bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increasing NPYergic transmission in the hippocampus rescues aging-related deficits of long-term potentiation in the mouse dentate gyrus
Authors: Klinger Katharina , del Ángel Miguel , Çalışkan Gürsel , Stork Oliver 
Published: August 2023

ABSTRACTLoss of neuropeptide Y (NPY)-expressing interneurons in the hippocampus and decaying cholinergic neuromodulation are thought to contribute to impaired cognitive function during aging. However, the interaction of these two neuromodulatory systems in maintaining hippocampal synaptic plasticity during healthy aging has not been explored so far. Here we report profound sex differences in the Neuropeptide-Y (NPY) levels in the dorsal dentate gyrus (DG) with higher NPY concentrations in the male mice compared to their female counterparts and a reduction of NPY levels during aging specifically in males. This change in aged males is accompanied by a deficit in theta burst-induced long-term potentiation (LTP) in the medial perforant path-to-dorsal DG (MPP-DG) synapse, which can be rescued by enhancing cholinergic activation with the acetylcholine esterase blocker, physostigmine. Importantly, NPYergic transmission is required for this rescue of LTP. Moreover, exogenous NPY application alone is sufficient to recover LTP induction in aged male mice, even in the absence of the cholinergic stimulator. Together, our results suggest that in male mice NPYergic neurotransmission is a critical factor for maintaining dorsal DG LTP during aging.
Successful regeneration of the adult zebrafish retina is dependent on inflammatory signaling
Authors: Bludau Oliver , Weber Anke , Bosak Viktoria , Kuscha Veronika , Dietrich Kristin , Hans Stefan , Brand Michael 
Published: August 2023

AbstractInflammation can lead to persistent and irreversible loss of retinal neurons and photoreceptors in mammalian vertebrates. In contrast, in the adult zebrafish brain, acute neural inflammation is both necessary and sufficient to stimulate regeneration of neurons. Here, we report on the critical, positive role of the immune system to support retina regeneration in adult zebrafish. After sterile, ablation of photoreceptors by phototoxicity, we find rapid response of tissue-resident microglia and neutrophils, which returns to homeostatic levels within 14 days post lesion. Pharmacological or genetic impairment of immune cell reactivity results in a reduced Müller glia stem cell response, seen as decreased reactive proliferation, and a strikingly reduced number of regenerated cells from them, including photoreceptors. Conversely, injection of the immune stimulators flagellin, zymosan, or M-CSF into the vitreous of the eye, in spite of the absence of a retinal lesion, leads to a robust proliferation response and the up-regulation of regeneration-associated marker genes in Müller glia. Our results suggest that neuroinflammation is a necessary and sufficient driver for retinal regeneration in the adult zebrafish retina.
Generation of Human Regulatory Dendritic Cells from Cryopreserved Healthy Donor Cells and Hematopoietic Stem Cell Transplant Recipients
Authors: Scroggins Sabrina M. , Schlueter Annette J. 
Published: August 2023

AbstractAcute graft versus host disease (GVHD) remains a significant complication following hematopoietic stem cell transplant (HSCT), despite improved human leukocyte antigen (HLA) matching and advances in prophylactic treatment regimens. Previous studies have shown promising results for future regulatory dendritic cell (DCreg) therapies in the amelioration of GVHD. This study evaluates the effects of cryopreservation on DCreg generation, generation of young and older DCreg in serum-free media, and the feasibility of DCreg generated from young and older HSCT donor monocytes. DCreg were generated in X-vivo 15 serum-free media from donor monocytes. Donors included young and older individuals, either healthy donors or HSCT patients. Phenotypic differences in cell populations were assessed via flow cytometry while pro-inflammatory and anti-inflammatory cytokine production was evaluated in culture supernatants. The number of DCreg generated from cryopreserved monocytes of healthy donors was not significantly different from freshly isolated monocytes. DCreg generated from cryopreserved monocytes had similar levels of co-stimulatory molecule expression, inhibitory molecule expression, and cytokine production as freshly isolated monocytes. Young and older healthy donor monocytes generated similar numbers of DCreg with similar cytokine production and phenotype. Although monocytes from older HSCT patients produced significantly fewer DCreg, DCreg from young and older HSCT patients have a comparable phenotype and cytokine production. Monocytes from young and older myelodysplastic syndrome (MDS) patients generated reduced numbers of DCreg compared to non-MDS monocytes. Results suggest cryopreservation of monocytes from many HSCT patients allows for cost effective generation of DCreg for the prevention and treatment of GVHD on an as needed basis. Although generation of DCreg from MDS patients require further assessment, these data support the possibility ofin vitrogenerated DCreg as a therapy to reduce GVHD-associated morbidity and morbidity in young and older HSCT recipients.
Informing virtual clinical trials of hepatocellular carcinoma with spatial multi-omics analysis of a human neoadjuvant immunotherapy clinical trial
Authors: Zhang Shuming , Deshpande Atul , Verma Babita K. , Wang Hanwen , Mi Haoyang , Yuan Long , Ho Won Jin , Jaffee Elizabeth M. , Zhu Qingfeng , Anders Robert A. , Yarchoan Mark , Kagohara Luciane T. , Fertig Elana J. , Popel Aleksander S. 
Published: August 2023

