bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplexed Ultrasound Imaging of Gene Expression
Authors: Nyström Nivin N. , Jin Zhiyang , Bennett Marisa E. , Zhang Ruby , Swift Margaret B. , Shapiro Mikhail G. 
Published: November 2024

ABSTRACTAcoustic reporter genes (ARGs) have enabled the imaging of gene expression with ultrasound, which provides high-resolution access to deep, optically opaque living tissues. However, unlike their fluorescent counterparts, ARGs have so far been limited to a single “color,” preventing multiplexed imaging of cellular states or populations. Here, we use rational protein design and directed evolution to develop two novel ARGs that can be distinguished from each other based on their acoustic pressure response profiles, enabling “two-color” ultrasound imaging of gene expression. We demonstrate the utility of multiplexed ARGs for delineating bacterial cell species and cell statesin vitro, and then apply them towards imaging distinct subpopulations of probiotics in the mouse gastrointestinal tract and in tumor-colonizing bacterial agentsin vivo. Just as the first wavelength-shifted derivatives of fluorescent proteins opened a vivid world for optical microscopy, our next-generation acoustic proteins set the stage for a richer symphony of ultrasound signals from living subjects.
GeneCover: A Combinatorial Approach for Label-free Marker Gene Selection
Authors: Wang An , Hicks Stephanie , Geman Donald , Younes Laurent 
Published: November 2024

AbstractThe selection of marker gene panels is critical for capturing the cellular and spatial hetero-geneity in the expanding atlases of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics data. Most current approaches to marker gene selection operate in a label-based framework, which is inherently limited by its dependency on predefined cell type labels or clustering results. In contrast, existing label-free methods often struggle to identify genes that characterize rare cell types or subtle spatial patterns, and they frequently fail to scale efficiently with large datasets. Here, we introduce geneCover, a label-free combinatorial method that selects an optimal panel of minimally redundant marker genes based on gene-gene correlations. Our method demonstrates excellent scalability to large datasets and identifies marker gene panels that capture distinct correlation structures across the transcriptome. This allows geneCover to distinguish cell states in various tissues of living organisms effectively, including those associated with rare or otherwise difficult-to-identify cell types. We evaluate the performance of geneCover across various scRNA-seq and spatial transcriptomics datasets, comparing it to other label-free algorithms to highlight its utility and potential in diverse biological contexts.
Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals
Authors: Forni Maria Fernanda , Pizzurro Gabriela A. , Krause Will , Alexander Amanda F. , Bridges Kate , Xu Yiting , Justynski Olivia , Gabry Anthony , Camara Niels Olsen Saraiva , Miller-Jensen Kathryn , Horsley Valerie 
Published: November 2024

SummaryThe cellular metabolism of macrophages depends on tissue niches and can control macrophage inflammatory or resolving phenotypes. Yet, the identity of signals within tissue niches that control macrophage metabolism is not well understood. Here, using single-cell RNA sequencing of macrophages in early mouse wounds, we find that, rather than gene expression of canonical inflammatory or resolving polarization markers, metabolic gene expression defines distinct populations of early wound macrophages. Single-cell secretomics and transcriptomics identify inflammatory and resolving cytokines expressed by early wound macrophages, and we show that these signals drive metabolic inputs and mitochondrial metabolism in an age-dependent manner. We show that aging alters the metabolome of early wound macrophages and rewires their metabolism from mitochondria to glycolysis. We further show that macrophage-derived Chi3l3 and IGF-1 can induce metabolic inputs and mitochondrial mass/metabolism in aged and bone marrow-derived macrophages. Together, these findings reveal that macrophage-derived signals drive the mitochondrial metabolism of macrophages within early wounds in an age-dependent manner and have implications for inflammatory diseases, chronic injuries, and age-related inflammatory diseases.In BriefThis study reveals that macrophage subsets in early inflammatory stages of skin wound healing are defined by their metabolic profiles rather than polarization phenotype. Using single-cell secretomics, we establish key macrophage cytokines that comprise thein vivowound niche and drive mitochondrial-based metabolism. Aging significantly alters macrophage heterogeneity and increases glycolytic metabolism, which can be restored to OxPHOS-based metabolism with young niche cytokines. These findings highlight the importance of the tissue niche in driving macrophage phenotypes, with implications for aging-related impairments in wound healing.HighlightsSingle cell transcriptional analysis reveals that reveals that metabolic gene expression identifies distinct macrophage populations in early skin wounds.Single-cell secretomic data show that young macrophages contribute to the wound bed niche by secreting molecules such as IGF-1 and Chi3l3.Old wound macrophages display altered metabolomics, elevated glycolytic metabolism and glucose uptake, and reduced lipid uptake and mitochondrial mass/metabolism.Chi3l3 but not IGF-1 secretion is altered in macrophages in an age dependent manner.Chi3l3 can restore mitochondrial mass/metabolism in aged macrophages.
H2S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes
Authors: Hanna David A. , Chen Brandon , Shah Yatrik M. , Khalimonchuk Oleh , Cunniff Brian , Banerjee Ruma 
Published: November 2024

