bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host-microbiome mutualisms emerge from community interactions among microbes
Authors: Laurich Jason R. , Lash Emma , Frederickson Megan E. 
Published: November 2023

AbstractMicrobiomes often benefit plants, conferring resistance to pathogens, improving stress tolerance, or promoting plant growth. As potential plant mutualists, however, microbiomes are not a single organism but a community of species with complex interactions among microbial taxa and between microbes and their shared host. The nature of ecological interactions among microbes in the microbiome can have important consequences for the net effects of microbiomes on hosts. Here, we compared the effects of individual microbial strains and 10-strain synthetic communities on microbial productivity and host growth using the common duckweedLemna minorand a synthetic, simplified version of its native microbiome. Except forPseudomonas protegens, which was a mutualist when tested alone, all of the single strains we tested were commensals on hosts, benefiting from plant presence but not increasing host growth relative to uninoculated controls. However, 10-strain synthetic microbial communities increased both microbial productivity and duckweed growth more than the average single-strain inoculation and uninoculated controls, meaning that host-microbiome mutualisms can emerge from community interactions among microbes on hosts. The effects of community inoculation were sub-additive, suggesting at least some competition among microbes in the duckweed microbiome. We also investigated the relationship betweenL. minorfitness and that of its microbes, providing some of the first empirical estimates of broad fitness alignment between plants and members of their microbiomes; hosts grew faster with more productive microbes or microbiomes.
Precision data-driven modeling of cortical dynamics reveals idiosyncratic mechanisms underlying canonical oscillations
Authors: Singh Matthew F. , Braver Todd S. , Cole Michael W. , Ching ShiNung 
Published: November 2023

AbstractTask-free brain activity affords unique insight into the functional structure of brain network dynamics and is a strong marker of individual differences. In this work, we present an algorithmic optimization framework that makes it possible to directly invert and parameterize brain-wide dynamical-systems models involving hundreds of interacting brain areas, from single-subject time-series recordings. This technique provides a powerful neurocomputational tool for interrogating mechanisms underlying individual brain dynamics (“precision brain models”) and making quantitative predictions. We extensively validate the models’ performance in forecasting future brain activity and predicting individual variability in key M/EEG markers. Lastly, we demonstrate the power of our technique in resolving individual differences in the generation of alpha and beta-frequency oscillations. We characterize subjects based upon model attractor topology and a dynamical-systems mechanism by which these topologies generate individual variation in the expression of alpha vs. beta rhythms. We trace these phenomena back to global variation in excitation-inhibition balance, highlighting the explanatory power of our framework in generating mechanistic insights.
Investigating Ecological Interactions in the Tumor Microenvironment using Joint Species Distribution Models for Point Patterns
Authors: Eliason Joel , Rao Arvind 
Published: November 2023

AbstractThe tumor microenvironment (TME) is a complex and dynamic ecosystem that involves interactions between different cell types, such as cancer cells, immune cells, and stromal cells. These interactions can promote or inhibit tumor growth and affect response to therapy. Multitype Gibbs point process (MGPP) models are statistical models used to study the spatial distribution and interaction of different types of objects, such as the distribution of cell types in a tissue sample. Such models are potentially useful for investigating the spatial relationships between different cell types in the tumor microenvironment, but so far studies of the TME using cell-resolution imaging have been largely limited to spatial descriptive statistics. However, MGPP models have many advantages over descriptive statistics, such as uncertainty quantification, incorporation of multiple covariates and the ability to make predictions. In this paper, we describe and apply a previously developed MGPP method, thesaturated pairwise interaction Gibbs point process model, to a publicly available multiplexed imaging dataset obtained from colorectal cancer patients. Importantly, we show how these methods can be used as joint species distribution models (JSDMs) to precisely frame and answer many relevant questions related to the ecology of the tumor microenvironment.
Extracellular Matrix Abnormalities Contribute to Cardiac Insulin Resistance and Associated Dysfunction in Diet-induced Obese Mice
Authors: Musale Vishal , Murdoch Colin E. , Banah Ayman K. , Hasib Annie , Hennayake Chandani K. , Dong Bo , Lang Chim C. , Wasserman David H. , Kang Li 
Published: November 2023

