bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-omic Profiling Reveals Early Immunological Indicators for Identifying COVID-19 Progressors
Authors: Drake Katherine A. , Talantov Dimitri , Tong Gary J. , Lin Jack T. , Verheijden Simon , Katz Samuel , Leung Jacqueline M. , Yuen Benjamin , Krishna Vinod , Wu Michelle J. , Sutherland Alex , Short Sarah A. , Kheradpour Pouya , Mumbach Maxwell , Franz Kate , Trifonov Vladimir , Lucas Molly V. , Merson James , Kim Charles C. ,   PRESCO Study Group
Published: May 2023

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a rapid response by the scientific community to further understand and combat its associated pathologic etiology. A focal point has been on the immune responses mounted during the acute and post-acute phases of infection, but the immediate post-diagnosis phase remains relatively understudied. We sought to better understand the immediate post-diagnosis phase by collecting blood from study participants soon after a positive test and identifying molecular associations with longitudinal disease outcomes. Multi-omic analyses identified differences in immune cell composition, cytokine levels, and cell subset-specific transcriptomic and epigenomic signatures between individuals on a more serious disease trajectory (Progressors) as compared to those on a milder course (Non-progressors). Higher levels of multiple cytokines were observed in Progressors, with IL-6 showing the largest difference. Blood monocyte cell subsets were also skewed, showing a comparative decrease in non-classical CD14−CD16+and intermediate CD14+CD16+monocytes. Additionally, in the lymphocyte compartment, CD8+T effector memory cells displayed a gene expression signature consistent with stronger T cell activation in Progressors. Importantly, the identification of these cellular and molecular immune changes occurred at the early stages of COVID-19 disease. These observations could serve as the basis for the development of prognostic biomarkers of disease risk and interventional strategies to improve the management of severe COVID-19.

One Sentence Summary

Immunological changes associated with COVID-19 progression can be detected during the early stages of infection.
Fast and flexible Bayesian Jolly Seber models and application to populations with transients
Authors: Saracco James F. , Yackulic Charles B.
Published: May 2023

Jolly Seber (JS) models are an appealing class of capture-recapture models for modeling open populations because they allow for inferences about an array of population parameters, including abundance, survival, and recruitment. Multiple formulations of JS models have been developed and include both maximum likelihood and Bayesian approaches. Bayesian approaches offer greater flexibility; however, they are often extremely slow when applied to moderate to large populations because the latent states of all observed individuals, as well as any potential unobserved individuals (parameter-expanded data augmentation), must be simulated at each time step.

JS model implementations can be sped up dramatically through marginalization, whereby the conditional likelihoods of states are tracked for unique capture histories, rather than the simulated states of all individuals. Here we describe a marginalized implementation of a multistate JS model and compare its performance to that of an implementation using simulated discrete states. We fit models to data generated under two scenarios, one in which no data was missing and another in which 25% of data was randomly removed. To illustrate how marginalization can accommodate more complex models and datasets, we describe a modified version of the model for application to populations with transients and fit the model to simulated data and to data collected on Kentucky Warblers (Geothlypis formosa) as part of the Monitoring Avian Productivity and Survivorship (MAPS) program.

Both the discrete latent state and marginalized JS model implementations performed similarly with respect to bias and coverage; however, the marginalized implementation was roughly 1,000 times faster when no data were missing and 100 times faster when 25% of data was missing. The marginalized model accommodating transients also converged quickly and a more complex version of the model applied to the larger multi-site Kentucky Warbler data set yielded useful estimates of most parameters within a reasonable time frame (hours).

Gains in efficiency provided by marginalization shown here should stimulate additional study and development of this useful class of models and provide new opportunities for real-world applications to large complex data sets.
Molecular Dynamics simulation of NRAS-Q61 oncogenes and new strategies forin silicodrug design
Authors: Hu Zheyao , Marti Jordi
Published: May 2023

The NRAS-mutant subset of melanoma represents the most aggressive and the deadliest types associated with poorer overall survival. Unfortunately, for more than 40 years, no therapeutic agent directly targeting NRAS mutations have been clinically approved yet. Herein, based on microsecond scale molecular dynamics simulations, the concept of NRAS-Q61 mutation classification was firstly proposed. NRAS Q61 positively charged mutations (Q61R and Q61K) was classified together, with a specific targetable pocket, while NRAS-Q61L classified into another category. Moreover, the isomer-sourced structure iteration (ISSI) method was developed for the in silico design of potential inhibitors (HM-516) targeting NRAS mutations. Overall, through this article, we hope to provide the academic and clinical community with new perspective and understanding of NRAS oncoproteins, and propose possible solution to this challenge.
Mapping oak wilt disease using phenological observations from space
Authors: Guzmán Q. J. Antonio , Pinto-Ledezma Jesús N. , Frantz David , Townsend Philip A. , Juzwik Jennifer , Cavender-Bares Jeannine
Published: May 2023

