varieties bred in Japan, and 254,205 variants were identified. This is the first report of the construction of reference genome sequences in E. grandiflorum as well as in the family Gentianaceae.
Local neuronal excitation and global inhibition during epileptic fast ripples in humans
Authors: Curot Jonathan , Barbeau Emmanuel , Despouy Elodie , Denuelle Marie , Sol Jean Christophe , Lotterie Jean-Albert , Valton Luc , Peyrache Adrien
Published: September 2021

Understanding the neuronal basis of epileptiform activity is a major challenge in neurology. Interictal epileptiform discharges are associated with fast ripples (FRs, >200 Hz) in the local field potential (LFP) and are a promising marker of the epileptogenic zone. Here, by using a novel hybrid macro-micro depth electrode, combining classic depth recording of LFP and two or three tetrodes enabling up to 15 neurons in local circuits to be recorded simultaneously, we have characterized neuronal responses to FRs on the same hybrid and other electrodes targeting other brain regions. While FRs were associated with increased neuronal activity in local circuits only, they were followed by inhibition in large-scale networks. Neuronal responses to FRs were homogeneous in local networks but differed across brain areas. Similarly, post-FR inhibition varied across recording locations and subjects and was shorter than typical inter-FR intervals, suggesting that this inhibition is a fundamental refractory process for the networks. These findings demonstrate that FRs engage local and global networks and point to network features that pave the way for new diagnostic and therapeutic strategies.
Comparative Genome Analysis of ‘Candidatus Phytoplasma luffae’ Reveals the Influential Roles of Potential Mobile Units in Phytoplasma Evolution
Authors: Huang Ching-Ting , Cho Shu-Ting , Lin Yu-Chen , Tan Choon-Meng , Chiu Yi-Ching , Yang Jun-Yi , Kuo Chih-Horng
Published: September 2021

Phytoplasmas are insect-transmitted plant pathogens that cause substantial losses in agriculture. In addition to economic impact, phytoplasmas induce distinct disease symptoms in infected plants, thus attracting attention for research on molecular plant-microbe interactions and plant developmental processes. Due to the difficulty of establishing an axenic culture of these bacteria, culture-independent genome characterization is a crucial tool for phytoplasma research. However, phytoplasma genomes have strong nucleotide composition biases and are repetitive, which make it challenging to produce complete assemblies. In this study, we utilized Illumina and Oxford Nanopore sequencing technologies to obtain the complete genome sequence of ‘Candidatus Phytoplasma luffae’ strain NCHU2019 that is associated with witches’ broom disease of loofah (Luffa aegyptiaca) in Taiwan. The fully assembled circular chromosome is 769 kb in size and is the first representative genome sequence of group 16SrVIII phytoplasmas. Comparative analysis with other phytoplasmas revealed that NCHU2019 has an exceptionally repetitive genome, possessing a pair of 75 kb repeats and at least 13 potential mobile units (PMUs) that account for ~25% of its chromosome. This level of genome repetitiveness is exceptional for bacteria, particularly among obligate pathogens with reduced genomes. Our genus-level analysis of PMUs demonstrated that these phytoplasma-specific mobile genetic elements can be classified into three major types that differ in gene organization and phylogenetic distribution. Notably, PMU abundance explains nearly 80% of the variance in phytoplasma genome sizes, a finding that provides a quantitative estimate for the importance of PMUs in phytoplasma genome variability. Finally, our investigation found that in addition to horizontal gene transfer, PMUs also contribute to intra-genomic duplications of effector genes, which may provide redundancy for neofunctionalization or subfunctionalization. Taken together, this work improves the taxon sampling for phytoplasma genome research and provides novel information regarding the roles of mobile genetic elements in phytoplasma evolution.
De-novo chromosome level assembly of plant genomes from long read sequence data
Authors: Sharma Priyanka , Masouleh Ardashir Kharabian , Topp Bruce , Furtado Agnelo , Henry Robert J.
Published: September 2021

Recent advances in the sequencing and assembly of plant genomes have allowed the generation of genomes with increasing contiguity and sequence accuracy. The chromosome level assembly of the contigs generated from long read sequencing has involved the use of proximity analysis (Hi-C) or traditional genetic maps to guide the placement of sequence contigs within chromosomes. The development of highly accurate long reads by repeated sequencing of circularized DNA (PacBio HiFi) has greatly increased the size of contigs. We now report the use of HiFiasm to assemble the genome of Macadamia jansenii. a genome that has been used as model to test sequencing and assembly. This achieved almost complete chromosome level assembly from the sequence data alone without the need for higher level chromosome map information. Eight of the 14 chromosomes were represented by a single large contig and the other 6 assembled into 2-4 main contigs. The small number of chromosome breaks appear to be due to highly repetitive regions of ribosomal genes that cannot be assembled by these approaches. De novo assembly of near complete chromosome level plant genomes now seems possible using these sequencing and assembly tools. Further targeted strategies might allow these remaining gaps to be closed.