AbstractMitochondrial form and function are intimately interconnected, responding to cellular stresses and changes in energy demand. Hydrogen sulfide, a product of amino acid metabolism, has dual roles as an electron transport chain substrate and complex IV (CIV) inhibitor, leading to a reductive shift, which has pleiotropic metabolic consequences. Luminal sulfide concentration in colon is high due to microbial activity, and in this study, we demonstrate that chronic sulfide exposure of colonocyte-derived cells leads to lower Mic60 and Mic19 expression that is correlated with a profound loss of cristae and lower mitochondrial networking. Sulfide-induced depolarization of the inner mitochondrial membrane activates Oma1-dependent cleavage of Opa1 and is associated with a profound loss of CI and CIV activities associated with respirasomes. Our study reveals a potential role for sulfide as an endogenous modulator of mitochondrial dynamics and suggests that this regulation is corrupted in hereditary or acquired diseases associated with elevated sulfide.Significance StatementHydrogen sulfide is a product of host as well as gut microbial metabolism and has the dual capacity for activating respiration as a substrate, and inhibiting it at the level of complex IV. In this study, we report that chronic albeit low-level sulfide exposure elicits profound changes in mitochondrial architecture in cultured human cells. Disruption of mitochondrial networks is reversed upon removal of sulfide from the growth chamber atmosphere. Sulfide-dependent depolarization of the inner mitochondrial membrane is associated with loss of cristae and respiratory supercomplexes. Our study reveals the potential for sulfide to be an endogenous regulator of mitochondrial ultrastructure and function via modulation of electron flux and for this process to be corrupted in sulfide dysregulated diseases.
The key role of cheaters in the persistence of cooperation
Authors: Babajanyan Sanasar G. , Wolf Yuri I. , Koonin Eugene V. , Rochman Nash D. 
Published: November 2024