Protecting the future of forests relies on our ability to observe changes in forest health. Thus, developing tools for sensing diseases in a timely fashion is critical for managing threats at broad scales. Oak wilt —a disease caused by a pathogenic fungus (Bretziella fagacearum)— is threatening oaks, killing thousands yearly while negatively impacting the ecosystem services they provide. Here we propose a novel workflow for mapping oak wilt by targeting temporal disease progression through symptoms using land surface phenology (LSP) from spaceborne observations. By doing so, we hypothesize that phenological changes in pigments and photosynthetic activity of trees affected by oak wilt can be tracked using LSP metrics derived from the Chlorophyll/Carotenoid Index (CCI). We used dense time-series observations from Sentinel-2 to create Analysis Ready Data across Minnesota and Wisconsin and to derive three LSP metrics: the value of CCI at the start and end of the growing season, and the coefficient of variation of the CCI during the growing season. We integrate high-resolution airborne imagery in multiple locations to select pixels (n =3,872) from the most common oak tree health conditions: healthy, symptomatic for oak wilt, and dead. These pixels were used to train an iterative Partial Least Square Discriminant (PLSD) model and derive the probability of an oak tree (i.e., pixel) in one of these conditions and the associated uncertainty. We assessed these models spatially and temporally on testing datasets revealing that it is feasible to discriminate among the three health conditions with overall accuracy between 80-82%. Within conditions, our models suggest that spatial variations among three CCI-derived LSP metrics can predict healthily (Area Under the Curve (AUC) = 0.98), symptomatic (AUC = 0.89), and dead (AUC = 0.94) oak trees with low false positive rates. The model performance was robust across different years as well. The predictive maps were used to guide local stakeholders in locating disease hotspots for ground verification and subsequent decision-making for treatment. Our results highlight the capabilities of LSP metrics from dense spaceborne observations to map diseases and their importance for monitoring changes in biodiversity at large scales.
Plasticity-led evolution as an intrinsic property of developmental gene regulatory networks
Authors: Ng Eden Tian Hwa , Kinjo Akira R.
Published: May 2023

The Modern Evolutionary Synthesis seemingly fails to explain how a population can survive a large environmental change: the pre-existence of heritable variants adapted to the novel environment is too opportunistic, whereas the search for new adaptive mutations after the environmental change is so slow that the population may go extinct. Plasticity-led evolution, the initial environmental induction of a novel adaptive phenotype followed by genetic accommodation, has been proposed to solve this problem. However, the mechanism enabling plasticity-led evolution remains unclear. Here, we present computational models that exhibit behaviors compatible with plasticity-led evolution by extending the Wagner model of gene regulatory networks. The models show adaptive plastic response and the uncovering of cryptic mutations under large environmental changes, followed by genetic accommodation. Moreover, these behaviors are consistently observed over distinct novel environments. We further show that environmental cues, developmental processes, and hierarchical regulation cooperatively amplify the above behaviors and accelerate evolution. These observations suggest plasticity-led evolution is a universal property of complex developmental systems independent of particular mutations.
Viral fusion proteins of class II and III recognize and reorganize complex biological membranes
Authors: Poojari Chetan S , Bommer Tobias , Hub Jochen S
Published: May 2023

Viral infection requires stable binding of viral fusion proteins to host membranes, which contain hundreds of lipid species. The mechanisms by which fusion proteins utilize specific host lipids to drive virus--host membrane fusion remains elusive. We conducted molecular simulations of class I, II, and III fusion proteins interacting with membranes of diverse lipid compositions. Free energy calculations reveal that class I fusion proteins generally exhibit stronger membrane binding compared to classes II and III --- a trend consistent across 74 fusion proteins from 13 viral families as suggested by sequence analysis. Class II fusion proteins utilize a lipid binding pocket formed by fusion protein monomers, stabilizing the initial binding of monomers to the host membrane prior to assembling into fusogentic trimers. In contrast, class III fusion proteins form a lipid binding pocket at the monomer--monomer interface through a unique fusion loop crossover. The distinct lipid binding modes correlate with the differing maturation pathways of class II and III proteins. Binding affinity was predominantly controlled by cholesterol and gangliosides as well as via local enrichment of polyunsaturated lipids, thereby enhancing membrane disorder. Our study reveals energetics and atomic details underlying lipid recognition and reorganization by different viral fusion protein classes, offering insights into their specialized membrane fusion pathways.
Multimodal gradients of basal forebrain connectivity across the neocortex
Authors: Chakraborty Sudesna , Haast Roy A.M. , Onuska Kate M. , Kanel Prabesh , Prado Marco A.M. , Prado Vania F. , Khan Ali R. , Schmitz Taylor W.
Published: May 2023

The cholinergic innervation of the cortex originates almost entirely from populations of neurons in the basal forebrain (BF). Structurally, the ascending BF cholinergic projections are highly branched, with individual cells targeting multiple different cortical regions. However, it is not known whether the structural organization of basal forebrain projections reflects their functional integration with the cortex. We therefore used high-resolution 7T diffusion and resting state functional MRI in humans to examine multimodal gradients of BF cholinergic connectivity with the cortex. Moving from anteromedial to posterolateral BF, we observed reduced tethering between structural and functional connectivity gradients, with the most pronounced dissimilarity localized in the nucleus basalis of Meynert (NbM). The cortical expression of this structure-function gradient revealed progressively weaker tethering moving from unimodal to transmodal cortex, with the lowest tethering in midcingulo-insular cortex. We used human [18F] fluoroethoxy-benzovesamicol (FEOBV) PET to demonstrate that cortical areas with higher concentrations of cholinergic innervation tend to exhibit lower tethering between BF structural and functional connectivity, suggesting a pattern of increasingly diffuse axonal arborization. Anterograde viral tracing of cholinergic projections and [18F] FEOBV PET in mice confirmed a gradient of axonal arborization across individual BF cholinergic neurons. Like humans, cholinergic neurons with the highest arborization project to cingulo-insular areas of the mouse isocortex. Altogether, our findings reveal that BF cholinergic neurons vary in their branch complexity, with certain subpopulations exhibiting greater modularity and others greater diffusivity in the functional integration of their cortical targets.
What can New Zealand bats tell us about Coronaviruses?
Authors: Tortosa Pablo , McInnes Kate , O’Donnell Colin F. J. , Pryde Moira , Gomard Yann , Lebarbenchon Camille , Poulin Robert
Published: May 2023

