bluuebunny/crossref_metadata_2025 huggingface dataset:
A mammalian herbivore prefers locally adapted populations in a common garden: implications for climate change mitigation
Authors: Lauger Kayla K. , Mahoney Sean M. , Rothwell Elizabeth M. , Corbin Jaclyn P. M. , Whitham Thomas G.
Published: December 2021

Climate change is expected to alter habitat more rapidly than the pace of evolution, leading to tree populations that are maladapted to new local conditions. Assisted migration is a mitigation strategy that proposes preemptively identifying and planting genotypes that are robust to the expected climate change-induced alterations of an area. Assisted migration however, may impact the broader community, including herbivores which often coevolved with local plant genotypes and their defenses. Although this question has been examined in arthropod herbivores, few studies have assessed this question in mammalian herbivores, and fewer still have leveraged experimental design to disentangle the genetic contribution to herbivore preference.

We examined the hypothesis that North American porcupine (Erethizon dorsatum) browsing on Fremont cottonwood (Populus fremontii) is under genetic control in a common garden, which allowed us to uncouple genetic and environmental contributions to browse preference.

Generally, porcupines selected local trees and trees from climatically similar areas, where trees from local and cooler climate populations suffered over 2x more extensive herbivory than trees from warmer areas. Plant genotype was a significant factor for selection, with the most heavily browsed genotype having on average >10x more herbivory than the least heavily browsed. Because genotypes within and among populations were replicated, we calculated broad-sense heritability in which tree palatability by porcupines was H2B = 0.28 (95% CI: 0.13-0.48) among genotypes.

Synthesis and applications. Our results indicate a genetic component to tree defenses against porcupine herbivory that can be predicted by the climate of the source population. This result has important implications for mammalian herbivores if climate change renders local tree genotypes maladaptive to new conditions. We recommend assisted migration efforts consider this implication and plant stock from both warmer and climatically similar areas to maintain genetic diversity in a changing environment, productivity and forage for mammalian herbivores.
Mathematical characterization of population dynamics in breast cancer cells treated with doxorubicin
Authors: Yang Emily Y. , Howard Grant R. , Brock Amy , Yankeelov Thomas E. , Lorenzo Guillermo
Published: December 2021

The development of chemoresistance remains a significant cause of treatment failure in breast cancer. We posit that a mathematical understanding of chemoresistance could assist in developing successful treatment strategies. Towards that end, we have developed a model that describes the effects of the standard chemotherapeutic drug doxorubicin on the MCF-7 breast cancer cell line. We assume that the tumor is composed of two subpopulations: drug-resistant cells, which continue proliferating after treatment, and drug-sensitive cells, which gradually transition from proliferating to treatment-induced death. The model is fit to experimental data including variations in drug concentration, inter-treatment interval, and number of doses. Our model recapitulates tumor growth dynamics in all these scenarios (as quantified by the concordance correlation coefficient, CCC > 0.95). In particular, superior tumor control is observed with higher doxorubicin concentrations, shorter inter-treatment intervals, and a higher number of doses (p < 0.05). Longer inter-treatment intervals require adapting the model parameterization after each doxorubicin dose, suggesting the promotion of chemoresistance. Additionally, we propose promising empirical formulas to describe the variation of model parameters as functions of doxorubicin concentration (CCC > 0.78). Thus, we conclude that our mathematical model could deepen our understanding of the effects of doxorubicin and could be used to explore practical drug regimens achieving optimal tumor control.
Comparing management strategies for conserving communities of climate-threatened species with a stochastic metacommunity model
Authors: Backus Gregory A. , Huang Yansong , Baskett Marissa L.
Published: December 2021

Many species are shifting their ranges to keep pace with climate change, but habitat fragmentation and limited dispersal could impede these range shifts. In the case of climate-vulnerable foundation species such as tropical reef corals and temperate forest trees, such limitations might put entire communities at risk of extinction. Restoring connectivity through corridors, stepping-stones, or enhanced quality of existing patches could prevent the extinction of several species, but dispersal-limited species might not benefit if other species block their dispersal. Alternatively, managers might relocate vulnerable species between habitats through assisted migration, but this is generally a species-by-species approach. To evaluate the relative efficacy of these strategies, we simulated the climate-tracking of species in randomized competitive metacommunities with alternative management interventions. We found that corridors and assisted migration were the most effective strategies at reducing extinction. Assisted migration was especially effective at reducing the extinction likelihood for short-dispersing species, but it often required moving several species repeatedly. Assisted migration was more effective at reducing extinction in environments with higher stochasticity, and corridors were more effective at reducing extinction in environments with lower stochasticity. We discuss the application of these approaches to an array of systems ranging from tropical corals to temperate forests.
Multivariate autoregressive model estimation for high dimensional intracranial electrophysiological data
Authors: Endemann Christopher , Krause Bryan M. , Nourski Kirill V. , Banks Matthew I. , Van Veen Barry
Published: December 2021

