bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signatures of selective sweeps in urban and rural white clover populations
Authors: Santangelo James S. , Johnson Marc T. J. , Ness Rob W. 
Published: November 2024

AbstractUrbanization is increasingly recognized as a powerful force of evolutionary change. However, anthropogenic sources of selection can often be similarly strong and multifarious in rural habitats, but these are often ignored in studies of urban evolutionary ecology. Despite numerous examples of phenotypic differentiation between urban and rural populations, we still lack an understanding of the genes enabling adaptation to these contrasting habitats and the genetic architecture underlying urban and rural adaptation. In this study, we conducted whole genome sequencing of 120 urban, suburban, and rural white clover plants from Toronto, Canada. We used these data to identify signatures of selective sweeps across the genome using both SFS and haplotype-based approaches, and characterize the architecture of selective sweeps. We found evidence for selection in genomic regions involved in abiotic stress tolerance and growth/development in both urban and rural populations. Urban and rural populations did not differ in the proportion of hard vs. soft sweeps, though urban populations were characterized by wider sweeps, which may indicate differences in the strength or timescale of selection. In addition, patterns of allele frequency and haplotype differentiation suggest that most sweeps are incomplete. These results highlight how both urban and rural habitats are driving ongoing selection in white clover populations, and motivate future work disentangling the genetic architecture of ecologically important phenotypes, and estimating the strength and timescale of selection underlying adaptation to contemporary anthropogenic habitats.
Synergy of LPS and Shiga-toxin exposure on the RNA expression program of cultured human umbilical vein endothelial cells
Authors: Svilar David , van der Ent Martijn A. , Siemieniak David , Ginsburg David , Cleuren Audrey C. 
Published: November 2024

AbstractBackgroundHemolytic uremic syndrome (HUS) is a primary thrombotic microangiopathy that can cause acute renal failure, particularly in children, and is commonly triggered by Shiga toxin-producingEscherichia coli(STEC) infection. Although previousin vitrostudies have shown that Shiga toxin (STX) can directly affect the endothelium, gram-negative bacteria such asE. colialso contain lipopolysaccharide (LPS) which is known to independently activate endothelial cells. Furthermore, studies in mice and baboons have shown a synergistic effect of LPS and STX in inducing HUS when administered simultaneously.ObjectiveDetermine how LPS, STX, or combined LPS/STX treatment affect the gene expression program of endothelial cells.MethodsHuman umbilical vein endothelial cells (HUVECs) were treated with STX, LPS or a combination of STX and LPS for either 4 or 24 hours, after which unbiased RNA sequencing analysis was performed.ResultsFour-hour treatment with LPS resulted in a greater number of differentially expressed genes as compared to treatment with STX. In contrast, 24-hour treatment with LPS or STX induced similar numbers of differentially expressed genes. Dual treatment with both toxins resulted in a synergistic effect, showing significant up-or downregulation of multiple transcripts that were not observed in either single treatment group, particularly at the 24-hour timepoint.ConclusionOur data provide a resource for assessing the role of endothelial cell gene expression in the pathogenesis of STEC infection and suggest that the responses of these cells to LPS, STX, or combined LPS/STX treatment are unique and temporally regulated.
Evidence of causality between Closure and Open-Ended Evolution in the Kauffman model
Authors: Faggian M. 
Published: November 2024

ABSTRACTEvolution is a highly intricate process marked by the generation of novelty, which necessitates the historical and collective organization of individuals. In this paper, we investigate the relationship between biological organization and Open-Ended Evolution (OEE), with a particular focus on the causal connection between the two. To provide quantitative evidence for this causal link within a chemical system, we apply assembly theory to assess how the emergence of auto-catalytic sets impacts the complexity dynamics within Kauffman’s model. In the second part of the paper, we strengthen this conjecture by analyzing the effects of the simplest auto-catalytic set on the complexity dynamics in Kauffman’s model, specifically in the absence of parametric correlation. By interpreting auto-catalytic sets as organizational structures in chemical systems, our findings provide the first numerical support for investigating the causal relationship between biological organization and OEE. This work represents a promising area for the initial study of the dynamical relationship between OEE and biological organization, and may advance the understanding of their connection in theoretical biology.
Reengineering mRNA lipid nanoparticles for systemic delivery to pancreas
Authors: Isaac Ivan , Patel Luv , Tran Nguyen , Singam Amarnath , Guha Prasun , Park Seungman , Bhattacharya Chandrabali 
Published: November 2024