The current Covid-19 pandemic emphasizes the dramatic consequences of emerging zoonotic pathogens and stimulates the need for an assessment of the evolution and natural cycle of such microbes in a One Health framework. A number of recent studies have revealed an astonishing diversity of bat-borne Coronaviruses, including in insular environments, which can be considered as simplified biological systems suited for the exploration of the transmission cycles of these viruses in nature. In this work, we present two new lineages of alpha Coronaviruses detected by screening the only two extant New Zealand bat species: the lesser short-tailed bat (Mystacina tuberculata) and the long-tailed bat (Chalinolobus tuberculatus). Infection prevalence reaching 60% in long-tailed bats makes this host-pathogen model relevant for the investigation of maintenance mechanisms in a bat reservoir with peculiar physiological adaptations to temperate climates. A phylogenetic analysis shows that these viral lineages do cluster with Coronaviruses hosted by bat sister species from Australia, supporting co-diversification processes and confirming that the evolution of these viruses is tightly linked to that of their hosts. These patterns provide an interesting framework for further research aiming at elucidating the natural history and biological cycles of these economically-devastating zoonotic viruses.
Sorgoleone degradation by sorghum-associated bacteria; an opportunity for enforcing plant growth promotion
Authors: Oda Yasuhiro , Elmore Joshua R. , Nelson William C. , Wilson Andrew , Farris Yuliya , Shrestha Ritu , Garcia Citlali Fonseca , Pettinga Dean , Ogden Aaron J. , Baldino Henri , Alexander William G. , Deutschbauer Adam M , Hurtado Catalina Vega , McDermott Jason E. , Guss Adam M. , Coleman-Derr Devin , McClure Ryan , Harwood Caroline S. , Egbert Robert G.
Published: May 2023

Metabolite exchange between plant roots and their associated rhizosphere microbiomes underpins plant growth promotion by microbes.Sorghum bicoloris a cereal crop that feeds animals and humans and is used for bioethanol production. Its root tips exude large amounts of a lipophilic benzoquinone called sorgoleone. Sorgoleone is an allelochemical that suppresses the growth of competing plant seedlings and is mineralized by microbes in soil. As an avenue to understand how sorghum and its root microbiome may be connected through root exudates, we identified the molecular determinants of microbial sorgoleone degradation and the distribution of this trait among microbes. We isolated and studied from sorghum-associated soils, three bacterial strains classified asAcinetobacter,Burkholderia, andPseudomonasspecies that grow with sorgoleone as a sole carbon and energy source. The genomes of these strains were sequenced and subjected to transcriptomic and gene fitness analyses to identify candidate sorgoleone degradation genes. Follow up mutational analysis showed that sorgoleone catabolism is dependent on four contiguous genes that are conserved among the species we sequenced. Phylogenetic analysis of the sorgoleone degradation gene cluster showed that sorgoleone catabolism is enriched in sorghum-associatedStreptomycesstrains. The discovery of bacteria that grow on a compound like sorgoleone that is plant specific and not widely distributed in the environment, provides an opportunity to study how a plant exudate can enforce the development of a rhizosphere specific microbiome for the mutual benefit of plant and microbe.

Significance

The grain crop sorghum exudes an herbicidal compound called sorgoleone from its root tips, which inhibits the growth of other plants. We isolated bacteria that grow on sorogleone and identified a cluster of bacterial genes required for sorogleone degradation that can be used as a biomarker for this trait. An approach to improve the production of crops in stressful conditions such as drought, is to encourage their association with plant growth promoting bacteria. Our discovery of sorgoleone degradation genes opens the door to engineering bacteria that receive benefit from sorghum in the form of a plant-specific growth substrate, and in return promote the growth of this crop.
ABI1 regulates transcriptional activity of Androgen Receptor by novel DNA and AR binding mechanism
Authors: Porter Baylee A. , Li Xiang , Arya Neeru , Zhang Fan , Kung Sonia H. Y. , Fazli Ladan , Zarni Oo Htoo , Li Yinan , Marincin Kenneth , Kukkonen Konsta , Urhonen Henna , Ortiz Maria A. , Kemraj Allysa P. , Corey Eva , Dong Xuesen , Kuznetsov Vladimir A. , Nykter Matti , Gleave Martin E. , Bratslavsky Gennady , Urbanucci Alfonso , Frueh Dominique , Bah Alaji , Kotula Leszek
Published: May 2023