AbstractIncreased deposition of extracellular matrix (ECM) components such as collagens and hyaluronan contributes to the pathogenesis of obesity-associated insulin resistance in muscle, liver, and adipose tissue. Despite the significance of the heart in cardiovascular and metabolic diseases, maladaptive ECM remodelling in obesity-associated cardiac insulin resistance and cardiac dysfunction has not been studied. Using genetic and pharmacological approaches in mice fed a high fat (HF) diet, we demonstrated a tight association between increased ECM deposition with cardiac insulin resistance. Increased collagen deposition by genetic deletion of matrix metalloproteinase 9 (MMP9) exacerbated cardiac insulin resistance and decreased hyaluronan deposition by treatment with PEGylated human recombinant hyaluronidase PH20 (PEGPH20) improved cardiac insulin resistance in obese mice. These relationships corresponded to functional changes in the heart. PEGPH20 treatment in obese mice ameliorated HF diet-induced abnormal myocardial remodelling. In addition to hyaluronan, increased collagen deposition is a characteristic of the obese mouse heart. We further demonstrated that pirfenidone, a clinically available anti-fibrotic medication which inhibits collagen expression, improved cardiac insulin resistance and cardiac function in obese mice. Our results provide important new insights into the role of ECM remodelling in the pathogenesis of cardiac insulin resistance and associated dysfunction in obesity of distinct mouse models. These findings support the novel therapeutic potential of targeting early cardiac ECM abnormalities in the prevention and treatment of obesity-related cardiovascular complications.
The influence of cross-border mobility on the COVID-19 epidemic in Nordic countries
Authors: Shubin Mikhail , Brustad Hilde Kjelgaard , Midtbø Jørgen Eriksson , Günther Felix , Alessandretti Laura , Ala-Nissila Tapio , Tomba Gianpaolo Scalia , Kivelä Mikko , Hin Chan Louis Yat , Leskelä Lasse 
Published: November 2023

AbstractRestrictions of cross-border mobility are typically used to prevent an emerging disease from entering a country in order to slow down its spread. However, such interventions can come with a significant societal cost and should thus be based on careful analysis and quantitative understanding on their effects. To this end, we model the influence of cross-border mobility on the spread of COVID-19 during 2020 in the neighbouring Nordic countries of Denmark, Finland, Norway and Sweden. We investigate the immediate impact of cross-border travel on disease spread and employ counterfactual scenarios to explore the cumulative effects of introducing additional infected individuals into a population during the ongoing epidemic. Our results indicate that border restrictions can significantly influence the course of an epidemic, but this impact is highly contingent on the prevailing epidemic status of the involved countries. In particular, there are several instances in which the contribution of cross-border movement was found to be negligible. Our findings underscore the critical importance of accurate data and models on both epidemic progression and travel patterns in informing decisions related to inter-country mobility restrictions.
GPT-4V(ision) Unsuitable for Clinical Care and Education: A Clinician-Evaluated Assessment
Authors: Senkaiahliyan M. Senthujan , Toma Augustin , Ma Jun , Chan An-Wen , Ha Andrew , An Kevin R. , Suresh Hrishikesh , Rubin Barry , Wang Bo 
Published: November 2023

AbstractOpenAI’s large multimodal model, GPT-4V(ision), was recently developed for general image interpretation. However, less is known about its capabilities with medical image interpretation and diagnosis. Board-certified physicians and senior residents assessed GPT-4V’s proficiency across a range of medical conditions using imaging modalities such as CT scans, MRIs, ECGs, and clinical photographs. Although GPT-4V is able to identify and explain medical images, its diagnostic accuracy and clinical decision-making abilities are poor, posing risks to patient safety. Despite the potential that large language models may have in enhancing medical education and delivery, the current limitations of GPT-4V in interpreting medical images reinforces the importance of appropriate caution when using it for clinical decision-making.
mRNA Vaccines Encoding Influenza Virus Hemagglutinin (HA) Elicits Immunity in Mice from Influenza A Virus Challenge
Authors: Reneer Z. Beau , Bergeron Harrison C. , Reynolds Stephen , Thornhill-Wadolowski Elena , Feng Lan , Bugno Marcin , Truax Agnieszka D. , Tripp Ralph A. 
Published: November 2023