AbstractLipid nanoparticles (LNPs) hold transformative potential for nucleic acid delivery, with applications ranging from clinical use, particularly in COVID-19 vaccines, to gene therapy and cancer immunotherapy. Traditional LNPs are composed of four components: ionizable lipids, cholesterol, helper lipids, and PEGylated lipids. However, a significant hurdle remains the need for more efficient and selective systemic delivery vehicles, as most targets are challenging to reach and primarily accumulate in the liver following intravenous administration, largely due to Apolipoprotein E (ApoE) mediated uptake in the blood. Recent studies have shown that introducing cationic or anionic lipids as a fifth component in the LNPs has resulted in lung- and spleen-specific mRNA expression. In this study, we report that incorporating endogenous ligands, such as vitamins, as a fifth component can enhance the extrahepatic localization of LNPs. Vitamins are highly biocompatible, possess excellent targeting potential, influence immune response, improve cellular uptake, and increase the stability of mRNA LNPs. We developed a library of 100 LNPs containing luciferase mRNA by partially replacing ionizable lipids with this fifth component and evaluated their efficacy both in vitro and in vivo. From comprehensive batch analysis screening, we identified two formulations with cholecalciferol (vitamin D3) as a fifth component that demonstrated selective systemic delivery to the pancreas (> 99%) with high efficacy. Among these, C-CholF3 emerged as the top formulation, exhibiting robust and sustained protein expression in the pancreas for up to 3 days in a dose-dependent manner with minimal toxicity that makes it suitable for repeated administration. Furthermore, C-CholF3 also demonstrated pancreas-specific gene editing in the Ai14 transgenic mouse model, showing high expression of TdTomato. This underscores its translational potential for protein replacement and CRISPR/Cas9-mediated gene editing in currently incurable pancreatic diseases.
Microtubule plus-end dynamics are tightly coupled to the turnover of the MOR1 polymerase
Authors: Eng Ryan C , Halat Laryssa S , Kuo Chak-Chung , Rakei Aida , Costain Cecily D , Diehl Kamryn A , Blutrich Ron , Lechner Bettina , Zhang Yi , Walia Ankit , Alonso Jose M , Coombs Daniel , Wasteneys Geoffrey O 
Published: November 2024

ABSTRACTMOR1/XMAP215/Dis1/Stu2 family proteins function as polymerases that promote microtubule assembly through tubulin-interacting N-terminal tumor-overexpressed gene (TOG) domains. It remains unclear how the polymerase activity of these proteins is coordinated with their movement along the growing microtubule lattice. Previously, it was found that a L174F mutation in the N-terminal TOG domain of the 217 kDaArabidopsis thalianaMICROTUBULE ORGANIZATION 1 (MOR1) protein impaired microtubule growth and shrinkage rates in a temperature-dependent manner. In this study, we used a homologous recombination strategy to generate stable transgenic lines expressing full-length MOR1 and mutant mor1-1L174Fproteins tagged with the yellow fluorescent protein YPet. When expressed inmor1mutant backgrounds, MOR1-3xYPet showed strong association with both the growing and shrinking microtubule plus ends, consistent with its involvement in both polymerization and depolymerization. By contrast, when expressed in a wild-type background, MOR1-3xYPet was redistributed along the microtubule lattice, microtubule growth rates were reduced, and plant growth was stunted. By quantifying fluorescence recovery after photobleaching, we confirmed that MOR1 has greater affinity for the plus end than the lattice. Exploiting the FRAP technique further, we identified a positive and linear correlation between microtubule polymerization rates and MOR1 turnover at the microtubule plus end. When microtubule growth rates were reduced in the mor1-1-YPet line by shifting the temperature from 21 to 30°C and for MOR1-3xYPet under taxol treatments, MOR1’s turnover was delayed. In contrast, microtubule growth rates and MOR1 turnover were hastened at 30°C or after CRISPR/Cas9-mediated knock out of the CLASP protein. These findings support a new model whereby MOR1 has finite processivity on the microtubule, catalyzing a limited fixed number of tubulin additions before dissociation.HIGHLIGHTSMOR1 has high affinity for both growing and shrinking microtubule plus ends, consistent with a function in both polymerization and depolymerization events.MOR1 has greater affinity for microtubule plus ends than the lattice, and lattice binding associated with overexpression is detrimental to plant growth.MOR1 transiently associates with the microtubule plus end, the duration of which is tightly coupled with its polymerase activity.
Spatially resolved mapping of cells associated with human complex traits
Authors: Song Liyang , Chen Wenhao , Hou Junren , Guo Minmin , Yang Jian 
Published: November 2024