Transcription regulates key functions of living organisms in normal and disease states, including cell growth and development, embryonic and adult tissue organization, and tumor progression. Here we identify a novel mechanism of transcriptional regulation by an actin regulatory and signaling protein, Abelson Interactor 1 (ABI1). Using prostate cancer models, we uncover a reciprocal regulation between ABI1 and the Androgen Receptor (AR). ABI1 is a direct, androgen-regulated target; in turn, ABI1 interacts with AR and its splice variant ARv7, and co-regulates a subset of specific transcriptional targets. ABI1 directs transcription through transient yet well-defined interaction of its intrinsically disordered region with DNA. Clinical evaluation shows that the ABI1-DNA binding (through Exon 4 splicing) and ABI1-AR interaction are regulated during androgen deprivation therapy and prostate cancer progression, thus controlling tumor plasticity through connecting actin cytoskeleton and cellular signaling to transcriptional regulation. We propose ABI1 as epigenetic regulator of transcriptional homeostasis in AR-driven cancers.

Statement of importance

This study describes fundamental discovery in prostate cancer identifying novel mechanism of transcription by unique DNA binding mechanism involving actin cytoskeleton regulatory protein ABI1. ABI1-DNA binding activity predicts survival of prostate cancer patients. Moreover, we discover ABI1-AR reciprocal regulation that has far reaching implications for tumor plasticity and androgen-sensitive pathogenesis.
ORPA: A Fast and Efficient Method for Constructing Genome-Wide Alignments of Organelle Genomes for Phylogenetic Analysis
Authors: Bi Guiqi , Luan Xinxin , Yan Jianbin
Published: May 2023

Creating a multi-gene alignment matrix for phylogenetic analysis using organelle genomes involves aligning single-gene datasets manually, a process that can be time-consuming and prone to errors. The HomBlocks pipeline has been created to eliminate the inaccuracies arising from manual operations. The processing of a large number of sequences, however, remains a time-consuming task. To conquer this challenge, we have developed a speedy and efficient method called ORPA. ORPA quickly generates multiple sequence alignments for whole-genome comparisons by parsing the result files of NCBI BLAST, completing the task in just one minute. With increasing data volume, ORPA’s efficiency is even more pronounced, over 300 times faster than HomBlocks in aligning 60 high-plant chloroplast genomes. The tool’s phylogenetic tree outputs demonstrate equivalent results to HomBlocks, indicating its outstanding efficiency. Due to its speed and accuracy, ORPA can identify species-level evolutionary conflicts, providing valuable insights into evolutionary cognition.
AATF-mediated Liver Damage and Inflammation to Cancer: Therapeutic Intervention by Curcumin in Experimental MASH-HCC
Authors: Srinivas Akshatha N. , Suresh Diwakar , Chidambaram Saravana Babu , Santhekadur Prasanna K. , Kumar Divya P.
Published: May 2023

In tandem with the expanding obesity pandemic, the prevalence of metabolic dysfunction associated steatohepatitis (MASH, formerly known as NASH)-driven hepatocellular carcinoma (HCC) is predicted to rise globally, creating a significant need for therapeutic interventions. We previously identified the upregulation of apoptosis antagonizing transcription factor (AATF), which is implicated in facilitating the progression from MASH to HCC. The objective of this study was to examine whether the intervention of curcumin could alleviate AATF-mediated MASH, inhibit tumor growth, and elucidate the underlying mechanism. A preclinical murine model mimicking human MASH-HCC was employed, subjecting mice to either a chow diet normal water (CDNW) or western diet sugar water (WDSW) along with very low dose of carbon tetrachloride (CCl4-0.2 μl/g, weekly). Mice receiving curcumin (CUR) alongside WDSW/CCl4exhibited significant improvements, including reduced liver enzymes, dyslipidemia, steatosis, inflammation, and hepatocellular ballooning. Curcumin treatment also suppressed hepatic expression of inflammatory, fibrogenic, and oncogenic markers. Of note, there was a significant reduction in the expression of AATF upon curcumin treatment in WDSW/CCl4mice and human HCC cells. In contrast, curcumin upregulated Kruppel-like factor 4 (KLF4) in MASH liver and HCC cells, which is known to downregulate sp1 (specificity protein-1) expression. Thus, curcumin treatment effectively inhibited the progression of MASH to HCC by downregulating the expression of AATF via the KLF4-Sp1 signaling pathway. These preclinical findings establish a novel molecular connection between curcumin and AATF in reducing hepatocarcinogenesis, and provide a strong rationale for the development of curcumin as a viable treatment for MASH-HCC in humans.
Syntenin and CD63 Promote Exosome Biogenesis from the Plasma Membrane by Blocking Cargo Endocytosis
Authors: Ai Yiwei , Guo Chenxu , Garcia-Contreras Marta , Sánchez B. Laura S. , Saftics Andras , Shodubi Oluwapelumi , Raghunandan Shankar , Xu Junhao , Tsai Shang Jui , Dong Yi , Li Rong , Jovanovic-Talisman Tijana , Gould Stephen J.
Published: May 2023

