bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating ARG-estimation methods in the context of estimating population-mean polygenic score histories
Authors: Peng Dandan , Mulder Obadiah J. , Edge Michael D. 
Published: May 2024

AbstractScalable methods for estimating marginal coalescent trees across the genome present new opportunities for studying evolution and have generated considerable excitement, with new methods extending scalability to thousands of samples. Benchmarking of the available methods has revealed general tradeoffs between accuracy and scalability, but performance in downstream applications has not always been easily predictable from general performance measures, suggesting that specific features of the ARG may be important for specific downstream applications of estimated ARGs. To exemplify this point, we benchmark ARG estimation methods with respect to a specific set of methods for estimating the historical time course of a population-mean polygenic score (PGS) using the marginal coalescent trees encoded by the ancestral recombination graph (ARG). Here we examine the performance in simulation of seven ARG estimation methods:ARGweaver, RENT+, Relate, tsinfer+tsdate, ARG-Needle, ASMC-clust, andSINGER, using their estimated coalescent trees and examining bias, mean squared error (MSE), confidence interval coverage, and Type I and II error rates of the downstream methods. Although it does not scale to the sample sizes attainable by other new methods,SINGERproduced the most accurate estimated PGS histories in many instances, even whenRelate, tsinfer+tsdate, ARG-NeedleandASMC-clustused samples ten or more times as large as those used bySINGER. In general, the best choice of method depends on the number of samples available and the historical time period of interest. In particular, the unprecedented sample sizes allowed byRelate, tsinfer+tsdate, ARG-Needle, andASMC-clustare of greatest importance when the recent past is of interest—further back in time, most of the tree has coalesced, and differences in contemporary sample size are less salient.
Likelihood Ratios for physical traits in forensic investigations
Authors: Marsico Franco , Egeland Thore 
Published: May 2024

AbstractRecent years have seen significant advances in DNA phenotyping, which predicts the physical traits of an unknown person, such as hair, eyes, and skin color, using DNA data. This technique is increasingly used in forensic investigations to identify missing persons, disaster victims, and suspects of crimes. A key contribution of DNA phenotyping is that it allows researchers to search through lists of individuals with similar characteristics, often gathered from testimonies, photographs, and social media data. However, despite their growing relevance, current methods lack comprehensive mathematical models to calculate likelihood ratios that accurately assess the statistical weight of evidence. Our work bridges this gap by developing new likelihood ratio models, validated through computational simulations. In addition, we demonstrate the ability of these models to improve forensic investigations in real-world scenarios. Furthermore, we introduce the R packageforensicolors, freely available on CRAN, to facilitate the application of the methodologies developed.
Skeleton-forming responses of reef-building corals under ocean acidification
Authors: Li Yixin , Zhao Hongwei , Zhao Yunpeng , Liao Xin , Chen J.-Y. , He Chunpeng , Lu Zuhong 
Published: May 2024

AbstractOcean acidification is increasing in frequency and is considered one of the most important causes of severe damage to global coral reefs. Therefore, there is an urgent need to study the impact of acid stress on the growth patterns of major reef-building corals. Here, we studied the skeleton forming strategies of four widely distributed coral species in a simulated acidified habitat with a pH of 7.6–7.8. We reconstructed and visualized the skeleton building process, quantified elemental calcium loss, and determined gene expression changes. The results suggest that different reef-building corals have diverse growing strategies in acidified seawater. A unique ‘cavity-like’ forming process starts from the inside of the skeletons ofAcropora muricata, which sacrifices skeleton density to protect its polyp-canal system. The forming patterns inPocillopora damicornis,Montipora capricornis, andM. foliosawere characterized by ‘osteoporosis’, exhibiting disordered skeletal structures, insufficient synthesis of adhesion proteins, and low bone mass, correspondingly. In addition, we found that skeletal areas near coral polyps suffered less and had later acidified damage than other skeletal areas in the colony. These results help to understand the skeleton-forming strategies of several major coral species under acid stress, thereby laying a foundation for coral reef protection and restoration under increasing ocean acidification.
Ancient eukaryotic protein interactions illuminate modern genetic traits and disorders
Authors: Cox Rachael M. , Papoulas Ophelia , Shril Shirlee , Lee Chanjae , Gardner Tynan , Battenhouse Anna M. , Lee Muyoung , Drew Kevin , McWhite Claire D. , Yang David , Leggere Janelle C. , Durand Dannie , Hildebrandt Friedhelm , Wallingford John B. , Marcotte Edward M. 
Published: May 2024

SUMMARYAll eukaryotes share a common ancestor from roughly 1.5 – 1.8 billion years ago, a single-celled, swimming microbe known as LECA, the Last Eukaryotic Common Ancestor. Nearly half of the genes in modern eukaryotes were present in LECA, and many current genetic diseases and traits stem from these ancient molecular systems. To better understand these systems, we compared genes across modern organisms and identified a core set of 10,092 shared protein-coding gene families likely present in LECA, a quarter of which are uncharacterized. We then integrated >26,000 mass spectrometry proteomics analyses from 31 species to infer how these proteins interact in higher-order complexes. The resulting interactome describes the biochemical organization of LECA, revealing both known and new assemblies. We analyzed these ancient protein interactions to find new human gene-disease relationships for bone density and congenital birth defects, demonstrating the value of ancestral protein interactions for guiding functional genetics today.
MARK2 regulates Golgi apparatus reorientation by phosphorylation of CAMSAP2 in directional cell migration
Authors: Xu Peipei , Zhang Rui , Zhou Zhengrong , Xu Honglin , Li Yuejia , Yang Mengge , Lin Ruifan , Wang Yingchun , Huang Xiahe , Xie Qi , Meng Wenxiang 
Published: May 2024