Fundamental to elucidating the functional organization of the brain is the assessment of causal interactions between different brain regions. Multivariate autoregressive (MVAR) modeling techniques applied to multisite electrophysiological recordings are a promising avenue for identifying such causal links. They estimate the degree to which past activity in one or more brain regions is predictive of another region’s present activity, while simultaneously accounting for the mediating effects of other regions. Including in the model as many mediating variables as possible has the benefit of drastically reducing the odds of detecting spurious causal connectivity. However, effective bounds on the number of MVAR model coefficients that can be estimated reliably from limited data make exploiting the potential of MVAR models challenging. Here, we utilize well-established dimensionality-reduction techniques to fit MVAR models to human intracranial data from ∽100 – 200 recording sites spanning dozens of anatomically and functionally distinct cortical regions. First, we show that high dimensional MVAR models can be successfully estimated from long segments of data and yield plausible connectivity profiles. Next, we use these models to generate synthetic data with known ground-truth connectivity to explore the utility of applying principal component analysis and group least absolute shrinkage and selection operator (LASSO) to reduce the number of parameters (connections) during model fitting to shorter data segments. We show that group LASSO is highly effective for recovering ground truth connectivity in the limited data regime, capturing important features of connectivity for high-dimensional models with as little as 10 s of data. The methods presented here have broad applicability to the analysis of high-dimensional time series data in neuroscience, facilitating the elucidation of the neural basis of sensation, cognition, and arousal.
Development of Web Application for the Comparison of Segment Variability with Sequence Evolution and Immunogenic Properties for Highly Variable Proteins: An Application to Viruses
Authors: Bala Sumit , Ghosh Ambarnil , Pradhan Subhra
Published: December 2021

High rate of mutation and structural flexibilities in viral proteins quickly make them resistant to the host immune system and existing antiviral strategies. For most of the pathogenic viruses, the key survival strategies lie in their ability to evolve rapidly through mutations that affects the protein structure and function. Along with the experimental research related to antiviral development, computational data mining also plays an important role in deciphering the molecular and genomic signatures of the viral adaptability. Uncovering conserved regions in viral proteins with diverse chemical and biological properties is an important area of research for developing antiviral therapeutics, though assigning those regions is not a trivial work. Advancement in protein structural information databases and repositories, made by experimental research accelerated the in-silico mining of the data to generate more integrative information. Despite of the huge effort on correlating the protein structural information with its sequence, it is still a challenge to defeat the high mutability and adaptability of the viral genomics structure. In this current study, the authors have developed a user-friendly web application interface that will allow users to study and visualize protein segment variabilities in viral proteins and may help to find antiviral strategies. The present work of web application development allows thorough mining of the surface properties and variabilities of viral proteins which in combination with immunogenicity and evolutionary properties make the visualization robust. In combination with previous research on 20-Dimensional Euclidian Geometry based sequence variability characterization algorithm, four other parameters has been considered for this platform: [1] predicted solvent accessibility information, [2] B-Cell epitopic potential, [3] T-Cell epitopic potential and [4] coevolving region of the viral protein. Uniqueness of this study lies in the fact that a protein sequence stretch is being characterized rather than single residue-based information, which helps to compare properties of protein segments with variability. In current work, as an example, beside presenting the web application platform, five proteins of SARS-CoV2 was presented with keeping focus on protein-S. Current web-application database contains 29 proteins from 7 viruses including a GitHub repository of the raw data used in this study. The web application is up and running in the following address: http://www.protsegvar.com.
ScRNA-Seq study of neutrophils reveals vast heterogeneity and breadth of inflammatory responses in severe COVID-19 patients
Authors: Xu Jintao , He Bing , Carver Kyle , Vanheyningen Debora , Parkin Brian , Garmire Lana X. , Olszewski Michal A. , Deng Jane C.
Published: December 2021

Severe cases of COVID-19 are characterized by dysregulated immune responses, but specific mechanisms contributing to the most severe outcomes remain unclear. Neutrophils are the most abundant leukocyte population in human hosts and reach markedly high numbers during severe COVID-19. However, a detailed examination of their responses has been largely overlooked in the COVID-19 literature to date. Here, we report for the first time a dedicated study of neutrophil responses using single-cell RNA sequencing (scRNA-Seq) of fresh leukocytes from 11 hospitalized adult patients with mild and severe COVID-19 disease and 5 healthy controls. We observed that neutrophils display a pronounced inflammatory profile, with dramatic disruption of predicted cell-cell interactions as the severity of the disease increases. We also identified unique mature and immature neutrophil subpopulations based on transcriptomic profiling, including an antiviral phenotype, and changes in the proportion of each population linked to the severity of the disease. Finally, pathway analysis revealed increased markers of oxidative phosphorylation and ribosomal genes, along with downregulation of many antiviral and host defense pathway genes during severe disease compared to mild infections. Collectively, our findings indicate that neutrophils are capable of mounting effective antiviral defenses but adopt a form of immune dysregulation characterized by excess cellular stress, thereby contributing to the pathogenesis of severe COVID-19.
Microenvironmental factors in cell segregation and heterogeneity in breast cancer development
Authors: Romero-Arias J. Roberto , González-Castro Carlos A. , Ramírez-Santiago Guillermo
Published: December 2021