Exosomes are small extracellular vesicles important in health and disease. Syntenin is thought to drive the biogenesis of CD63 exosomes by recruiting Alix and the ESCRT machinery to endosomes, initiating an endosome-mediated pathway of exosome biogenesis. Contrary to this model, we show here that syntenin drives the biogenesis of CD63 exosomes by blocking CD63 endocytosis, thereby allowing CD63 to accumulate at the plasma membrane, the primary site of exosome biogenesis. Consistent with these results, we find that inhibitors of endocytosis induce the exosomal secretion of CD63, that endocytosis inhibits the vesicular secretion of exosome cargo proteins, and that high-level expression of CD63 itself also inhibits endocytosis. These and other results indicate that exosomes bud primarily from the plasma membrane, that endocytosis inhibits their loading into exosomes, that syntenin and CD63 are expression-dependent regulators of exosome biogenesis, and that syntenin drives the biogenesis of CD63 exosomes even in Alix knockout cells.
Simulating the cellular context in synthetic datasets for cryo-electron tomography
Authors: Martinez-Sanchez Antonio , Lamm Lorenz , Jasnin Marion , Phelippeau Harold
Published: May 2023

Cryo-electron tomography (cryo-ET) allows to visualize the cellular context at macromolecular level. To date, the impossibility of obtaining a reliable ground truth is limiting the application of deep learning-based image processing algorithms in this field. As a consequence, there is a growing demand of realistic synthetic datasets for training deep learning algorithms. In addition, besides assisting the acquisition and interpretation of experimental data, synthetic tomograms are used as reference models for cellular organization analysis from cellular tomograms. Current simulators in cryo-ET focus on reproducing distortions from image acquisition and tomogram reconstruction, however, they can not generate many of the low order features present in cellular tomograms.

Here we propose several geometric and organization models to simulate low order cellular structures imaged by cryo-ET. Specifically, clusters of any known cytosolic or membrane bound macromolecules, membranes with different geometries as well as different filamentous structures such as microtubules or actin-like networks. Moreover, we use parametrizable stochastic models to generate a high diversity of geometries and organizations to simulate representative and generalized datasets, including very crowded environments like those observed in native cells.

These models have been implemented in a multiplatform open-source Python package, including scripts to generate cryo-tomograms with adjustable sizes and resolutions. In addition, these scripts provide also distortion-free density maps besides the ground truth in different file formats for efficient access and advanced visualization. We show that such a realistic synthetic dataset can be readily used to train generalizable deep learning algorithms.
Near-perfect precise on-target editing of human hematopoietic stem and progenitor cells
Authors: Cloarec-Ung Fanny-Meï , Beaulieu Jamie , Suthananthan Arunan , Lehnertz Bernhard , Sauvageau Guy , Sheppard Hilary M , Knapp David JHF
Published: May 2023

Precision gene editing in primary hematopoietic stem and progenitor cells (HSPCs) would facilitate both curative treatments for monogenic disorders as well as disease modelling. Precise efficiencies even with the CRISPR/Cas system, however, remain limited. Through an optimization of guide RNA delivery, donor design, and additives, we have now obtained mean precise editing efficiencies >90% on primary cord blood HSCPs with minimal toxicity and without observed off-target editing. The main protocol modifications needed to achieve such high efficiencies were the addition of the DNA-PK inhibitor AZD7648, and the inclusion of spacer-breaking silent mutations in the donor in addition to mutations disrupting the PAM sequence. Critically, editing was even across the progenitor hierarchy, did not substantially distort the hierarchy or affect lineage outputs in colony-forming cell assays or the frequency of high self-renewal potential long-term culture initiating cells. As modelling of many diseases requires heterozygosity, we also demonstrated that the overall editing and zygosity can be tuned by adding in defined mixtures of mutant and wild-type donor. With these optimizations, editing at near-perfect efficiency can now be accomplished directly in human HSPCs. This will open new avenues in both therapeutic strategies and disease modelling.
The reaction-diffusion basis of animated patterns in eukaryotic flagella
Authors: Cass James , Bloomfield-Gadêlha Hermes
Published: May 2023

We show that the flagellar beat of bull spermatozoa andChlamydomonas Reinhardtiican be modelled by a minimal, geometrically nonlinear, sliding-controlled, reaction-diffusion system. Model solutions are spatio-temporallyanimated patternsdescribing flagellar bending waves, further connecting beating patterns of cilia and flagella with, seemly unrelated, chemical patterns from classical reaction-diffusion systems. Instead of chemical species freely reacting and diffusing in space, our system describes the tug-of-war reaction-kinetics of molecular motors that are anchored in the flagellar structure, but the shear deformation that they generate candiffuseaway via the bending elasticity of the flagellum. Synchronization of the reaction-kinetics in neighbouring elements occurs via asliding-controlmechanism. We derive from first principles the reaction-diffusion basis of animated patterns, and show that this is a direct consequence of the highinternalenergy dissipation by the flagellum relative to theexternaldissipation by the fluid environment. By fitting, for the first time, nonlinear, large-amplitude solutions of a specific motor cross-bridge reaction-kinetics, we show that reaction-diffusion successfully accounts for beating patterns of bothbull spermandChlamydomonas(wild-type and mbo2-mutant), unifying these distant eukaryotic species under the same minimal model. Our results suggest that the flagellar beat occurs far from equilibrium, in the strongly nonlinear regime, and that in contrary to the conclusions of small amplitude studies, a unified mechanism may exist for dynein molecular motor control that is regulated by axonemal sliding, without requiring curvature-sensing or the fine-tuning of basal compliance, and only weakly influenced by hydrodynamic dissipation and the cell body boundary condition. High internal dissipation allows the emergence of base-to-tip autonomous travelling waves, independently of, and without relying on, the external fluid viscosity, when small. This enables progressive swimming, otherwise not possible, in low viscosity environments, and may be critical for external fertilizers and aquatic microorganisms. The reaction-diffusion model may prove a powerful tool for studying the pattern formation of movement in flagella, cilia, and more generally, oscillations of animated filament-bundles at the microscale.
Motor cortex latent dynamics encode spatial and temporal arm movement parameters independently
Authors: Colins Rodriguez Andrea , Perich Matthew G. , Miller Lee , Humphries Mark D.
Published: May 2023