AbstractDepicting spatial distributions of disease-relevant cells is crucial for understanding disease pathology. Here, we present a method, gsMap, that integrates spatial transcriptomics (ST) data with genome-wide association study (GWAS) summary statistics to map cells to human complex traits, including diseases, in a spatially resolved manner. Using embryonic ST datasets covering 25 organs, we benchmarked gsMap through simulation and by corroborating known trait-associated cells or regions in various organs. Applying gsMap to brain ST data, we revealed that the spatial distribution of glutamatergic neurons (glu-neurons) associated with schizophrenia more closely resembles that for cognitive traits than that for mood traits, such as depression. The schizophrenia-associated glu-neurons were distributed near the dorsal hippocampus, with upregulated calcium signaling and regulation genes, while the depression-associated glu-neurons were distributed near the deep medial prefrontal cortex, with upregulated neuroplasticity genes. Our study provides a method for spatially resolved mapping trait-associated cells and demonstrates the gain of biological insights (e.g., spatial distribution of trait-relevant cells and related signature genes) through these maps.
Immunosuppression Drugs Exhibit Differential Effects on Endothelial Cell Function
Authors: Elezaby Aly , Dexheimer Ryan , Wu David , Chan Sze Yu , Chen Ian Y. , Sayed Nazish , Sallam Karim 
Published: November 2024

AbstractImmunosuppressive medications are widely used to treat patients with neoplasms, autoimmune conditions, and solid organ transplants. Prior studies indicate that immunosuppression drugs can cause adverse vascular remodeling. Given the systemic effects of the drugs, elucidating cell-type specific drug-effects has been challenging. We utilized induced pluripotent stem-cell derived endothelial cells to investigate the role of widely used immunosuppression drugs on endothelial function. We found that among immunosuppression agents, sirolimus reduced basic endothelial cell functions including cell migration, proliferation, acetylated LDL uptake, and angiogenesis properties; while tacrolimus only reduced nitric oxide release. This model allows for investigation of differential effect of immunosuppression drugs on endothelial function that can elucidate mechanisms contributing to adverse vascular profiles observed clinically.
Gene expression and pollen performance indicate altered postmating selection betweenSolanumspecies with different mating systems
Authors: Biewer-Heisler Timothy J , Gibson Matthew JS , Sornay Emily , Moyle Leonie C 
Published: November 2024