We analyzed a quantitative model that describes the epigenetic dynamics during the growth and evolution of an avascular tumor. A gene regulatory network (GRN) formed by a set of ten genes that are believed to play an important role in breast cancer development was kinetically coupled to the microenvironmental agents: glucose, estrogens and oxygen. The dynamics of spontaneous mutations was described by a Yule-Furry master equation whose solution represents the probability that a given cell in the tissue undergoes a certain number of mutations at a given time. We assumed that mutations rate is modified by nutrients spatial gradients. The tumor mass was grown by means of a cellular automata supplemented with a set of reaction diffusion equations that described the transport of the microenvironmental agents. By analyzing the epigenetic states space described by the GRN dynamics, we found three attractors that were identified with the cellular epigenetic states: normal, precancer and cancer. For two-dimensional (2D) and three-dimensional (3D) tumors we calculated the spatial distributions of the following quantities: (i) number of mutations, (ii) mutations of each gene and, (iii) phenotypes. Using estrogens as the principal microenvironmental agent that regulates cells proliferation process, we obtained the tumor shapes for different values of the estrogen consumption and supply rates. It was found that he majority of mutations occurred in cells that were located close to the 2D tumor perimeter or close to the 3D tumor surface. Also It was found that the occurrence of different phenotypes in the tumor are controlled by the levels of estrogen concentration since they can change the individual cell threshold and gene expression levels. All the results were consistently observed for 2D and 3D tumors.
The Evolutionary Dynamics of Hyperparasites
Authors: Northrup Graham R , Parratt Steven R , Rozins Carly , Laine Anna-Liisa , Boots Mike
Published: December 2021

Evolutionary theory has typically focused on pairwise interactions, such as those between hosts and parasites, with relatively little work on more complex interactions including hyperparasites: parasites of parasites. Hyperparasites are common in nature, with the chestnut blight fungus virus CHV-1 a well-known natural example, but also notably include the phages of important human bacterial diseases. Theory on hyperparasitism has mostly focused on their impact on the evolution of virulence of their parasite host and relatively little is known about evolutionary trajectories of hyperparasites themselves. Our general modeling framework highlights the central role the that ability of a hyperparasite to be transmitted with its parasite plays in their evolution. Hyperparasites which transmit with their parasite hosts (hitchhike) will be selected for lower virulence, trending towards hypermutualism or hypercommensalism and select against causing a reduction in parasite virulence (hypovirulence). We examine the impact on the evolution of hyperparasite systems a of a wide range of host and parasite traits showing, for example, that high parasite virulence selects for higher hyperparasite virulence feeding back into selection for hypovirulence in the parasite. Our results have implications for hyperparasite research, both as biocontrol agents and for understanding of how hyperparasites shape community ecology and evolution.
Cationic inhalable particles for enhanced drug delivery to M. tuberculosis infected macrophages
Authors: Sharma Pallavi Raj , Dravid Ameya Atul , Kalapala Yeswanth Chakravarthy , Gupta Vishal K , Jeyasankar Sharumathi , Goswami Avijit , Agarwal Rachit
Published: December 2021

Inhalable microparticle-based drug delivery platforms are being investigated extensively for Tuberculosis (TB) treatment as they offer efficient deposition in lungs and improved pharmacokinetics of the encapsulated cargo. However, the effect of physical parameters of microcarriers on interaction with Mycobacterium tuberculosis (Mtb) infected mammalian cells is underexplored. In this study, we report that Mtb-infected macrophages are highly phagocytic and microparticle surface charge plays a major role in particle internalization by infected cells. Microparticles of different sizes (0.5 - 2 μm) were internalized in large numbers by Mtb-infected THP-1 macrophages and murine primary Bone Marrow Derived Macrophages in vitro. Drastic improvement in particle uptake was observed with cationic particles in vitro and in mice lungs. Rapid uptake of rifampicin-loaded cationic microparticles allowed high intracellular accumulation of the drug and lead to enhanced anti-bacterial function when compared to non-modified rifampicin-loaded microparticles. Cytocompatibility assay and histological analysis in vivo confirmed that the formulations were safe and did not elicit any adverse reaction. Additionally, pulmonary delivery of cationic particles in mice resulted in two-fold higher uptake in resident alveolar macrophages compared to non-modified particles. This study provides a framework for future design of drug carriers to improve delivery of anti-TB drugs inside Mtb-infected cells.
DeepLPI: a novel deep learning-based model for protein-ligand interaction prediction for drug repurposing
Authors: Wei Bomin , Zhang Yue , Gong Xiang
Published: December 2021

The substantial cost of new drug research and development has consistently posed a huge burden for both pharmaceutical companies and patients. In order to lower the expenditure and development failure rate, repurposing existing and approved drugs by identifying interactions between drug molecules and target proteins based on computational methods have gained growing attention. Here, we propose the DeepLPI, a novel deep learning-based model that mainly consists of ResNet-based 1-dimensional convolutional neural network (1D CNN) and bi-directional long short term memory network (biLSTM), to establish an end-to-end framework for protein-ligand interaction prediction. We first encode the raw drug molecular sequences and target protein sequences into dense vector representations, which go through two ResNet-based 1D CNN modules to derive features, respectively. The extracted feature vectors are concatenated and further fed into the biLSTM network, followed by the MLP module to finally predict protein-ligand interaction. We downloaded the well-known BindingDB and Davis dataset for training and testing our DeepLPI model. We also applied DeepLPI on a COVID-19 dataset for externally evaluating the prediction ability of DeepLPI. To benchmark our model, we compared our DeepLPI with the state-of-the-art methods of DeepCDA and DeepDTA, and observed that our DeepLPI outperformed these methods, suggesting the high accuracy of the DeepLPI towards protein-ligand interaction prediction. The high prediction performance of DeepLPI on the different datasets displayed its high capability of protein-ligand interaction in generalization, demonstrating that the DeepLPI has the potential to pinpoint new drug-target interactions and to find better destinations for proven drugs.
HSC-independent definitive hematopoietic cells persist into adult life
Authors: Kobayashi Michihiro , Wei Haichao , Yamanashi Takashi , Shih David J , Portilho Nathalia Azevedo , Cornelius Samuel , Valiente Noemi , Nishida Chika , Zheng Wenjin J , Kang Joonsoo , Seita Jun , Wu Jia Qian , Yoshimoto Momoko
Published: December 2021