The fluid movement of an arm requires multiple spatiotemporal parameters to be set independently. Recent studies have argued that arm movements are generated by the collective dynamics of neurons in motor cortex. An untested prediction of this hypothesis is that independent parameters of movement must map to independent components of the neural dynamics. Using a task where monkeys made a sequence of reaching movements to randomly placed targets, we show that the spatial and temporal parameters of arm movements are independently encoded in the low-dimensional trajectories of population activity in motor cortex: Each movement’s direction corre-sponds to a fixed neural trajectory through neural state space and its speed to how quickly that trajectory is traversed. Recurrent neural network models show this coding allows independent control over the spatial and temporal parameters of movement by separate network parameters. Our results support a key prediction of the dynamical systems view of motor cortex, but also argue that not all parameters of movement are defined by different trajectories of population activity.

Significance Statement

From delicate strokes while drawing to ballistic swings while playing tennis, a skilled arm movement requires precise control of both its direction and speed. Motor cortex is thought to play a key role in controlling both, but it is unclear how they are jointly controlled. We show here that the population activity in motor cortex represents both the spatial and temporal properties of arm movements in the same low-dimensional signal. This representation was remarkably simple: the movement’s direction is represented by the trajectory that signal takes; the movement’s speed by how quickly the signal moves along its trajectory. Our network modelling shows this encoding allows an arm movement’s direction and speed to be simultaneously and independently controlled.
Transcriptomic landscape of posterior regeneration in the annelidPlatynereis dumerilii
Authors: Paré Louis , Bideau Loïc , Baduel Loeiza , Dalle Caroline , Benchouaia Médine , Schneider Stephan Q. , Laplane Lucie , Clément Yves , Vervoort Michel , Gazave Eve
Published: May 2023

Background:Restorative regeneration, the capacity to reform a lost body part following amputation or injury, is an important and still poorly understood process in animals. Annelids, or segmented worms, show amazing regenerative capabilities, and as such are a crucial group to investigate. Elucidating the molecular mechanisms that underpin regeneration in this major group remains a key goal. Among annelids, the nereididaePlatynereis dumerilii(re)emerged recently as a front-line regeneration model. Following amputation of its posterior part,Platynereisworms can regenerate both differentiated tissues of their terminal part as well as a growth zone that contains putative stem cells. While this regeneration process follows specific and reproducible stages that have been well characterized, the transcriptomic landscape of these stages remains to be uncovered.

Results:We generated a high qualityde novoReference transcriptome for the annelidPlatynereis dumerilii. To do so, we produced and analyzed three RNA-sequencing datasets, encompassing five stages of posterior regeneration, along with blastema stages and non-amputated tissues as controls. We included these regeneration RNA-seq datasets, as well as embryonic and tissue-specific datasets from the literature to produce a Reference transcriptome. We used this Reference transcriptome to perform in depth analyzes of RNA-seq data during the course of regeneration to reveal the important dynamics of the gene expression, process with thousands of genes differentially expressed between stages, as well as unique and specific genes expression at each regeneration stage. The study of these genes highlighted the importance of the nervous system at both early and late stages of regeneration, as well as the enrichment of RNA-binding proteins (RBPs) during almost the entire regeneration process.

Conclusions:In this study, we provided a high-qualityde novoReference transcriptome for the annelidPlatynereisthat is useful for investigating various developmental processes, including regeneration. Our extensive stage-specific transcriptional analysis during the course of posterior regeneration shed light upon major molecular mechanisms and pathways, and will foster many specific studies in the future.
Dilated cardiomyopathy variant R14del increases phospholamban pentamer stability, blunting dynamic regulation of cardiac calcium handling
Authors: Cleary Sean R. , Teng Allen C. T. , Kongmeneck Audrey Deyawe , Fang Xuan , Phillips Taylor A. , Cho Ellen E. , Kekenes-Huskey Peter , Gramolini Anthony O. , Robia Seth L.
Published: May 2023