Significance statement (of up to two sentences)

De novo assembly of near complete chromosome level plant genomes is now possible using current long read sequencing and assembly tools.
Distinct and diverse chromatin-proteomes of ageing mouse organs reveal protein signatures that correlate with physiological functions
Authors: Oliviero Giorgio , Kovalchuk Sergey , Rogowska-Wrzesinska Adelina , Schwämmle Veit , Jensen Ole N.
Published: September 2021

Temporal molecular changes in ageing mammalian organs are of relevance to disease etiology because many age-related diseases are linked to changes in the transcriptional and epigenetic machinery that regulate gene expression. We performed quantitative proteome analysis of chromatin-enriched protein extracts to investigate the dynamics of the chromatin-proteomes of the mouse brain, heart, lung, kidney, liver, and spleen at 3, 5, 10, and 15 months of age. Each organ exhibited a distinct chromatin-proteome and sets of unique proteins. The brain and spleen chromatin-proteomes were the most extensive, diverse, and heterogenous among the six organs. The spleen chromatin proteome appeared static during the lifespan, presenting a young phenotype that reflects the permanent alertness state and important role of this organ in physiological defense and immunity. We identified a total of 5928 proteins, including 2472 nuclear or chromatin associated proteins across the six mouse organs. Up to 3125 proteins were quantified in each organ demonstrating distinct and organ-specific temporal protein expression timelines and regulation at the post-translational level. Bioinformatics meta- analysis of these chromatin proteomes revealed distinct physiological and ageing- related features for each organ. Our results demonstrate the efficiency of organelle specific proteomics for in vivo studies of a model organism and consolidate the hypothesis that chromatin-associated proteins are involved in distinct and specific physiological functions in ageing organs.

HIGHLIGHTS

Quantitative chromatin-proteome analysis during mouse lifespan;

Chromatin analysis in vitro and in vivo mouse models;

Distinct chromatin proteomes of six organs during mouse lifespan;

Correlations between ageing and chromatin regulation in mammalian lifespan.
Deep Learning-based Prediction of Early Cerebrovascular Events after Transcatheter Aortic Valve Replacement
Authors: Okuno Taishi , Overtchouk Pavel , Asami Masahiko , Tomii Daijiro , Stortecky Stefan , Praz Fabien , Lanz Jonas , Siontis George CM , Gräni Christoph , Windecker Stephan , Pilgrim Thomas
Published: September 2021

Background

Cerebrovascular events (CVE) are one of the most feared complications of transcatheter aortic valve replacement (TAVR). CVE appear difficult to predict due to their multifactorial origin incompletely explained by clinical predictors. We aimed to build a deep learning-based predictive tool for TAVR-related CVE.

Methods

Integrated clinical and imaging characteristics from consecutive patients enrolled into a prospective TAVR registry were analysed. CVE comprised any strokes and transient ischemic attacks. Predictive variables were selected by recursive feature reduction to train an autoencoder predictive model. Area under the curve (AUC) represented the model’s performance to predict 30-day CVE.

Results

Among 2,279 patients included between 2007 and 2019, both clinical and imaging data were available in 1,492 patients. Median age was 83 years and STS score was 4.6%. Acute (<24 hours) and subacute (day 2-30) CVE occurred in 19 (1.3%) and 36 (2.4%) patients, respectively. The occurrence of CVE was associated with an increased risk of death (HR [95%CI]: 2.62 [1.82-3.78]). The constructed predictive model uses less than 107 clinical and imaging variables and has an AUC of 0.79 (0.65-0.93).