AbstractHuman clinical trials are important tools to advance novel systemic therapies improve treatment outcomes for cancer patients. The few durable treatment options have led to a critical need to advance new therapeutics in hepatocellular carcinoma (HCC). Recent human clinical trials have shown that new combination immunotherapeutic regimens provide unprecedented clinical response in a subset of patients. Computational methods that can simulate tumors from mathematical equations describing cellular and molecular interactions are emerging as promising tools to simulate the impact of therapy entirelyin silico. To facilitate designing dosing regimen and identifying potential biomarkers, we developed a new computational model to track tumor progression at organ scale while reflecting the spatial heterogeneity in the tumor at tissue scale in HCC. This computational model is called a spatial quantitative systems pharmacology (spQSP) platform and it is also designed to simulate the effects of combination immunotherapy. We then validate the results from the spQSP system by leveraging real-world spatial multi-omics data from a neoadjuvant HCC clinical trial combining anti-PD-1 immunotherapy and a multitargeted tyrosine kinase inhibitor (TKI) cabozantinib. The model output is compared with spatial data from Imaging Mass Cytometry (IMC). Both IMC data and simulation results suggest closer proximity between CD8 T cell and macrophages among non-responders while the reverse trend was observed for responders. The analyses also imply wider dispersion of immune cells and less scattered cancer cells in responders’ samples. We also compared the model output with Visium spatial transcriptomics analyses of samples from post-treatment tumor resections in the original clinical trial. Both spatial transcriptomic data and simulation results identify the role of spatial patterns of tumor vasculature and TGFβ in tumor and immune cell interactions. To our knowledge, this is the first spatial tumor model for virtual clinical trials at a molecular scale that is grounded in high-throughput spatial multi-omics data from a human clinical trial.
Ecological predictors of organelle genome evolution: Phylogenetic correlations with taxonomically broad, sparse, unsystematized data
Authors: Giannakis Konstantinos , Richards Luke , Johnston Iain G. 
Published: August 2023

AbstractComparative analysis of variables across phylogenetically linked observations can reveal mechanisms and insights in evolutionary biology. As the taxonomic breadth of the sample of interest increases, challenges of data sparsity, poor phylogenetic resolution, and complicated evolutionary dynamics emerge. Here, we investigate a cross-eukaryotic question where all these problems exist: which organismal ecology features are correlated with gene retention in mitochondrial and chloroplast DNA (organelle DNA or oDNA). Through a wide palette of synthetic control studies, we characterize the specificity and sensitivity of a collection of parametric and non-parametric phylogenetic comparative approaches to identify relationships in the face of such sparse and awkward datasets. We combine and curate ecological data coupled to oDNA genome information across eukaryotes, including a new semi-automated approach for gathering data on organismal traits from less systematized open-access resources including encyclopedia articles on species and taxa. Combining this unique dataset with our benchmarked comparative approaches, we confirm support for several known links between organismal ecology and organelle gene retention, identify several previously unidentified relationships constituting possible ecological contributors to oDNA genome evolution, and provide support for a recently hypothesized link between environmental demand and oDNA retention. We, with caution, discuss the implications of these findings for organelle evolution and of this pipeline for broad comparative analyses in other fields.
WITHDRAWN: I feel your pain: Higher empathy is associated with higher posterior default mode network activity
Authors: Oliva Valeria , Riegner Gabriel , Dean Jon , Khatib Lora A. , Allen Alessandro , Barrows Daniel , Chen Conan , Fuentes Richard , Jacobson Aaron , Lopez Carolina , Mosbey Dwayne , Reyes Mikaila , Ross Jacob , Uvarova Alexandra , Liu Thomas , Mobley William , Zeidan Fadel 
Published: August 2023