The stem cell theory that all blood cells are derived from hematopoietic stem cell (HSC) is a central dogma in hematology. However, various types of blood cells are already produced from hemogenic endothelial cells (HECs) before the first HSCs appear at embryonic day (E)11 in the mouse embryo. This early blood cell production from HECs, called HSC-independent hematopoiesis, includes primitive and definitive erythromyeloid progenitors that transiently support fetal blood homeostasis until HSC-derived hematopoiesis is established. Lymphoid potential has traditionally been detected in the extra-embryonic yolk sac (YS) and/or embryos before HSC emergence, but the actual presence of lymphoid progenitors at this stage remains unknown. In addition, whether HSCs in the fetal liver are the main source of innate-like B-1a cells has been controversial. Here, using complementary lineage tracing mouse models, we show that HSC-independent multipotent progenitors (MPPs) and HSC-independent adoptive B-lymphoid progenitors persist into adult life. Furthermore, HSCs minimally contribute to the peritoneal B-1a cell pool; most B-1a cells are originated directly from ECs in the YS and embryo and HSC-independent for life. Our discovery of extensive HSC-independent MPP and B-lymphoid progenitors in adults attests to the complex blood developmental dynamics through embryo to adult that underpin the immune system and challenges the paradigm of HSC theory in hematology.
Self-confined expression in theArabidopsisroot stem cell niche
Authors: Mercadal Josep , Betegón-Putze Isabel , Bosch Nadja , Caño-Delgado Ana I. , Ibañes Marta
Published: December 2021

Stem cell niches are local microenvironments that preserve their unique identity while communicating with adjacent tissues. In the primary root ofArabidopsis thaliana, the stem cell niche comprises the expression of two transcription factors, BRAVO and WOX5, among others. Intriguingly, these proteins confine their own gene expression to the niche, as evidenced in each mutant background. Here we propose through mathematical modeling that BRAVO confines its own expression domain to the stem cell niche by attenuating its WOX5-dependent diffusible activator. This negative feedback drives WOX5 action to be spatially restricted as well. The results show that WOX5 diffusion and sequestration by binding to BRAVO is sufficient to drive realistic confinedBRAVOexpression at the stem cell niche. We propose that attenuation of a diffusible activator can be a general mechanism to confine genetic activity to a small region while at the same time maintain signaling within it and with the surrounding cells.
Epiphany: predicting Hi-C contact maps from 1D epigenomic signals
Authors: Yang Rui , Das Arnav , Gao Vianne R. , Karbalayghareh Alireza , Noble William S. , Bilmes Jeffrey A. , Leslie Christina S.
Published: December 2021

Recent deep learning models that predict the Hi-C contact map from DNA sequence achieve promising accuracy but cannot generalize to new cell types and indeed do not capture cell-type-specific differences among training cell types. We propose Epiphany, a neural network to predict cell-type-specific Hi-C contact maps from five epigenomic tracks that are already available in hundreds of cell types and tissues: DNase I hypersensitive sites and ChIP-seq for CTCF, H3K27ac, H3K27me3, and H3K4me3. Epiphany uses 1D convolutional layers to learn local representations from the input tracks, a bidirectional long short-term memory (Bi-LSTM) layers to capture long term dependencies along the epigenome, as well as a generative adversarial network (GAN) architecture to encourage contact map realism. To improve the usability of predicted contact matrices, we trained and evaluated models using multiple normalization and matrix balancing techniques including KR, ICE, and HiC-DC+ Z-score and observed-over-expected count ratio. Epiphany is trained with a combination of MSE and adversarial (i.a., a GAN) loss to enhance its ability to produce realistic Hi-C contact maps for downstream analysis. Epiphany shows robust performance and generalization to held-out chromosomes within and across cell types and species, and its predicted contact matrices yield accurate TAD and significant interaction calls. At inference time, Epiphany can be used to study the contribution of specific epigenomic peaks to 3D architecture and to predict the structural changes caused by perturbations of epigenomic signals.
A stepwise route to domesticate rice by controlling seed shattering and panicle shape
Authors: Ishikawa Ryo , Castillo Cristina Cobo , Htun Than Myint , Numaguchi Koji , Inoue Kazuya , Oka Yumi , Ogasawara Miki , Sugiyama Shohei , Takama Natsumi , Orn Chhourn , Inoue Chizuru , Nonomura Ken-ichi , Allaby Robin , Fuller Dorian Q , Ishii Takashige
Published: December 2021