AbstractPostmating prezygotic (PMPZ) traits play an important role in mating success, especially in species where gametes from multiple males compete. Despite this, the effect of mating system transitions, and attendant shifts in the intensity of sexual selection, on specific PMPZ traits and their underlying loci is still poorly understood. Here we assessed differences in pollen PMPZ traits and tissue-specific gene expression (in leaf, pollen, and style) between two closely related plant species with different mating systems—Solanum lycopersicum(selfing) &Solanum pennellii(outcrossing). We focused on species differences in loci with known roles in pollen tube growth rate, including pectin methylesterases (PMEs) and their inhibitors (PMEIs), andin- vitro&in-vivopollen tube growth rates. Among the gene expression differences observed between species, we found that the expression domain of pollen-biased genes was much narrower in the selfing speciesS. lycopersicumcompared to the outcrossing speciesS. pennellii, including for most reproductive PMEs and PMEIs. In addition,S. pennelliihad faster pollen tube growth ratesin-vivo, whileS. lycopersicumhad fasterin-vitropollen tube growth rates. We propose that the lower expression of pollen tube development genes inS. lycopersicumstyle tissue, and reducedin-vivopollen performance, is a result of reduced allocation to stylar mechanisms that modulate pollen tube growth, potentially consistent with relaxed selection on cryptic female choice in the selfing species.Article SummaryThis study investigates the evidence for differential postmating sexual selection in plants, by analyzing reproductive gene expression and pollen performance in twoSolanumspecies with different mating systems. It finds that species differ systematically in pollen tube growth rates, and that pollen (‘male’)-biased genes have higher secondary expression in stylar (‘female’) tissues in the outcrossing species. These observations are consistent with the outcrossing species experiencing stronger selection on female reproductive tract traits that influence male postmating performance. This study evaluates key expectations of sexual selection on postmating traits but does so in the uncommon context of flowering plants.
High G-Forces in Unintentionally Improper Infant Handling: Implications for Shaken Baby Syndrome Diagnosis
Authors: Lee-Confer Jonathan S. , Wayman Lila T. , Havens Kathryn L. 
Published: November 2024

AbstractIntroductionAbusive head trauma (AHT), commonly referred to as Shaken Baby Syndrome (SBS), is diagnosed in approximately 33 per 100,000 infants annually in the United States. Traditional diagnostic criteria for SBS include subdural, subarachnoid, and retinal hemorrhages. While intentional shaking is a known cause, the potential for similar forces acting on the head resulting from accidental trauma has not been fully explored. This study investigates the biomechanical forces on a model infant’s head during improper handling to determine if such forces could contribute to SBS without malicious intent.MethodsA realistic silicone infant model was equipped with an inertial measurement unit (IMU) to quantify head accelerations during two conditions: (1) placement of the infant model on a table with the head unsupported, and (2) manual shaking at maximum effort by 2 participants holding the model by the torso. Peak head accelerations were recorded for both conditions, and the results were analyzed for comparative assessment of the forces involved.ResultsThe average peak head acceleration when placing the infant model on a table with the head unsupported was +30,952.67 ± 6,540.79 mg, with a range of +19,234.40 to +43,406.30 mg across trials. The average peak head accelerations during maximum effort shaking were significantly lower than placing the infant on the table, averaging 11,430.48 ± 9,539.06,867 vs. 30,952.67 ± 6,540.79 mg, p < 0.0001). There were no significant differences in head accelerations between participants when placing the infant model on the table with the head unsupported (p = 0.93) nor with shaking the baby with maximum effort (p = 0.97).DiscussionThe G-force in this study resulted in higher forces than experienced in an 18-mph car crash and a 5-mph bumper car collision. The study highlights that even accidental non-recommended handling of infants can result in high G-forces to the head, potentially leading to injuries similar to those observed in SBS. These findings highlight the necessity of supporting an infant’s head during handling and warrants caution against prematurely attributing physical abuse in SBS cases without considering unintentional causes.
Smile-to-Bert: A BERT architecture trained for physicochemical properties prediction and SMILES embeddings generation
Authors: Barranco-Altirriba Maria , Würf Vivian , Manzini Enrico , Pauling Josch K. , Perera-Lluna Alexandre 
Published: November 2024