Withdrawal StatementThe authors discovered an error in the primary analysis and have withdrawn the results from this version of the investigation.
Antigen presentation by tumor-associated macrophages drives tumor-infiltrating T cells from a progenitor exhaustion state to terminal exhaustion
Authors: Waibl Polania Jessica , Hoyt-Miggelbrink Alexandra , Tomaszewski William H. , Wachsmuth Lucas P. , Lorrey Selena J. , Wilkinson Daniel S. , Lerner Emily , Woroniecka Karolina , Finlay John B. , Ayasoufi Katayoun , Fecci Peter E. 
Published: August 2023

SUMMARYWhereas terminally exhausted T (Tex_term) cells retain anti-tumor cytotoxic functions, the frequencies of stem-like progenitor exhausted T (Tex_prog) cells better reflect immunotherapeutic responsivity. Here, we examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion. We defined a metric reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), which decreased with tumor progression in solid cancers. Single cell analyses of Tex_prog cells and Tex_term cells in glioblastoma (GBM), a setting of severe T cell exhaustion, revealed disproportionate loss of Tex_prog cells over time. Exhaustion concentrated within tumor-specific T cell subsets, with cognate antigen exposure requisite for acquisition of the Tex_term phenotype. Tumor-associated macrophages (TAM) - not tumor cells - were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion increased frequencies of Tex_prog cells in multiple tumor models, increased PETER, and promoted responsiveness to αPD-1 immunotherapy. Thus, targeting TAM – T cell interactions may further license checkpoint blockade responses.
Competition-driven eco-evolutionary feedback reshapes bacterio-phage lambda’s fitness landscape and enables speciation
Authors: Doud Michael B. , Gupta Animesh , Li Victor , Medina Sarah J. , De La Fuente Caesar A. , Meyer Justin R. 
Published: August 2023

AbstractA major challenge in evolutionary biology is explaining how populations navigate rugged fitness landscapes without getting trapped on local optima. One idea illustrated by adaptive dynamics theory is that as populations adapt, their newly enhanced capacities to exploit resources alter fitness payoffs and restructure the landscape in ways that promote speciation by opening new adaptive pathways. While there have been indirect tests of this theory, none have measured how fitness landscapes deform during adaptation, or test whether these shifts promote diversification. Here, we achieve this by studying bacteriophage ⋋, a virus that readily speciates into co-existing receptor specialists under controlled laboratory conditions. We used a high-throughput gene editing-phenotyping technology to measure ⋋’s fitness landscape in the presence of different evolved-⋋ competitors and found that the fitness effects of individual mutations, and their epistatic interactions, depend on the competitor. Using these empirical data, we simulated ⋋’s evolution on an un-changing landscape and one that recapitulates how the landscape deforms during evolution. ⋋ heterogeneity only evolved in the shifting landscape regime. This study provides a test of adaptive dynamics, and, more broadly, shows how fitness landscapes dynamically change during adaptation, potentiating phenomena like speciation by opening new adaptive pathways.
Co-evolution of gene transfer agents and their alphaproteobacterial hosts
Authors: Kogay Roman , Zhaxybayeva Olga 
Published: August 2023