AbstractInfluenza viruses cause epidemics and can cause pandemics with substantial morbidity with some mortality every year. Seasonal influenza vaccines have incomplete effectiveness and elicit a narrow antibody response that often does not protect against mutations occurring in influenza viruses. Thus, various vaccine approaches have been investigated to improve safety and efficacy. Here, we evaluate an mRNA influenza vaccine encoding hemagglutinin (HA) proteins in a BALB/c mouse model. The results show that mRNA vaccination elicits neutralizing and serum antibodies to each influenza virus strain contained in the current quadrivalent vaccine that is designed to protect against four different influenza viruses including two influenza A viruses (IAV) and two influenza B (IBV), as well as several antigenically distinct influenza virus strains in both hemagglutination inhibition assay (HAI) and virus neutralization assays. The quadrivalent mRNA vaccines had antibody titers comparable to the antibodies elicited by the monovalent vaccines to each tested virus regardless of dosage following an mRNA booster vaccine. Mice vaccinated with mRNA encoding an H1 HA had decreased weight loss and decreased lung viral titers compared to mice not vaccinated with an mRNA encoding an H1 HA. Overall, this study demonstrates the efficacy of mRNA-based seasonal influenza vaccines are their potential to replace both the currently available split-inactivated, and live-attenuated seasonal influenza vaccines.
Fast and scalable querying of eukaryotic linear motifs withgget elm
Authors: Luebbert Laura , Hoang Chi , Kumar Manjeet , Pachter Lior 
Published: November 2023

AbstractMotivationEukaryotic linear motifs (ELMs), or Short Linear Motifs (SLiMs), are protein interaction modules that play an essential role in cellular processes and signaling networks and are often involved in diseases like cancer. The ELM database is a collection of manually curated motif knowledge from scientific papers. It has become a crucial resource for cataloging motif biology and recognizing candidate ELMs in novel amino acid sequences. Users can search amino acid sequences or UniProt IDs on the ELM resource web interface. However, as with many web services, there are limitations in the swift processing of large-scale queries through the ELM web interface or API calls, and, therefore, integration into protein function analysis pipelines is limited.ResultsTo allow swift, large-scale motif analyses on protein sequences using ELMs curated on the ELM database, we have developed a Python and command line tool,gget elm, which relies on local computations for efficiently finding candidate ELMs in user-submitted amino acid sequences and UniProt identifiers.gget elmincreases accessibility to the information stored in the ELM database and allows scalable searches for motif-mediated interaction sites in the amino acid sequences.Availability and implementationThe manual and source code are available athttps://github.com/pachterlab/gget.
Raman microscopy of cryofixed biological specimens for high-resolution and high-sensitivity chemical imaging
Authors: Mizushima Kenta , Kumamoto Yasuaki , Tamura Shoko , Yamanaka Masahito , Mochizuki Kentaro , Li Menglu , Egoshi Syusuke , Dodo Kosuke , Harada Yoshinori , Smith Nicholas I. , Sodeoka Mikiko , Tanaka Hideo , Fujita Katsumasa 
Published: November 2023

AbstractRaman microscopy is an emerging molecular imaging technology, yet its signal-to-noise-ratio (SNR) in measurements of biological specimens is severely limited due to the small cross-section of Raman scattering. Here, we present Raman imaging techniques of cryofixed specimens to overcome SNR limitations by enabling long exposure of specimens under highly stabilized low-temperature conditions. The observation of frozen specimens in a cryostat at a constant low temperature immediately after rapid freezing enabled the improvement of SNR and significantly enhanced spatial and spectral resolution. We also confirmed that the cryofixation can preserve physicochemical states of specimens by observing alkyne-labeled coenzyme Q in cytosol and hemeproteins in acute ischemic myocardium, which cannot be done by fixation using chemical reagents. Finally, we applied the technique for multiplex Raman imaging of label-free endogenous molecules and alkyne-tagged molecules in cryofixed HeLa cells, demonstrating its capability of high-content imaging of complex biological phenomena while maintaining physiological conditions.
The Impact of SIV-Induced Immunodeficiency on Clinical Manifestation, Immune Response, and Viral Dynamics in SARS-CoV-2 Coinfection
Authors: Melton Alexandra , Rowe Lori A , Penney Toni , Krzykwa Clara , Goff Kelly , Scheuermann Sarah , Melton Hunter J , Williams Kelsey , Golden Nadia , Green Kristyn Moore , Smith Brandon , Russell-Lodrigue Kasi , Dufour Jason P , Doyle-Meyers Lara A , Schiro Faith , Aye Pyone P , Lifson Jeffery D , Beddingfield Brandon J , Blair Robert V , Bohm Rudolf P , Kolls Jay K , Rappaport Jay , Hoxie James A , Maness Nicholas J 
Published: November 2023