AbstractEvolution of cooperation is a major, extensively studied problem in evolutionary biology. Cooperation is beneficial for a population as a whole but costly for the bearers of social traits such that cheaters enjoy a selective advantage over cooperators. Here we focus on coevolution of cooperators and cheaters in a multi-level selection framework, by modeling competition among groups composed of cooperators and cheaters. Cheaters enjoy a reproductive advantage over cooperators at the individual level, independent of the presence of cooperators in the group. Cooperators carry a social trait that provides a fitness advantage to the respective groups. In the case of absolute fitness advantage, where the survival probability of a group is independent of the composition of other groups, the survival of cooperators does not correlate with the presence of cheaters. By contrast, in the case of relative fitness advantage, where the survival probability of a group depends on the composition of all groups, the survival of cooperators positively correlates with the presence of cheaters. Increasing the strength of the social trait alone fails to ensure survival of cooperators, and the increase of the reproduction advantage of the cheaters is necessary to avoid population extinction. We validate these theoretical results with an agent-based model of a bacterial biofilm where emergence of the cooperative trait is facilitated by the presence of cheaters, leading to evolution of spatial organization. This finding contrasts the classical view that spatial organization facilitates cooperation. Our results suggest that, counterintuitively, cheaters often promote, not destabilize, evolution of cooperation.SignificanceCooperation is central to the evolution of life and the emergence of multicellularity. Social traits stabilize populations against environmental volatility and enable division of labor. However, evolution of cooperation is beset by cheaters that benefit from cooperation without paying the cost. Analysis of a multilevel selection model of population evolution shows that, counterintuitively, the presence of cheaters can be beneficial or even essential for the survival of cooperators. This unexpected effect comes from multilevel selection whereby cheaters at the individual level become altruists at the group level, enabling overall growth of the population that is essential for the persistence of cooperators. These findings have broad implications for understanding the emergence of cooperation and host-parasite coevolution throughout the history of life.
HSP70 is upregulated after heat but not freezing stress in the freeze-tolerant cricketGryllus veletis
Authors: Adams Victoria E. , van Oirschot Maranda L. , Toxopeus Jantina 
Published: November 2024

AbstractHeat shock proteins (HSPs) are well known to prevent and repair protein damage caused by various abiotic stressors, but their role in low temperature and freezing stress is not well-characterized compared to other thermal challenges. Ice formation in and around cells is hypothesized to cause protein damage, yet many species of insects can survive freezing, suggesting HSPs may be an important mechanism in freeze tolerance. Here, we studied HSP70 in a freeze-tolerant cricketGryllus veletisto better understand the role of HSPs in this phenomenon. We measured expression of one heat-inducible HSP70 isoform at the mRNA level (using RT-qPCR), as well as the relative abundance of total HSP70 protein (using semi-quantitative Western blotting), in five tissues from crickets exposed to a survivable heat treatment (2 h at 40°C), a 6-week fall-like acclimation that induces freeze tolerance, and a survivable freezing treatment (1.5 h at -8°C). While HSP70 expression was upregulated by heat at the mRNA or protein level in all tissues studied (fat body, Malphigian tubules, midgut, femur muscle, nervous system ganglia), no tissue exhibited HSP70 upregulation within 2 – 24 h following a survivable freezing stress. During fall-like acclimation to mild low temperatures, we only saw moderate upregulation of HSP70 at the protein level in muscle, and at the RNA level in fat body and nervous tissue. Although HSP70 is important for responding to a wide range of stressors, our work suggests that this chaperone may be less critical in the preparation for, and response to, moderate freezing stress.HighlightsHeat shock protein 70 (HSP70) may not contribute substantially to freeze toleranceHeat stress caused HSP70 mRNA and protein upregulation in the spring field cricketAcclimation prior to freezing was correlated with slight HSP70 upregulationHSP70 was not upregulated after freezing in this freeze-tolerant insectFurther work is needed to determine whether freezing causes protein damageGraphical abstract
A Modular Layer-by-Layer Nanoparticle Platform for Hematopoietic Progenitor and Stem Cell Targeting
Authors: Dacoba Tamara G. , Nabar Namita , Hammond Paula T. 
Published: November 2024