AbstractGene transfer agents (GTAs) are enigmatic elements that resemble small viruses and are known to be produced during nutritional stress by some bacteria and archaea. The production of GTAs is regulated by quorum sensing, under which a small fraction of the population acts as GTA producers, while the rest become GTA recipients. In contrast to canonical viruses, GTAs cannot propagate themselves because they package pieces of the producing cell’s genome. In alphaproteobacteria, GTAs are mostly vertically inherited and reside in their hosts’ genomes for hundreds of millions of years. While GTAs’ ability to transfer genetic material within a population and their long-term preservation suggests an increased fitness of GTA-producing microbes, the associated benefits and type of selection that maintains GTAs are poorly understood. By comparing rates of evolutionary change in GTA genes to the rates in gene families abundantly present across 293 alphaproteobacterial genomes, we detected 59 gene families that likely co-evolve with GTA genes. These gene families are predominantly involved in stress response, DNA repair, and biofilm formation. We hypothesize that biofilm formation enables the physical proximity of GTA-producing cells, limiting GTA-derived benefits only to a group of closely related cells. We further conjecture that population structure of biofilm-forming sub-populations ensures that the trait of GTA production is maintained despite the inevitable rise of “cheating” genotypes. Because release of GTA particles kills the producing cell, maintenance of GTAs is an exciting example of social evolution in a microbial population.ImportanceGene transfer agents (GTAs) are viruses domesticated by some archaea and bacteria as vehicles for carrying pieces of the host genome. Produced under certain environmental conditions, GTA particles can deliver DNA to neighboring, closely related cells. Function of GTAs remains uncertain. While making GTAs is suicidal for a cell, GTA-encoding genes are widespread in genomes of alphaproteobacteria. Such GTA persistence implies functional benefits but raises question about how selection maintains this lethal trait. By showing that GTA genes co-evolve with genes involved in stress response, DNA repair, and biofilm formation, we provide support for the hypothesis that GTAs facilitate DNA exchange during the stress conditions and present a model for how GTAs persist in biofilm-forming bacterial populations despite being lethal.
Hybrid protein-ligand binding residue prediction with protein language models: Does the structure matter?
Authors: Gamouh Hamza , Novotný Marian , Hoksza David 
Published: August 2023

AbstractBackgroundPredicting protein-ligand binding sites is crucial in studying protein interactions with applications in biotechnology and drug discovery. Two distinct paradigms have emerged for this purpose: sequence-based methods, which leverage protein sequence information, and structure-based methods, which rely on the three-dimensional (3D) structure of the protein. We propose to study a hybrid approach combining both paradigms’ strengths by integrating two recent deep learning architectures: protein language models (pLMs) from the sequence-based paradigm and Graph Neural Networks (GNNs) from the structure-based paradigm. Specifically, we construct a residue-level Graph Attention Network (GAT) model based on the protein’s 3D structure that uses pre-trained pLM embeddings as node features. This integration enables us to study the interplay between the sequential information encoded in the protein sequence and the spatial relationships within the protein structure on the model’s performance.ResultsBy exploiting a benchmark dataset over a range of ligands and ligand types, we have shown that using the structure information consistently enhances the predictive power of baselines in absolute terms. Nevertheless, as more complex pLMs are employed to represent node features, the relative impact of the structure information represented by the GNN architecture diminishes.ConclusionsThe above observations suggest that, although using the experimental protein structure almost always improves the accuracy binding site prediction, complex pLMs still contain structural information that lead to good predictive performance even without using 3D structure.
Second Harmonic Generation Imaging Reveals Entanglement of Collagen Fibers in the Elephant Trunk Skin Dermis
Authors: Schulz Andrew K. , Plotczyk Magdalena , Sordilla Sophia , Boyle Madeline , Singal Krishma , Reidenberg Joy S. , Hu David L. , Higgins Claire A. 
Published: August 2023

AbstractForm-function relationships often have tradeoffs: if a material is tough, it is often inflexible, and vice versa. This is particularly relevant for the elephant trunk, where the skin should be protective yet elastic. To investigate how this is achieved, we used classical histochemical staining and second harmonic generation microscopy to describe the morphology and composition of elephant trunk skin. We report structure at the macro and micro scales, from the thickness of the dermis to the interaction of 10μm thick collagen fibers. We analyzed several sites along the length of the trunk, to compare and contrast the dorsal-ventral and proximal-distal skin morphologies and compositions. We find the dorsal skin of the elephant trunk can have keratin armor layers over 2mm thick, which is nearly 100 times the thickness of the equivalent layer in human skin. We also found that the structural support layer (the dermis) of elephant trunk contains a distribution of collagen-I (COL1) fibers in both perpendicular and parallel arrangement. The bimodal distribution of collagen is seen across all portions of the trunk, and is dissimilar from that of human skin where one orientation dominates within a body site. We hypothesize that this distribution of COL1 in the elephant trunk allows both flexibility and load-bearing capabilities. Additionally, when viewing individual fiber interaction of 10μm thick collagen, we find the fiber crossings per unit volume are five times more common than in human skin, suggesting that the fibers are entangled. We surmise that these intriguing structures permit both flexibility and strength in the elephant trunk. The complex nature of the elephant skin may inspire the design of materials that can combine strength and flexibility.
Honey beeApis melliferaL. Responses to Oxidative Stress Induced by Pharmacological and Pesticide Compounds
Authors: Tahir Faizan , Goblirsch Michael , Adamczyk John , Karim Shahid , Alburaki Mohamed 
Published: August 2023