AbstractPersistent and uncontrolled SARS-CoV-2 replication in immunocompromised individuals has been observed and may be a contributing source of novel viral variants that continue to drive the pandemic. Importantly, the effects of immunodeficiency associated with chronic HIV infection on COVID-19 disease and viral persistence have not been directly addressed in a controlled setting. Here we conducted a pilot study wherein two pigtail macaques (PTM) chronically infected with SIVmac239 were exposed to SARS-CoV-2 and monitored for six weeks for clinical disease, viral replication, and viral evolution, and compared to our previously published cohort of SIV-naïve PTM infected with SARS-CoV-2. At the time of SARS-CoV-2 infection, one PTM had minimal to no detectable CD4+ T cells in gut, blood, or bronchoalveolar lavage (BAL), while the other PTM harbored a small population of CD4+ T cells in all compartments. Clinical signs were not observed in either PTM; however, the more immunocompromised PTM exhibited a progressive increase in pulmonary infiltrating monocytes throughout SARS-CoV-2 infection. Single-cell RNA sequencing (scRNAseq) of the infiltrating monocytes revealed a less activated/inert phenotype. Neither SIV-infected PTM mounted detectable anti-SARS-CoV-2 T cell responses in blood or BAL, nor anti-SARS-CoV-2 neutralizing antibodies. Interestingly, despite the diminished cellular and humoral immune responses, SARS-CoV-2 viral kinetics and evolution were indistinguishable from SIV-naïve PTM in all sampled mucosal sites (nasal, oral, and rectal), with clearance of virus by 3-4 weeks post infection. SIV-induced immunodeficiency significantly impacted immune responses to SARS-CoV-2 but did not alter disease progression, viral kinetics or evolution in the PTM model. SIV-induced immunodeficiency alone may not be sufficient to drive the emergence of novel viral variants.
A putative rhamnogalacturonan-II CMP-β-Kdo transferase identified using CRISPR/Cas9 gene edited callus to circumvent embryo lethality
Authors: Zhang Yuan , Sharma Deepak , Liang Yan , Downs Nick , Dolman Fleur , Thorne Kristen , Black Ian M. , Pereira Jose Henrique , Adams Paul , Scheller Henrik V. , O’Neill Malcolm , Urbanowicz Breeanna , Mortimer Jenny C. 
Published: November 2023

AbstractRhamnogalacturonan II (RG-II) is a structurally complex and conserved domain of the pectin present in the primary cell walls of vascular plants. Borate crosslinking of RG-II is required for plants to grow and develop normally. Mutations that alter RG-II structure also affect crosslinking and are lethal or severely impair growth. Thus, few genes involved in RG-II synthesis have been identified. Here we developed a method using CRISPR/Cas9-mediated gene to generate callus carrying loss-of-function mutations in theMPG2gene that encodes a putative family GT29 glycosyltransferase. Plants homozygous for this mutation do not survive. We show that in the callus mutant cell walls, RG-II does not crosslink normally because it lacks 3-deoxy-D-manno- octulosonic acid (Kdo) and thus cannot form the α-L-Rhap-(1→5)-α-D-kdop-(1→ sidechain. We suggest that MGP2 encodes an inverting CMP-β-Kdo transferase (RCKT1). Our discovery provides further insight into the role of sidechains in RG-II dimerization.
Molecular determinants of antagonist interactions with chemokine receptors CCR2 and CCR5
Authors: Dawson John R.D. , Wadman Grant M. , Zhang Penglie , Tebben Andrew , Carter Percy H. , Gu Siyi , Shroka Thomas , Borrega-Roman Leire , Salanga Catherina L. , Handel Tracy M. , Kufareva Irina 
Published: November 2023