ABSTRACTEffective delivery of drug and gene cargos to hematopoietic stem and progenitor cells (HSPCs) is a major challenge. Current therapeutic strategies in genetic disorders or hematological malignancies are hindered by high costs, low accessibility, and high off-target toxicities. Layer-by-Layer nanoparticles (LbL NPs) are modular systems with tunable surface properties to enable highly specific targeting. In this work, we developed LbL NPs that target HSPCs via antibody functionalization with reduced off-target uptake by circulating myeloid cells. NPs layered with poly(acrylic acid), a bioinert polymer, provided more stealth properties in vivo than other tested bioactive polyanions. The additional conjugation of anti-cKit and anti-CD90 antibodies improved NP uptake by 2-to 3-fold in non-differentiated bone marrow cells in vitro. By contrast, anti-CD105 functionalized NPs showed the highest association to HSPCs in vivo, ranging from 3.0–8.5% in progenitor subpopulations. This LbL NP platform was then adapted to target human HSPC receptors, with similar targeting trends in healthy CD34+ human cells. By contrast, anti-CXCR4 functionalization demonstrated the greatest targeting to human B-cell lymphoma and leukemia cells. Taken together, these results underscore the therapeutic potential of this modular LbL NP platform with the capacity to target HSPCs in a disease-dependent context.
Utilizing blood single-cell transcriptomics to integrate intrinsic and systemic immune aging
Authors: Tomusiak Alan , Lore Sierra , Scheibye-Knudsen Morten , Verdin Eric 
Published: November 2024

AbstractBiomarkers of aging provide insight into the biological effects of interventions and diseases. However, most biomarkers today are based on measurements derived from bulk cell measurements, making it challenging to interpret whether an effect is due to changes in cell type composition (systemic factors) or a cell intrinsic effect. Single-cell RNA sequencing provides a unique platform to simultaneously compare aging-associated changes on both a cellular and bulk level. We first generated a single-cell combined automated human blood cell type and age predictor (clock) for six distinct human T cell subsets. We applied these tools to find acute COVID is associated with a shift in CD8+ cytotoxic cell proportions, while cell type proportions are stable in patients with HIV on long-term ART treatment (HIV+ART). Both COVID and HIV+ART were associated with an increase in naive CD8 T cell transcriptomic age. We further found our single-cell aging biomarker is linked to ribosomal gene expression and has a link to mean cellular transcript length. This study highlights the potential of single cell transcriptomic biomarkers for understanding how the human immune system is impacted by age-associated systemic changes in cell type composition and intrinsic cellular aging.
The NGAGE Model Developed at the Rush Alzheimer’s Disease Research Center: An Approach to Community Engagement and Inclusion in Dementia Research with Diverse Community-Dwelling Older Adults
Authors: Glover Crystal M. , Schneider Julie A. , Bennett David A. , Barnes Lisa L. , Marquez David X. , Aggarwal Neelum T. , Leurgans Sue , Graham Karen L. , Frick Susan , Shah Raj C. 
Published: November 2024

ABSTRACTBackgroundOne of the biggest challenges in the field of Alzheimer’s disease and related dementias (ADRD) is the severe inequitable inclusion of Black and Latino adults in clinical research studies. Despite consistent and persistent efforts, rates of participation among diverse older adults remain critically low.ObjectiveThe purpose of this paper is to set forth The NGAGE Model, one developed at the Rush Alzheimer’s Disease Research Center (Rush ADRC) to facilitate community engagement and research participation among diverse older adults.MethodsThe NGAGE Model consists of five steps that are conceptually distinct but overlapping in practice: 1) Networking, 2) Give first, 3) Advocate for research, 4) Give back, and 5) Evaluate. We define and describe each step. For steps 1 through 4, we calculated the number of events, number of attendees for each event, and percentages of attendees by racial and ethnic categorizations annually from July 1, 2011, through June 30, 2023, resulting in data for 12 distinct years, as provided in annual progress reports to the National Institute on Aging. For Step 5, we counted the number of persons and computed percentages of people by racial and ethnic groups who consented to our Data and Specimen Repository and enrolled in a research study.ResultsOver 12 years, the Rush ADRC conducted 5,362 events with 265,794 attendees. Give First activities represented the NGAGE step with both the highest number of events (n=2,247) and the most attendees (n=124,403). Among Black adults, the highest attendee percentage existed for Advocate for Research events (47%), while the highest for Latinos occurred for Give First activities (26%). Furthermore, 2,135 persons consented to the Data and Specimen Repository and 5,905 enrolled in a research study across 12 years. Higher percentages of both Black (37%) and Latino (10%) adults enrolled in research studies compared to the Repository with 21% and 7%, respectively.ConclusionsThe NGAGE Model facilitated community engagement and research inclusion among Black and Latino adults, particularly via Give First and Advocate for Research activities. We discuss the impacts of study milestones, staff resources, and the COVID-19 pandemic on The NGAGE Model activities and outcomes.
Incorporating epidemiological data into the genomic analysis of partially sampled infectious disease outbreaks
Authors: Carson Jake , Keeling Matt , Ribeca Paolo , Didelot Xavier 
Published: November 2024