Asian rice (Oryza sativa L.) is consumed by more than half of the world’s population. Despite its global importance, the process of early rice domestication remains unclear. During domestication, wild rice (O. rufipogon Griff.) acquired non-seed-shattering behaviour, allowing humans to increase grain yield. Previous studies argued that the sh4 mutation triggered a reduction in seed shattering during rice domestication; but our experiments using wild introgression lines of O. rufipogon show that the domesticated sh4 allele alone is insufficient for shattering loss. Here, we identified the interaction between three key mutations associated with the interruption of abscission layer formation and panicle architecture that were causal in early rice domestication. An interruption of abscission layer formation requires both sh4 and qSH3 mutations, presenting an apparent barrier to the selection of shattering loss. We identified a causal single-nucleotide polymorphism at qSH3 within the seed-shattering gene OsSh1, which is conserved in indica and japonica subspecies but absent in the circum-aus group of rice. Through harvest experiments, we demonstrated that seed shattering alone did not significantly impact yield; rather yield increases were observed with closed panicle formation controlled by SPR3, which is further augmented by the integration of sh4 and qSH3 alleles. Complementary manipulation of seed shattering and panicle shape result in a mechanically stable panicle structure. We propose a stepwise route for the earliest phase of rice domestication, wherein selection of visible SPR3-controlled closed panicle morphology was instrumental in the sequential recruitment of sh4 and qSH3, which led to the loss of shattering.

Significance Statement

Rice is one of the most important crops worldwide. Loss of seed shattering in domesticated rice, previously attributed to single mutations such as those in sh4, is considered the principal genetic change which resulted in yield increases. However, we show that sh4 alone is insufficient and other genes, such as qSH3, are required to cause abscission layer disruption. The evolution of non-seed-shattering therefore required multiple mutations. Furthermore, shattering loss in genetic backgrounds of wild rice does not correspondingly increase yields. We have identified an interaction in which a second trait, closed panicle formation controlled by SPR3, that both increases the yield and facilitates recruitment of sh4 and qSH3, which synergistically augment yield, leading to a stepwise model for rice domestication.
An ecological perspective on microbial genes of unknown function in soil
Authors: Holland-Moritz Hannah , Vanni Chiara , Fernandez-Guerra Antonio , Bissett Andrew , Fierer Noah
Published: December 2021

Genes that remain hypothetical, uncharacterized, and unannotated comprise a substantial portion of metagenomic datasets and are likely to be particularly prevalent in soils where poorly characterized taxa predominate. Documenting the prevalence, distribution, and potential roles of these genes of unknown function is an important first step to understanding their functional contributions in soil communities. We identified genes of unknown function from 50 soil metagenomes and analyzed their environmental distributions and ecological associations. We found that genes of unknown function are prevalent in soils, particularly fine-textured, higher pH soils that harbor greater abundances of Crenarchaeota, Gemmatimonadota, Nitrospirota, and Methylomirabilota. We identified 43 dominant (abundant and ubiquitous) gene clusters of unknown function and determined their associations with soil microbial phyla and other “known” genes. We found that these dominant unknown genes were commonly associated with microbial phyla that are relatively uncharacterized, with the majority of these dominant unknown genes associated with mobile genetic elements. This work demonstrates a strategy for investigating genes of unknown function in soils, emphasizes the biological insights that can be learned by adopting this strategy, and highlights specific hypotheses that warrant further investigation regarding the functional roles of abundant and ubiquitous genes of unknown function in soil metagenomes.
Mitochondrial antiviral-signalling protein is a client of the BAG6 protein quality control complex
Authors: Roboti Peristera , Lawless Craig , High Stephen
Published: December 2021

The heterotrimeric BAG6 complex coordinates the direct handover of newly synthesised tail-anchored (TA) membrane proteins from an SGTA-bound preloading complex to the endoplasmic reticulum (ER) delivery component TRC40. In contrast, defective precursors, including aberrant TA proteins, form a stable complex with this cytosolic protein quality control factor, enabling such clients to be either productively re-routed or selectively degraded. We identify the mitochondrial TA protein MAVS (mitochondrial antiviral-signalling protein) as an endogenous client of both SGTA and the BAG6 complex. Our data suggest that the BAG6 complex binds to a cytosolic pool of MAVS before its misinsertion into the ER membrane, from where it can subsequently be removed via ATP13A1-mediated dislocation. This BAG6- associated fraction of MAVS is dynamic and responds to the activation of an innate immune response, suggesting that BAG6 may modulate the pool of MAVS that is available for coordinating the cellular response to viral infection.

SUMMARY STATEMENT

Mitochondrial antiviral-signalling (MAVS) protein is a favoured client of the cytosolic BAG6 complex. We discuss how this dynamic interaction may modulate MAVS biogenesis at signalling membranes.
Specific plasticity loci and their synergism mediate operant conditioning
Authors: Momohara Yuto , Neveu Curtis L. , Chen Hsin-Mei , Baxter Douglas A. , Byrne John H.
Published: December 2021

Despite numerous studies examining the mechanisms of operant conditioning (OC), the diversity of plasticity loci and their synergism have not been examined sufficiently. In the well-characterized feeding neural circuit of Aplysia, appetitive OC increases neuronal excitability and electrical coupling among several neurons. Here we found OC decreased the intrinsic excitability of B4 and the strength of its inhibitory connection to a key decision-making neuron, B51. The OC-induced changes were specific without affecting the B4-to-B8 inhibitory connection or excitability of another neuron critical for feeding behavior, B8. A conductance-based circuit model indicated certain sites of plasticity mediated the OC phenotype more effectively and that plasticity loci acted synergistically. This synergy was specific in that only certain combinations of loci synergistically enhanced feeding. Taken together, these results suggest modifications of diverse loci work synergistically to mediate OC.