Conclusions

TAVR-related CVE can be estimated using a deep learning-based predictive algorithm. The model was implemented online for broad usage. (https://www.welcome.alviss.ai/#/cvecalculator).
TerraFlow, A New High Parameter Data Analysis Tool, Reveals Systemic T-cell Exhaustion and Dysfunctional Cytokine Production in Classical Hodgkin Lymphoma
Authors: Freeman Daniel , Diefenbach Catherine , Lam Linda , Le Tri , Alexandre Jason , Raphael Bruce , Grossbard Michael , Kaminetzky David , Ruan Jia , Chattopadhyay Pratip K.
Published: September 2021

The incredible variety of proteins associated with immune responses presents a major challenge in immune monitoring. When combinations of these proteins are measured, cell types that influence disease can be precisely identified. Here, we introduce TerraFlow, a novel data analysis tool that performs an exhaustive search of disease-associated cell populations from high-parameter flow cytometry experiments. Using a newly generated dataset, from 24-color immune checkpoint-focused and 18-color immune function-focused experiments, we apply TerraFlow to classical Hodgkin lymphoma (cHL), where systemic T-cell immunity has not been investigated in detail. We reveal novel immune perturbations in newly diagnosed cHL, as well as persistent immune perturbations after treatment. Newly diagnosed patients have elevated levels of activated (CD278+), exhausted (e.g., CD366+ and CD152+ phenotypes), and IL17-expressing cells, along with diminished levels of naïve and central memory (CD127+) T-cells and fewer IFNγ+ and TNF+ T-cells. Exhaustion signatures are reduced with treatment, but compared to healthy individuals, treated patients still exhibit more activated (CD278+ phenotypes), exhausted (CD366+), and IL17-expressing cells. Notably, TerraFlow identifies more phenotypic differences between patient groups than FlowSOM and CellCNN, often with better predictive power. Finally, we introduce a new non-gating approach for data analysis that obviates the need for time-consuming and subjective setting of fluorescence thresholds. Our results benchmark TerraFlow against common methods, provide mechanistic support for past reports of immune deficiency in cHL, and provide a roadmap for future immunotherapy and biomarker studies.
Reproduction in deep-sea vent shrimps is shaped by diet and phylogeny, with rhythms unlinked to surface production
Authors: Methou Pierre , Chen Chong , Watanabe Hiromi K. , Cambon-Bonavita Marie-Anne , Pradillon Florence
Published: September 2021

Variations in offspring production according to feeding strategies or food supply have been recognized in many animals from various ecosystems. Despite an unusual trophic structure based on non-photosynthetic primary production, these relationships remain largely under-studied in chemosynthetic ecosystems. Here, we useRimicarisshrimps from deep-sea hydrothermal vents as a study case to explore relations between reproduction, diets and food supply in these environments. For that, we compared reproductive outputs of three congeneric shrimps differing by their diets. They inhabit vents located under oligotrophic waters of tropical gyres with opposed latitudes, allowing us to also examine the prevalence of phylogenetic vs environmental drivers in their reproductive rhythms. For this we used both our original data and a compilation of published observations on the presence of ovigerous females covering various seasons over the past 35 years. We report distinct egg production trends betweenRimicarisspecies relying solely on chemosymbiosis –R. exoculataandR. kairei– and those relying on mixotrophy –R. chacei– whereR. chaceiproduces broods with higher numbers of smaller eggs. Besides, our data and historical records suggest a reproductive period with substantial proportions of brooding females mostly between January and early April for all examined species whatever the region. Intriguingly, this periodicity does not correspond to seasonal variations in surface production with presence of brooding females during either boreal winter or austral summer. These observations contrast with the long-standing paradigm in deep-sea species for which periodic reproductive patterns have always been attributed to seasonal variations of photosynthetic production sinking from surface. Our results suggest the presence of intrinsic basis for biological rhythms in the deep sea, and bring to light the importance of having year-round observations in order to understand life history of vent animals.
Induction of transposable element expression is central to innate sensing
Authors: Rookhuizen Derek C. , Bonte Pierre-Emmanuel , Ye Mengliang , Hoyler Thomas , Gentili Matteo , Burgdorf Nina , Durand Sylvère , Aprahamian Fanny , Kroemer Guido , Manel Nicolas , Waterfall Joshua J , Milne Richard , Goudot Christel , Towers Greg J. , Amigorena Sebastian
Published: September 2021