The sarco(endo)plasmic reticulum Ca2+ATPase (SERCA) is a membrane transporter that creates and maintains intracellular Ca2+stores. In the heart, SERCA is regulated by an inhibitory interaction with the monomeric form of the transmembrane micropeptide phospholamban (PLB). PLB also forms avid homo-pentamers, and dynamic exchange of PLB between pentamers and the regulatory complex with SERCA is an important determinant of cardiac responsiveness to exercise. Here, we investigated two naturally occurring pathogenic mutations of PLB, a cysteine substitution of arginine 9 (R9C) and an in-frame deletion of arginine 14 (R14del). Both mutations are associated with dilated cardiomyopathy. We previously showed that the R9C mutation causes disulfide crosslinking and hyperstabilization of pentamers. While the pathogenic mechanism of R14del is unclear, we hypothesized that this mutation may also alter PLB homo-oligomerization and disrupt the PLB-SERCA regulatory interaction. SDS-PAGE revealed a significantly increased pentamer:monomer ratio for R14del-PLB when compared to WT-PLB. In addition, we quantified homo-oligomerization and SERCA-binding in live cells using fluorescence resonance energy transfer (FRET) microscopy. R14del-PLB showed an increased affinity for homo-oligomerization and decreased binding affinity for SERCA compared to WT, suggesting that, like R9C, the R14del mutation stabilizes PLB in its pentameric form, decreasing its ability to regulate SERCA. Moreover, the R14del mutation reduces the rate of PLB unbinding from the pentamer after a transient Ca2+elevation, limiting the rate of re-binding to SERCA. A computational model predicted that hyperstabilization of PLB pentamers by R14del impairs the ability of cardiac Ca2+handling to respond to changing heart rates between rest and exercise. We postulate that impaired responsiveness to physiological stress contributes to arrhythmogenesis in human carriers of the R14del mutation.
Polarized Mechanosensitive Signaling Domains Protect Arterial Endothelial Cells Against Inflammation
Authors: Hong Soon-Gook , Ashby Julianne W. , Kennelly John P. , Wu Meigan , Chattopadhyay Eesha , Foreman Rob , Tontonoz Peter , Turowski Patric , Gallagher-Jones Marcus , Mack Julia J.
Published: May 2023

Endothelial cells (ECs) in the descending aorta are exposed to high laminar shear stress, which supports an anti-inflammatory phenotype that protects them from atherosclerosis. High laminar shear stress also supports flow-aligned cell elongation and front-rear polarity, but whether this is required for athero-protective signaling is unclear. Here, we show that Caveolin-1-rich microdomains become polarized at the downstream end of ECs exposed to continuous high laminar flow. These microdomains are characterized by higher membrane rigidity, filamentous actin (F-actin) and lipid accumulation. Transient receptor potential vanilloid-type 4 (Trpv4) ion channels, while ubiquitously expressed, mediate localized Ca2+entry at these microdomains where they physically interact with clustered Caveolin-1. The resultant focal bursts in Ca2+activate the anti-inflammatory factor endothelial nitric oxide synthase (eNOS) within the confines of these domains. Importantly, we find that signaling at these domains requires both cell body elongation and sustained flow. Finally, Trpv4 signaling at these domains is necessary and sufficient to suppress inflammatory gene expression. Our work reveals a novel polarized mechanosensitive signaling hub that induces an anti-inflammatory response in arterial ECs exposed to high laminar shear stress.
Metabolic disruption impacts tick fitness and microbial relationships
Authors: Samaddar Sourabh , O’Neal Anya J. , Marnin Liron , Rolandelli Agustin , Singh Nisha , Wang Xiaowei , Butler L. Rainer , Rangghran Parisa , Laukaitis Hanna J. , Cabrera Paz Francy E. , Fiskum Gary M. , Polster Brian M. , Pedra Joao H. F.
Published: May 2023

Arthropod-borne microbes rely on the metabolic state of a host to cycle between evolutionarily distant species. For instance, arthropod tolerance to infection may be due to redistribution of metabolic resources, often leading to microbial transmission to mammals. Conversely, metabolic alterations aids in pathogen elimination in humans, who do not ordinarily harbor arthropod-borne microbes. To ascertain the effect of metabolism on interspecies relationships, we engineered a system to evaluate glycolysis and oxidative phosphorylation in the tickIxodes scapularis. Using a metabolic flux assay, we determined that the rickettsial bacteriumAnaplasma phagocytophilumand the Lyme disease spirocheteBorrelia burgdorferi, which are transstadially transmitted in nature, induced glycolysis in ticks. On the other hand, the endosymbiontRickettsia buchneri,which is transovarially maintained, had a minimal effect onI. scapularisbioenergetics. Importantly, the metabolite β-aminoisobutyric acid (BAIBA) was elevated duringA. phagocytophiluminfection of tick cells following an unbiased metabolomics approach. Thus, we manipulated the expression of genes associated with the catabolism and anabolism of BAIBA inI. scapularisand detected impaired feeding on mammals, reduced bacterial acquisition, and decreased tick survival. Collectively, we reveal the importance of metabolism for tick-microbe relationships and unveil a valuable metabolite forI. scapularisfitness.
Cortical microtubules oppose actomyosin-driven membrane ingression duringC. elegansmeiosis I polar body extrusion
Authors: Quiogue Alyssa R. , Sumiyoshi Eisuke , Fries Adam , Chuang Chien-Hui , Bowerman Bruce
Published: May 2023