Significance Statement

The diversity and synergism of plasticity loci mediating operant conditioning (OC) is poorly understood. Here we found that OC decreased the intrinsic excitability of a critical neuron mediating Aplysia feeding behavior and specifically reduced the strength of one of its inhibitory connections to a key decision-making neuron. A conductance-based computational model indicated that the known plasticity loci showed a surprising level of synergism to mediate the behavioral changes associated with OC. These results highlight the importance of understanding the diversity, specificity and synergy among different types of plasticity that encode memory. Also, because OC in Aplysia is mediated by dopamine (DA), the present study provides insights into specific and synergistic mechanisms of DA-mediated reinforcement of behaviors.
Microbial ecology of sulfur biogeochemical cycling at a mesothermic hot spring atop Northern Himalayas, India
Authors: Nagar Shekhar , Talwar Chandni , Motelica-Heino Mikael , Richnow Hans-Hermann , Shakarad Mallikarjun , Lal Rup , Negi Ram Krishan
Published: December 2021

Graphical Abstract

Sulfur Related Prokaryotes (SRP) residing in hot spring present good opportunity for exploring the limitless possibilities of integral ecosystem processes. Metagenomic analysis further expand the phylogenetic breadth of these extraordinary sulfur metabolizing microorganisms, as well a their complex metabolic networks and syntrophic interactions in environmental biosystems. Through this study, we explored and expanded the microbial genetic repertoire with focus on sulfur cycling genes through metagenomic analysis of sulfur (S) contaminated hot spring, located at the Northern Himalayas. The analysis revealed rich diversity of microbial consortia with established roles in S cycling such asPseudomonas,Thioalkalivibrio,DesulfovibrioandDesulfobulbaceae(Proteobacteria). The major gene families inferred to be abundant across microbial mat, sediment and water were assigned toProteobacteriaas reflected from the RPKs (reads per kilobase) categorized into translation and ribosomal structure and biogenesis. Analysis of sequence similarity showed conserved pattern of bothdsrABgenes (n=178) retrieved from all metagenomes while other sulfur disproportionation proteins were diverged due to different structural and chemical substrates. The diversity of sulfur oxidizing bacteria (SOB) and sulfate reducing bacteria (SRB) with conserved (r)dsrABsuggests for it to be an important adaptation for microbial fitness at this site. Here, we confirm that (i) SRBs belongs toδ-Proteobacteriaoccurring independent LGT ofdsrgenes to different and few novel lineages (ii) also, the oxidative and reductivedsrevolutionary time scale phylogeny, proved that the earliest (not first)dsrABproteins belong to anaerobicThiobacilluswith other (rdsr) oxidizers. Further, the structural prediction of unassigned DsrAB proteins confirmed their relatedness with species ofDesulfovibrio(TM score= 0.86; 0.98; 0.96) andArchaeoglobus fulgidus(TM score= 0.97; 0.98). We proposed that the genetic repertoire might provide the basis of studying time scale evolution and horizontal gene transfer of these genes in biogeochemical S cycling and the complementary genes could be implemented in biotechnology and bioremediation applications.
Aboveground impacts of a belowground invader: how invasive earthworms alter aboveground arthropod communities in a northern North American forest
Authors: Jochum Malte , Thouvenot Lise , Ferlian Olga , Zeiss Romy , Klarner Bernhard , Pruschitzki Ulrich , Johnson Edward A. , Eisenhauer Nico
Published: December 2021

Declining arthropod communities have recently gained a lot of attention with climate and land-use change among the most-frequently discussed drivers. Here, we focus on a seemingly underrepresented driver of arthropod-community decline: biological invasions. For ∼12,000 years, earthworms have been absent from wide parts of northern North America, but they have been re-introduced with dramatic consequences. Most studies investigating earthworm-invasion impacts focus on the belowground world, resulting in limited knowledge on aboveground-community changes. We present observational data on earthworm, plant, and aboveground-arthropod communities in 60 plots, distributed across areas with increasing invasion status (low, medium, high) in a Canadian forest. We analyzed how earthworm-invasion status and biomass impact aboveground arthropod community abundance, biomass, and species richness, and how earthworm impacts cascade across trophic levels. We sampled ∼13,000 arthropods, dominated by Hemiptera, Diptera, Araneae, Thysanoptera, and Hymenoptera. Total arthropod abundance, biomass, and species richness declined significantly from areas of low to those with high invasion status with reductions of 61, 27, and 18%, respectively. Structural Equation Models unraveled that earthworms directly and indirectly impact arthropods across trophic levels. We show that earthworm invasion can alter aboveground multitrophic arthropod communities and suggest that belowground invasions can be important drivers of aboveground-arthropod decline.
CV-containing vesicle budding from chloroplast inner envelope membrane is mediated by clathrin but inhibited by GAPC
Authors: Pan Ting , Liu Yangxuan , Ling Chengcheng , Tang Yuying , Tang Wei , Liu Yongsheng , Guo Liang , Kim Chanhong , Fang Jun , Lin Honghui , Blumwald Eduardo , Wang Songhu
Published: December 2021