Evidence indicates that transposable elements (TEs) stimulate innate sensing pathways in various pathologies but it is not clear whether they are sensed during normal physiological responses. Here we show that, during activation with an exogenous pathogen associated molecular pattern (PAMP), dendritic cells (DCs) epigenetically remodel heterochromatin at TEs by depleting the methyltransferase Suv39h1 and reducing histone-3 lysine-9 trimethylation (H3K9me3). TLR4 signaling activates TE expression to enhance innate responses through the DNA sensor cGAS. Cytosolic cGAS-bound DNA comprised LINE1 TEs as the predominant endogenous ligands. Concordantly, LINE1 inhibition attenuated the type-I IFN response to LPS and rescued influenza virus infection. We propose that in healthy cells, exogenous PAMPs epigenetically activate self-derived PAMPs (LINE1) that engage cGAS to enhance responses. These data explain why pathogens employ redundant and broad innate immune countermeasures, to suppress activation of host PAMPs and illustrate a hitherto unappreciated role for host genome-derived PAMPs in response to pathogens.
Environmental niche and demographic modeling of American chestnut near its southwestern range limit
Authors: Laport Robert G. , Brookover Zoe S. , Christman Brian D. , Ng Julienne , Philley Kevin , Craddock J. Hill
Published: September 2021

Abstract

The inadvertent introduction and rapid spread of chestnut blight (caused byCryphonectria parasitica(Murr.) Barr) in the early 20th century resulted in the demise of American chestnut (Castanea dentata(Marsh.) Borkh.; Fagaceae) as a major component of forest canopies and had negative impacts on eastern forest communities. Research efforts over the last century have documented the persistence of occasional trees and root crown/stump sprouts throughout much of the species’ historic range providing the basis for ongoing breeding of blight-resistant stock and restoration efforts. Unfortunately, it remains unclear how much of the historic range remains climatically suitable for remnant trees that may harbor unique genetic variation for successful reintroduction efforts. Here we investigate whether the southwestern portion of the historical range remains environmentally suitable for undiscovered remnant populations ofC. dentatausing environmental niche modeling. We also use stage-structured matrix projection models to investigate the potential demographic future ofC. dentatain W Tennessee, N Mississippi, SW Kentucky, and NW Alabama based upon observations of American chestnut in these areas over the last several decades. We found that suitable habitat associated with higher elevations and areas of high forest canopy cover occurs throughout much of the southwestern portion of the historical range and that populations of American chestnut in these areas are predicted to drastically decline over the next ~100-200 years without conservation interventions to mitigate the negative consequences of chestnut blight.
Germinal center activity and B cell maturation promote protective antibody responses against Plasmodium pre-erythrocytic infection
Authors: Visweswaran Ganesh Ram R. , Vijayan Kamalakannan , Chandrasekaran Ramyavardhanee , Trakhimets Olesya , Whiteside Samantha L. , Vigdorovich Vladimir , Yang Ashton , Raappana Andrew , Watson Alex , Selman William , Zuck Meghan , Dambrauskas Nicholas , Kaushansky Alexis , Sather D. Noah
Published: September 2021

Blocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. Rodent-infectious species of Plasmodium such as P. yoelii (Py) serve as key tools to study vaccine efficacy and disease biology in immune-competent experimental animals. Here we evaluated the differences in vaccine-elicited humoral immunity in two widely used, and vastly diverged, inbred mouse strains, BALB/cJ and C57BL/6J, and identified immunological factors associated with protection. We vaccinated with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated protective efficacy after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice, whereas; all C57BL/6J mice were infected similar to controls. Interestingly, protection was mediated by antibodies, and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, PyCSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer germinal center experienced, CSP-specific class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in PyCSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that BALB/cJ mice achieved higher levels of B cell maturation in response to vaccination with PyCSP, which likely enabled the development of protective antibody responses. Overall, our study indicates that germinal center activity and B cell maturation are key processes in the development of vaccine-elicited protective antibodies against CSP.
How biological cells including platelets and megakaryocytes decide complex problems fast but risky
Authors: Prada Juan , Balkenhol Johannes , Kaltdorf Martin , Osmanoglu Özge , Stoerkle Martin , Heinze Katrin , Manukjan Georgi , Schulze Harald , Dandekar Thomas
Published: September 2021

Short Abstract

Mathematical decision processes are accurate but sometimes take very long time or simply do not happen. Decisions in biology happen fast and driven by evolution, optimizing survival chances. This results in stochastic decisions with on average good adaptation to the environment but an inherent risk of individual errors e.g. developing cancer during cell regeneration. We calculate and show in platelets and megakaryocytes how cellular decision processes increases risk for errors and inflammation. Short cut solutions adapted from nature improve computer strategies for protein folding and network decision processes. Complex problems are not always solved in foreseeable time, instead the fast solutions in biology speed up errors everywhere including biochemical aging of blood vessels, misfolded proteins, mis-programmed cells, cancer and heart failure.