ABSTRACTThe western honey bee,Apis melliferaL., is a eusocial insect that plays major roles in ecosystem balances and pollination of plants and food crops. Honey bees face multiple biotic and abiotic stressors, such as pathogens, diseases, chemical pesticides, and climate change, which all contribute to honey bee colony loss. This study investigated the impacts of multiple pharmacological and pesticide molecules on honey bee survival and gene regulation responses. In an 11-day cage experiment, sublethal doses of tunicamycin, thapsigargin, metformin, paraquat, hydrogen peroxide, and imidacloprid were administered to newly emerged sister bees. Daily treatment consumption and mortality were recorded, as well as the transcription expression of twelve major genes (AChE-2,Apisimin,Apidaecin,mrjp1,Sodq,cp450,SelT,SelK,Ire1,Xbp1,Derl-1,Hsc70), some of which are markers of oxidative and endoplasmic reticulum (ER) stresses in honey bees. At day 9 of the treatments, protein damage was quantified in caged bees. Kaplan-Meier model indicated significant (p< 0.001) toxicological effects of paraquat, H2O2and tunicamycin on bee survivorship compared to controls with better survivals for other molecules. Post-ingestive aversion responses were recorded only in the case of tunicamycin, hydrogen peroxide and imidacloprid. Nonetheless, significantly higher protein damage on day 9 was only identified in bees exposed to paraquat and imidacloprid. Some antioxidant genes significantly regulated vis-à-vis specific treatments. Our results reveal age-related regulation of other major genes with significant inter-gene positive correlations.
VISTA: An integrated framework for structural variant discovery
Authors: Sarwal Varuni , Lee Seungmo , Yang Jianzhi , Sankararaman Sriram , Chaisson Mark , Eskin Eleazar , Mangul Serghei 
Published: August 2023

AbstractStructural variation (SV), refers to insertions, deletions, inversions, and duplications in human genomes. With advances in whole genome sequencing (WGS) technologies, a plethora of SV detection methods have been developed. However, dissecting SVs from WGS data remains a challenge, with the majority of SV detection methods prone to a high false-positive rate, and no existing method able to precisely detect a full range of SV’s present in a sample. Previous studies have shown that none of the existing SV callers can maintain high accuracy across various SV lengths and genomic coverages. Here, we report an integrated structural variant calling framework, VISTA (Variant Identification and Structural Variant Analysis) that leverages the results of individual callers using a novel and robust filtering and merging algorithm. In contrast to existing consensus-based tools which ignore the length and coverage, VISTA overcomes this limitation by executing various combinations of top-performing callers based on variant length and genomic coverage to generate SV events with high accuracy. We evaluated the performance of VISTA on using comprehensive gold-standard datasets across varying organisms and coverage. We benchmarked VISTA using the Genome-in-a-Bottle (GIAB) gold standard SV set, haplotype-resolved de novo assemblies from The Human Pangenome Reference Consortium (HPRC)1,2, along with an in-house PCR-validated mouse gold standard set. VISTA maintained the highest F1 score among top consensus-based tools measured using a comprehensive gold standard across both mouse and human genomes. VISTA also has an optimized mode, where the calls can be optimized for precision or recall. VISTA-optimized is able to attain 100% precision and the highest sensitivity among other variant callers. In conclusion, VISTA represents a significant advancement in structural variant calling, offering a robust and accurate framework that outperforms existing consensus-based tools and sets a new standard for SV detection in genomic research.