DuringC. elegansoocyte meiosis I, cortical actomyosin is locally remodeled to assemble a contractile ring near the spindle. In contrast to mitosis, when most cortical actomyosin converges into a contractile ring, the small oocyte ring forms within and remains part of a much larger and actively contractile cortical actomyosin network. This network both mediates contractile ring dynamics and generates shallow ingressions throughout the oocyte cortex during polar body extrusion. Based on our analysis of requirements for CLS-2, a member of the CLASP family of proteins that stabilize microtubules, we recently proposed that a balance of actomyosin-mediated tension and microtubule-mediated stiffness are required for contractile ring assembly within the oocyte cortical actomyosin network. Here, using live cell imaging and fluorescent protein fusions, we show that CLS-2 is part of a complex of kinetochore proteins, including the scaffold KNL-1 and the kinase BUB-1, that also co-localize to patches distributed throughout the oocyte cortex during meiosis I. By reducing their function, we further show that KNL-1 and BUB-1, like CLS-2, are required for cortical microtubule stability, to limit membrane ingression throughout the oocyte, and for meiotic contractile ring assembly and polar body extrusion. Moreover, nocodazole or taxol treatment to destabilize or stabilize oocyte microtubules, respectively, leads to excess or decreased membrane ingression throughout the oocyte and defective polar body extrusion. Finally, genetic backgrounds that elevate cortical microtubule levels suppress the excess membrane ingression incls-2mutant oocytes. These results support our hypothesis that CLS-2, as part of a sub-complex of kinetochore proteins that also co-localize to patches throughout the oocyte cortex, stabilizes microtubules to stiffen the oocyte cortex and limit membrane ingression throughout the oocyte, thereby facilitating contractile ring dynamics and the successful completion of polar body extrusion during meiosis I.
Comprehensive screening of a light-inducible split Cre recombinase with domain insertion profiling
Authors: Tague Nathan , Andreani Virgile , Fan Yunfan , Timp Winston , Dunlop Mary J.
Published: May 2023

Splitting proteins with light- or chemically-inducible dimers provides a mechanism for post-translational control of protein function. However, current methods for engineering stimulus-responsive split proteins often require significant protein engineering expertise and laborious screening of individual constructs. To address this challenge, we use a pooled library approach that enables rapid generation and screening of nearly all possible split protein constructs in parallel, where results can be read out using sequencing. We perform our method on Cre recombinase with optogenetic dimers as a proof of concept, resulting in comprehensive data on split sites throughout the protein. To improve accuracy in predicting split protein behavior, we develop a Bayesian computational approach to contextualize errors inherent to experimental procedures. Overall, our method provides a streamlined approach for achieving inducible post-translational control of a protein of interest.
Complex films formed on Al alloy surface via vapor phase assembly of benzotriazole and dodecyltrimethoxysilane
Authors: Wang Qiang , Zhang Hongliang , Zhang Da Quan , Zheng Hongai , Gao Lixin
Published: May 2023

Purpose

The purpose of this paper is to study the effect of vapor assembly sequence and assembly temperature on the corrosion protection of the complex silane films Al alloy. The performance and application range of silane films are enhanced.

Design/methodology/approach

The complex silane films were successfully prepared on the surface of aluminum alloy using via vapor phase assembly of 1,2,3-benzotriazole (BTA) and dodecyltrimethoxysilanes (DTMS). The protection of the assembly films against corrosion of Al alloy is investigated by the electrochemical measurements and the alkaline solution accelerated corrosion test. Thickness and hydrophobicity of the complex films are studied using ellipsometric spectroscopy and contact angle tests.

Findings

It shows that the anti-corrosion ability of the complex films is overall superior to that of the single-component assembled films. DTMS-BTA films have larger thickness and best anti-corrosion ability. The alkyl chains in DTMS have better compatibility with BTA molecules. The rigid BTA molecule can permeate into the long alkyl chain of DTMS as fillers and improve the barrier properties of the complex films.

Originality/value

In this paper, a green and efficient method of vapor phase assembly is proposed to rust prevention during manufacture of Al alloy workpiece.
Higher education by fields and foreign direct investments: insights from OECD countries
Authors: Şeri̇foğlu Müzeyyen Merve , Öge Güney Pelin
Published: May 2023

Purpose

This paper investigates the two-way relationship between foreign direct investment (FDI) inflows and higher education across 36 Organisation for Economic Co-operation and Development (OECD) countries for 1998–2019 periods. To demonstrate this relationship, the authors take into account the total number of graduates as well as the number of graduates from different fields. Accordingly, the authors gathered graduates in four groups which are education, social sciences, technical sciences (tech) and health. In addition to investigating two-way relationship between FDI and graduates, the authors also examined the contribution of primary and secondary level education to FDI.

Design/methodology/approach

The authors use two models to investigate the bidirectional relationship between FDI inflows and graduates from four fields. In the first model, the dependent variable is FDI inflows, and in the second model, graduates from each field are the dependent variable. To investigate the dual relationship, the authors employ ordinary least squares (OLS) and two-step system generalized method of moments (GMM) developed by Arellano Bover (1995) and Blundell Bond (1998).

Findings

For the first model, the results show that secondary level and higher education have a positive impact on FDI. In terms of graduates by fields, it is seen that education and health graduates contributed the most to FDI. For the second model in which the authors analysed the effect of FDI on total graduates and graduates from different fields, the authors find that FDI positively affects the number of graduates from all fields, and the strongest effect is on graduates from the social science field.

Practical implications

Based on the results, the authors can say that well-educated people promote FDI inflows to OECD countries, and FDI is also a driving force in raising highly educated people. So, the authors think that the results will help design higher education policies in accordance with FDI and higher education connection.

Originality/value

To the best of the authors’ knowledge, this paper is the first to examine the impact of FDI inflows on graduates by fields and also to investigate the impact of graduates by fields on FDI.