One sentence abstract

We investigate in biological networks how complex decision problems are mastered not by an accurate but unforeseeable long mathematical search but rather pragmatic and fast, with an inherent risk of error, a basis for inflammation and cancer.
A model-guided pipeline for drug cardiotoxicity screening with human stem-cell derived cardiomyocytes
Authors: Clark Alexander P. , Wei Siyu , Krogh-Madsen Trine , Christini David J.
Published: September 2021

New therapeutic compounds go through a preclinical drug cardiotoxicity screening process that is overly conservative and provides limited mechanistic insight, leading to the misclassification of potentially beneficial drugs as proarrhythmic. There is a need to develop a screening paradigm that maintains this high sensitivity, while ensuring non-cardiotoxic compounds pass this phase of the drug approval process. In this study, we develop an in vitro-in silico pipeline using human induced stem-cell derived cardiomyocytes (iPSC-CMs) to address this problem. The pipeline includes a model-guided optimization that produces a voltage-clamp (VC) protocol to determine drug block of seven cardiac ion channels. Such VC data, along with action potential (AP) recordings, were acquired from iPSC-CMs before and after treatment with a control solution or a low-, intermediate-, or high-risk drug. We identified significant AP prolongation (a proarrhythmia indicator) in two high-risk drugs and, from the VC data, determined strong ion channel blocks that led to the AP changes. The VC data also uncovered an undocumented funny current (If) block by quinine, which we confirmed with experiments using a HEK-293 expression line. We present a new approach to cardiotoxicity screening that simultaneously evaluates proarrhythmia risk (e.g. AP prolongation) and mechanism (e.g. channel block) from iPSC-CMs.
Long-term effects of wildfire smoke exposure during early-life on the nasal epigenome in rhesus macaques
Authors: Brown Anthony P. , Cai Lucy , Laufer Benjamin I. , Miller Lisa A. , LaSalle Janine M. , Ji Hong
Published: September 2021

Background

Wildfire smoke is responsible for around 20% of all particulate emissions in the U.S. and affects millions of people worldwide. Children are especially vulnerable, as ambient air pollution exposure during early childhood is associated with reduced lung function. Most studies, however, have focused on the short-term impacts of wildfire smoke exposures. We aimed to identify long-term baseline epigenetic changes associated with early-life exposure to wildfire smoke. We collected nasal epithelium samples for whole genome bisulfite sequencing (WGBS) from two groups of adult female rhesus macaques: one group born just before the 2008 California wildfire season and exposed to wildfire smoke during early-life (n = 8), and the other group born in 2009 with no wildfire smoke exposure during early-life (n = 14). RNA-sequencing was also performed on a subset of these samples.

Results

We identified 3370 differentially methylated regions (DMRs) (difference in methylation ≥ 5% empirical p < 0.05) and 1 differentially expressed gene (FLOT2) (FDR< 0.05, fold of change ≥ 1.2). The DMRs were annotated to genes significantly enriched for synaptogenesis signaling, protein kinase A signaling, and a variety of immune processes, and some DMRs significantly correlated with gene expression differences. DMRs were also significantly enriched within regions of bivalent chromatin (top odds ratio = 1.46, q-value < 3 x 10-6) that often silence key developmental genes while keeping them poised for activation in pluripotent cells.

Conclusions

These data suggest that early-life exposure to wildfire smoke leads to long-term changes in the methylome over genes impacting the nervous and immune systems, but follow-up studies will be required to test whether these changes influence transcription following an immune/respiratory challenge.
Social hosts evade predation but have deadlier parasites
Authors: Walsman Jason C. , Janecka Mary J. , Clark David R. , Kramp Rachael D. , Rovenolt Faith , Patrick Regina , Mohammed Ryan S. , Konczal Mateusz , Cressler Clayton E. , Stephenson Jessica F.
Published: September 2021

Parasites exploit hosts to replicate and transmit, but overexploitation kills host and parasite (1): predators may shift this cost-benefit balance by consuming hosts (2–4) or changing host behavior, but the strength of these effects remains unclear. Modeling both, we find a primary, strong effect: hosts group to defend against predators (5), increasing parasite transmission, thus multiple infections, and therefore favoring more exploitative, virulent, parasites (6). Indeed, among 18 TrinidadianGyrodactyusspp. parasite lines, those collected from high predation guppy populations were more virulent in common garden than those from low predation populations. Our model accurately predicted this result when parametrized with our experimentally demonstrated virulence-transmission trade-off, implicating the behavioral effects of predation. Broadly, our results indicate that reduced social contact selects against parasite virulence.

One-Sentence Summary

Our theory and data show predators cause increased host social grouping; the resulting transmission favors parasite virulence.