Clathrin-mediated vesicular formation and trafficking are highly conserved in eukaryotic cells and are responsible for molecular cargo transport and signal transduction among organelles. It remains largely unknown whether clathrin-coated vesicles can be generated from chloroplasts. CHLOROPLAST VESICULATION (CV)-containing vesicles (CVVs) generate from chloroplasts and mediate chloroplast degradation under abiotic stress. In this study, we showed that CV interacted with the clathrin heavy chain (CHC) and induced vesicle budding from the chloroplast inner envelope membrane. Defects on CHC2 and the dynamin-encoding DRP1A gene affected CVV budding and releasing from chloroplast. CHC2 is also required for CV-induced chloroplast degradation and hypersensitivity to water stress. Moreover, GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE (GAPC) interacts with CV and impairs the CV-CHC2 interaction. GAPC1 overexpression inhibited CV-mediated chloroplast degradation and hypersensitivity to water stress. CV silencing alleviated the hypersensitivity of gapc1gapc2 plant to water stress. Together, our work revealed a pathway of clathrin-assisted CVV budding from the chloroplast inner envelope membrane, which mediated the stress-induced chloroplast degradation and stress response.
NamZ1 and NamZ2 from the oral pathogen Tannerella forsythia are peptidoglycan processing exo-β-N-acetylmuramidases with distinct substrate specificity
Authors: Borisova Marina , Balbuchta Katja , Lovering Andrew , Titz Alexander , Mayer Christoph
Published: December 2021

The Gram-negative periodontal pathogen Tannerella forsythia is inherently auxotrophic for N-acetylmuramic acid (MurNAc), which is an essential carbohydrate constituent of the peptidoglycan (PGN) of the bacterial cell wall. Thus, to build up its cell wall, T. forsythia strictly depends on the salvage of exogenous MurNAc or sources of MurNAc, such as polymeric or fragmentary PGN, derived from cohabiting bacteria within the oral microbiome. In our effort to elucidate how T. forsythia satisfies its demand for MurNAc, we recognized that the organism possesses three putative orthologs of the exo-β-N-acetylmuramidase BsNamZ from Bacillus subtilis, which cleaves non-reducing end, terminal MurNAc entities from the artificial substrate pNP-MurNAc and the naturally-occurring disaccharide substrate MurNAc-β-1,4-N-acetylglucosamine (GlcNAc). TfNamZ1 and TfNamZ2 were successfully purified as soluble, pure recombinant His6-fusions and characterized as exo-lytic β-N-acetylmuramidases with distinct substrate specificities. The activity of TfNamZ1 was considerably lower compared to TfNamZ2 and BsNamZ, in the cleavage of pNP-MurNAc and MurNAc-GlcNAc. When peptide-free PGN glycans were used as substrates, we revealed striking differences in the specificity and mode of action of these enzymes, as analyzed by mass spectrometry. TfNamZ1, but not TfNamZ2 or BsNamZ, released GlcNAc-MurNAc disaccharides from these glycans. In addition, glucosamine (GlcN)-MurNAc disaccharides were generated when partially N-deacetylated PGN glycans from B. subtilis 168 were applied. This characterizes TfNamZ1 as a unique disaccharide-forming exo-lytic β-N-acetylmuramidase (exo-disaccharidase), and, TfNamZ2 and BsNamZ as sole MurNAc monosaccharide-lytic exo-β-N-acetylmuramidases.

IMPORTANCE

Two exo-β-N-acetylmuramidases from T. forsythia belonging to glycosidase family GH171 (www.cazy.org) were shown to differ in their activities, thus revealing a functional diversity within this family: NamZ1 releases disaccharides (GlcNAc-MurNAc/GlcN-MurNAc) from the non-reducing ends of PGN glycans, whereas NamZ2 releases terminal MurNAc monosaccharides. This work provides a better understanding of how T. forsythia may acquire the essential growth factor MurNAc by the salvage of PGN from cohabiting bacteria in the oral microbiome, which may pave avenues for the development of anti-periodontal drugs. On a broad scale, our study indicates that the utilization of PGN as a nutrient source, involving exo-lytic N-acetylmuramidases with different modes of action, appears to be a general feature of bacteria, particularly among the phylum Bacteroidetes.
Smart3-ATAC: a highly sensitive method for joint accessibility and full-length transcriptome analysis in single cells
Authors: Cheng Huaitao , Pui Han-pin , Lentini Antonio , Kolbeinsdóttir Solrún , Andrews Nathanael , Pei Yu , Reinius Björn , Deng Qiaolin , Enge Martin
Published: December 2021

Joint single-cell measurements of gene expression and DNA regulatory element activity holds great promise as a tool to understand transcriptional regulation. Towards this goal we have developed Smart3-ATAC, a highly sensitive method which allows joint mRNA and chromatin accessibility analysis genome wide in single cells. With Smart3-ATAC, we are able to obtain the highest possible quality measurements per cell. The method combines transcriptomic profiling based on the highly sensitive Smart-seq3 protocol on cytosolic mRNA, with a novel low-loss single-cell ATAC (scATAC) protocol to measure chromatin accessibility. Compared to current droplet multiome methods, the yield of both the scATAC protocol and mRNA-seq protocol is markedly higher.
Relationship between high-frequency activity in the cortical sensory and the motor hand areas, and their myelin content
Authors: Tomasevic Leo , Siebner Hartwig Roman , Thielscher Axel , Manganelli Fiore , Pontillo Giuseppe , Dubbioso Raffaele
Published: December 2021