AbstractBy driving monocyte chemotaxis, the chemokine receptor CCR2 shapes inflammatory responses and the formation of tumor microenvironments. This makes it a promising target in inflammation and immuno-oncology; however, despite extensive efforts, there are no FDA-approved CCR2-targeting therapeutics. Cited challenges include the redundancy of the chemokine system, suboptimal properties of compound candidates, and species differences that confound the translation of results from animals to humans. Structure-based drug design can rationalize and accelerate the discovery and optimization of CCR2 antagonists to address these challenges. The prerequisites for such efforts include an atomic-level understanding of the molecular determinants of action of existing antagonists.In this study, using molecular docking and artificial-intelligence-powered compound library screening, we uncover the structural principles of small molecule antagonism and selectivity towards CCR2 and its sister receptor CCR5. CCR2 orthosteric inhibitors are shown to universally occupy an inactive-state-specific tunnel between receptor helices 1 and 7; we also discover an unexpected role for an extra-helical groove accessible through this tunnel, suggesting its potential as a new targetable interface for CCR2 and CCR5 modulation. By contrast, only shape complementarity and limited helix 8 hydrogen bonding govern the binding of various chemotypes of allosteric antagonists. CCR2 residues S1012.63and V2446.36are implicated as determinants of CCR2/CCR5 and human/mouse orthosteric and allosteric antagonist selectivity, respectively, and the role of S1012.63is corroborated through experimental gain-of-function mutagenesis. We establish a critical role of induced fit in antagonist recognition, reveal strong chemotype selectivity of existing structures, and demonstrate the high predictive potential of a new deep-learning-based compound scoring function. Finally, this study expands the available CCR2 structural landscape with computationally generated chemotype-specific models well-suited for structure-based antagonist design.
The polyamines spermine and spermidine inhibit or induce programmed cell death inArabidopsis thaliana in vitroandin vivoin a dose dependent manner
Authors: Burke Rory , Nicotra Daniele , Phelan Jim , McCabe Paul F. , Kacprzyk Joanna 
Published: November 2023

AbstractPolyamines are ubiquitous biomolecules with a number of established functions in eukaryotic cells. In plant cells, polyamines have previously been linked to abiotic and biotic stress tolerance, as well as to the modulation of programmed cell death (PCD), with contrasting reports on their pro-PCD and pro-survival effects. Here, we used two well established platforms for the study of plant PCD;Arabidopsis thalianasuspension cultures cells and the root hair assay, to examine the roles of the polyamines spermine and spermidine in the regulation of PCD. We demonstrate that both polyamines can trigger PCD when applied exogenously at higher doses, whereas at lower concentrations they inhibit PCD induced by both biotic and abiotic stimuli. Furthermore, we show that concentrations of polyamines resulting in inhibition of PCD generated a transient ROS burst in our experimental system, and activated the expression of oxidative stress- and pathogen response-associated genes. Finally, we examined PCD responses in existingArabidopsispolyamine synthesis mutants, and identified a subtle PCD phenotype inArabidopsisseedlings deficient in thermo-spermine. The presented data show that polyamines can have a role in PCD regulation, however that role is dose-dependent and consequently they may act as either inhibitors, or inducers, of PCD inArabidopsis.
Idiosyncrasies unveiled: examining the pace, patterns and predictors of biotic diversification in peninsular India
Authors: Roy Pragyadeep , Joshi Jahnavi 
Published: November 2023

AbstractThe Peninsular Indian Plate (PIP), an ancient Gondwanan landmass, the oldest region for diversification with complex geoclimatic history in Tropical Asia, harbours highly diverse and endemic biota with distinct biogeographic affinities. However, our understanding of the diversification dynamics of its biota in a quantitative framework is limited. Given this, we used time-calibrated molecular phylogenies and birth-death models to examine the diversification tempo, mode, and drivers across 34 well-studied endemic lineages (∼670 species). Lineage identity and biogeographic affinity differentially influenced the diversification rates, where plants had the highest and soil arthropods had the lowest diversification rates. Also, younger Asian groups diversified faster than older Gondwanan taxa. The gradual accumulation was supported in 19 lineages, suggesting that the historical stability of their habitat was an important driver, although the region has had a dynamic geoclimatic past. Miocene aridification, monsoon intensification, changes in paleotemperature, and species diversity explained diversification patterns among the other 15 lineages. The diversification rates predicted the species diversity better than clade age across lineages. Our results highlight the role of regional biogeographic, geoclimatic processes, and phylogenetic history on diversification dynamics, which is critical for predicting how PIP biota may respond to global change amid significant anthropogenic threats.