ABSTRACTPathogen genomic data is increasingly being used to investigate transmission dynamics in infectious disease outbreaks. Combining genomic data with epidemiological data should substantially increase our understanding of outbreaks, but this is highly challenging when the outbreak under study is only partially sampled, so that both genomic and epidemiological data are missing for intermediate links in the transmission chains. Here we present a new dynamic programming algorithm to perform this task efficiently. We implement this methodology into the well-established TransPhylo framework to reconstruct partially sampled outbreaks using a combination of genomic and epidemiological data. We use simulated datasets to show that including epidemiological data can improve the accuracy of the inferred transmission links compared to inference based on genomic data only. This also allows us to estimate parameters specific to the epidemiological data (such as transmission rates between particular groups) which would otherwise not be possible. We then apply these methods to two real-world examples. Firstly, we use genomic data from an outbreak of tuberculosis in Argentina, for which data was also available on the HIV status of sampled individuals, in order to investigate the role of HIV co-infection in the spread of this tuberculosis outbreak. Second, we use genomic and geographical data from the 2003 epidemic of avian influenza H7N7 in the Netherlands to reconstruct its spatial epidemiology. In both cases we show that incorporating epidemiological data into the genomic analysis allows us to investigate the role of epidemiological properties in the spread of infectious diseases.
Anticoagulation after hemorrhagic transformation in acute cardioembolic ischemic stroke
Authors: Kim Hyunsoo , An Ye-Eun , Seo Beom-Seok , Kim Jae-Myung , Choi Kang-Ho , Park Man-Seok , Lee Ji Sung , Kim Joon-Tae 
Published: November 2024

AbstractBackgroundThe safety and efficacy of anticoagulation in the presence of hemorrhagic transformation (HT) in cardioembolic acute ischemic stroke (AIS) remain uncertain.MethodsThis retrospective study enrolled patients presenting with cardioembolic AIS within 48 hours at a tertiary stroke center between January 2011 and August 2023. Patients who developed HT during hospitalization and underwent follow-up imaging were included, focusing on those with hemorrhagic infarction or parenchymal hematoma type 1. Primary outcomes were HT exacerbation on follow-up imaging and 3-month modified Rankin Scale (mRS) distribution shift, comparing anticoagulation therapy (AC), antiplatelet therapy (APT), and drug discontinuation (NM). The safety outcome was symptomatic intracerebral hemorrhage (sICH) occurrence.ResultsAmong 763 patients with HT (mean age 74.6±8.9 years, 48.1% male), AC was associated with a higher incidence of HT exacerbation compared to APT (adjusted OR 0.48, 95% CI 0.29-0.80, p-value =0.005). However, AC demonstrated improved 3-month mRS outcomes versus APT (adjusted OR 0.63, 95% CI 0.43-0.92, p-value =0.017) and NM (adjusted OR 0.38, 95% CI 0.26-0.55, p-value <0.001). sICH occurred in 5% of cases overall, with rates of 1.5%, 2.1%, and 11.7% in the AC, APT, and NM groups, respectively (adjusted OR for NM vs. AC: 3.93, 95% CI 1.18-13.16, p-value =0.026).ConclusionIn cardioembolic AIS patients with HT, excluding those with PH-2, anticoagulation may lead to radiological exacerbation without increasing sICH risk, while potentially improving functional outcomes. These findings suggest that the presence of HT should not necessarily preclude the use of anticoagulation therapy in this patient population.