Background

The human primary sensory (S1) and primary motor (M1) hand areas feature high-frequency neuronal responses. Electrical nerve stimulation evokes high-frequency oscillations (HFO) at around 650 Hz in the contralateral S1. Likewise, transcranial magnetic stimulation (TMS) of M1 can evoke a series of descending volleys in the corticospinal pathway that can be detected non-invasively with a paired-pulse TMS protocol, called short interval intracortical facilitation (SICF). SICF features several peaks of facilitation of motor evoked potentials in contralateral hand muscles, which are separated by inter-peak intervals resembling HFO rhythmicity.

Hypothesis

In this study, we tested the hypothesis that the individual expressions of HFO and SICF are tightly related to each other and to the regional myelin content in the sensorimotor cortex.

Methods

In 24 healthy volunteers, we recorded HFO and SICF, and, in a subgroup of 20 participants, we mapped the cortical myelin content using the ratio between the T1- and T2-weighted MRI signal as read-out.

Results

The individual frequencies and magnitudes of HFO and SICF curves were tightly correlated: the intervals between the first and second peak of cortical HFO and SICF showed a positive linear relationship (r= 0.703, p< 0.001), while their amplitudes were inversely related (r= −0.613, p= 0.001). The rhythmicity, but not the magnitude of the high-frequency responses, was related to the cortical myelin content: the higher the cortical myelin content, the shorter the inter-peak intervals of HFO and SICF.

Conclusion

The results confirm a tight functional relationship between high-frequency responses in S1 (i.e., HFO) and M1 (i.e., as measured with SICF). They also establish a link between the degree of regional cortical myelination and the expression of high-frequency responses in the human sensorimotor cortex, giving further the opportunity to infer their generators.
A nuclear import pathway exploited by pathogenic noncoding RNAs
Authors: Ma Junfei , Dissanayaka Mudiyanselage Shachinthaka D. , Park Woong June , Wang Mo , Takeda Ryuta , Liu Bin , Wang Ying
Published: December 2021

The prevailing view regarding intracellular RNA trafficking in eukaryotic cells describes that RNAs transcribed in the nucleus either stay in the nucleus or cross the nuclear envelope entering the cytoplasm for function. Interestingly, emerging evidence illustrates numerous functional RNAs trafficking in the reverse direction from the cytoplasm to the nucleus. However, the mechanism underlying the RNA nuclear import has not been well elucidated. Viroids are single-stranded circular noncoding RNAs that infect plants. Using nuclear-replicating viroids as a model, we showed that cellular Importin alpha-4 is likely involved in viroid RNA nuclear import, empirically supporting the involvement of Importin-based cellular pathway in RNA nuclear import. We also confirmed the involvement of a cellular protein (Virp1) that binds both Importin alpha-4 and viroids. Furthermore, a conserved C-loop in nuclear-replicating viroids is critical for Virp1 binding. Disrupting C-loop impairs Virp1 binding, viroid nuclear accumulation and infectivity. Further, C-loop exists in a subviral satellite noncoding RNA that relies on Virp1 for nuclear import. These results have significant implications for understanding the infection process of subviral agents. In addition, our data outline a cellular pathway responsible for the nuclear import of RNAs and uncover a 3-dimensional RNA motif-based regulation over RNA nuclear import.
Sensory-thresholded switch of neural firing states in a computational model of the ventromedial hypothalamus
Authors: Rahy Ryan , Asari Hiroki , Gross Cornelius T.
Published: December 2021

The mouse ventromedial hypothalamus (VMH) is both necessary and sufficient for defensive responses to predator and social threats. Defensive behaviors typically involve cautious approach toward potentially threatening stimuli aimed at obtaining information about the risk involved, followed by sudden avoidance and flight behavior to escape harm. In vivo neural recording studies in mice have identified two major populations of VMH neurons that either increase their firing activity as the animal approaches the threat (called Assessment+ cells) or increase their activity as the animal flees the threat (called Flight+ cells). Interestingly, Assessment+ and Flight+ cells abruptly decrease and increase their firing activity, respectively, at the decision point for flight, creating an escape-related “switch” in functional state. This suggests that the activity of the two cell types in VMH is coordinated and could result from local circuit interactions. Here, we used computational modelling to test if a local inhibitory feedback circuit could give rise to key features of the neural activity seen in VMH during the approach-to-flight transition. Starting from a simple dual-population inhibitory feedback circuit receiving repeated trains of monotonically increasing sensory input to mimic approach to threat, we tested the requirement for balanced sensory input, balanced feedback, short-term synaptic plasticity, rebound excitation, and inhibitory feedback exclusivity to reproduce an abrupt, sensory-thresholded reciprocal firing change that resembles Assessment+ and Flight+ cell activity seen in vivo. Our work demonstrates that a relatively simple local circuit architecture is sufficient for the emergence of firing patterns similar to those seen in vivo and suggests that a reiterative process of experimental and computational work may be a fruitful avenue for better understanding the functional organization of mammalian instinctive behaviors at the circuit level.