AbstractBinding affinity and molecular property prediction are crucial for drug discovery. Over the years, deep learning models have been widely used for these tasks; however, large datasets are often needed to achieve strong performances. Pre-training models on vast unlabelled data has emerged as a method to extract contextualised embeddings that boost performance on smaller datasets. SMILES (Simplified Molecular Input Line Entry System) encode molecular structures as strings, making them suitable for natural language processing (NLP). Transformers, known for capturing long-range dependencies, are well-suited for processing SMILES. One such transformer-based architecture is BERT (Bidirectional Encoder Representations from Transformers), which only uses the encoder part of the Transformer and performs classification and regression tasks. Pre-trained transformer-based architectures using SMILES have significantly improved predictions on smaller datasets. Public data repositories such as PubChem, which provide SMILES and physicochemical properties among other data, are essential for pre-training these models. SMILES embeddings that combine chemical structure and physicochemical properties information could further enhance performance on tasks such as binding affinity prediction. For this reason, we introduce Smile-to-Bert, a pre-trained BERT architecture that predicts seven physicochemical properties from SMILES using PubChem data and two different SMILES tokenizers. Moreover, this model generates embeddings that integrate information about molecular structure and physicochemical properties. Regarding the prediction of physicochemical properties, the mean absolute errors obtained are: H-bond acceptors (0.0502), H-bond donors (0.0048), rotatable bonds (0.0949), exact mass (0.5678), TPSA (0.4961), heavy atom count (0.0345), and log-P (0.2219). Additionally, the usefulness of the generated embeddings is evaluated using two binding affinity datasets and their performance is compared to embeddings created by a state-of-the-art Transformer. We show that the SmilesPE tokenizer works better than the atom-level one and that integrating the embeddings generated by Smile-to-Bert to the state-of-the-art Transformer embeddings improves the prediction of binding affinity in one of the datasets. A dashboard for the prediction of physicochemical properties is available athttp://147.83.252.32:8050/, and the code is accessible athttps://github.com/m-baralt/smile-to-bert.
An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells
Authors: Kaluba Faith C. , Rogers Thomas J. , Jeong Yu-Jin , Waldhart Althea , Sokol Kelly H. , Lee Cameron J. , Daniels Samuel R. , Longo Joseph , Johnson Amy , Sheldon Ryan D. , Jones Russell G. , Lien Evan C. 
Published: November 2024

AbstractCancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation1–3. Recent work has shown that ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors4–7. Here, we discover a non-canonical route for β-OHB metabolism, in which β-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA forde novofatty acid synthesis in cancer cells. We show that β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into acetyl-CoA for fatty acid synthesis. This alternative metabolic routing of β-OHB allows it to avoid oxidation in the mitochondria and net contribute to anabolic biosynthetic processes. In cancer cells, β-OHB is used for fatty acid synthesis to support cell proliferation under lipid-limited conditionsin vitroand contributes to tumor growth under lipid-limited conditions induced by a calorie-restricted dietin vivo. Together, these data demonstrate that β-OHB is preferentially used for fatty acid synthesis in cancer cells to support tumor growth.
TET1 Functions as a Tumor Suppressor in Lung Adenocarcinoma Through Epigenetic Remodeling and Immune Modulation
Authors: Rahim Abdur , Ruis Brian , Rajczewski Andrew T. , Kruk Monica , Tretyakova Natalia Y. 
Published: November 2024

AbstractTen-Eleven Translocation (TET1-3) dioxygenases oxidize 5-methylcytosine (5mC) in DNA to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), initiating DNA demethylation. The three proteins share significant sequence homology and catalyze the same chemical reaction utilizing alpha-ketoglutarate cofactor and non-heme iron to oxidize the methyl group of 5mC. Since their discovery in 2009, there have been contradictory reports regarding the roles of TET proteins in cancer.TETgenes have been characterized as tumor suppressor genes because their expression levels are reduced in many human cancers including lymphoma, prostate, and pancreas, andTET2gene mutations are common in hematological cancers. However,TET1was recently reported to be overexpressed in triple negative breast cancer and to act as a protooncogene in lung cancer. In the present study, we employed genetic approaches to directly address the function of TET1 protein in lung adenocarcinoma. We found that overexpression ofTET1in human lung adenocarcinoma (H441) cells decreased their proliferation and inhibited colony formation, cell migration, and 3D spheroid tumorigenesis. In contrast,TET1knockout in lung adenocarcinoma accelerated cell growth and promoted colony formation, cell migration, and 3D spheroid tumorigenesis. Transcriptomics and proteomics analyses revealed thatTET1overexpression was associated with overexpression of immune markers, primarily via activation of TNF and NF-kB signaling pathways.TET1knockout in lung adenocarcinoma cells induces the expression of genes involved in cellular metabolism and cell growth. Our results are consistent with a tumor suppressor role ofTET1gene in lung adenocarcinoma and reveal its role in activating antitumor immunity.