ABSTRACTThe reorientation of the Golgi apparatus is crucial for cell migration and is regulated by multi-polarity signals. A number of non-centrosomal microtubules anchor at the surface of the Golgi apparatus and play a vital role in the Golgi reorientation, but how the Golgi are regulated by polarity signals remains unclear. Calmodulin-regulated spectrin-associated protein 2 (CAMSAP2) is a protein that anchors microtubules to the Golgi, a cellular organelle. Our research indicates that CAMSAP2 is dynamically localized at the Golgi during its reorientation processing. Further research shows that CAMSAP2 is potentially regulated by a polarity signaling molecule called MARK2, which interacts with CAMSAP2. We used mass spectrometry to find that MARK2 phosphorylates CAMSAP2 at serine 835, which affects its interaction with the Golgi associated protein USO1 but not with CG-NAP or CLASPs. This interaction is critical for anchoring microtubules to the Golgi during cell migration, altering microtubule polarity distribution, and aiding Golgi reorientation. Our study reveals an important signaling pathway in Golgi reorientation during cell migration, which can provide insights for research in cancer cell migration, immune response, and targeted drug development.
Effects of Ca2+on the Structure and Dynamics of PIP3 in Model Membranes Containing PC and PS
Authors: Bernstein Ashley D. , Yang Yanxing , Osborn Popp Thomas M. , Ampadu Gertrude Asante , Acharya Gobin Raj , Nieuwkoop Andrew J. 
Published: May 2024

ABSTRACTPhosphatidylinositol phosphates (PIPs) are a family of seven different eukaryotic membrane lipids that have a large role in cell viability, despite their minor concentration in eukaryotic cellular membranes. PIPs tightly regulate cellular processes such as cellular growth, metabolism, immunity, and development through direct interactions with partner proteins. Understanding the biophysical properties of PIPs in the complex membrane environment is important to understand how PIPs selectively regulate a partner protein. Here we investigate the structure and dynamics of PIP3 in lipid bilayers that are simplified models of the natural membrane environment. We probe the effects of the anionic lipid phosphatidylserine (PS) and the divalent cation Ca2+. We use solution and solid-state1H,31P, and13C NMR all at natural abundance combined with MD simulations to characterize the structure and dynamics of PIPs.1H and31P 1D spectra show good resolution at high temperatures with isolated peaks in the headgroup, interfacial, and bilayer regions. Site specific assignment of these 1D reporters were made and used to measure the effects of Ca2+and PS. In particular, the resolved31P signals of the PIP3 headgroup allowed for extremely well localized information about PIP3 phosphate dynamics, which the MD simulations were able to help explain. Cross polarization kinetics provided additional site-specific dynamics measurements for the PIP3 headgroups.
Modular, inducible, and titratable expression systems forEscherichia coliandAcinetobacter baumannii
Authors: Bacon Emily E. , Tran Jennifer S. , Nadig Nischala , Peters Jason M. 
Published: May 2024

AbstractGene expression systems that transcend species barriers are needed for cross-species analysis of gene function. In particular, expression systems that can be utilized in both model and pathogenic bacteria underpin comparative functional approaches that inform conserved and variable features of bacterial physiology. Here, we develop replicative and integrative vectors alongside a novel, IPTG-inducible promoter that can be used in the model bacteriumEscherichia coliK-12 as well as strains of the antibiotic-resistant pathogen,Acinetobacter baumannii. We generate modular vectors that transfer by conjugation at high efficiency and either replicate or integrate into the genome, depending on design. Embedded in these vectors, we also developed a synthetic, IPTG-inducible promoter, PabstBR, that induces to a high level, but is less leaky than the commonly usedtrcpromoter. We show that PabstBRis titratable at both the population and single cell level, regardless of species, highlighting the utility of our expression systems for cross-species functional studies. Finally, as a proof of principle, we use our integrating vector to develop a reporter for theE. colienvelope stress σ factor, RpoE, and deploy the reporter inE. coliandA. baumannii, finding thatA. baumanniidoes not recognize RpoE-dependent promoters unless RpoE is heterologously expressed. We envision that these vector and promoter tools will be valuable for the community of researchers that study fundamental biology ofE. coliandA. baumannii.ImportanceAcinetobacter baumanniiis a multidrug-resistant, hospital-acquired pathogen with the ability to cause severe infections. Understanding the unique biology of this non-model bacterium may lead to the discovery of new weaknesses that can be targeted to treat antibiotic-resistant infections. Here, we provide expression tools that can be used to study gene function inA. baumannii, including in drug-resistant clinical isolates. These tools are also compatible with the model bacterium,Escherichia coli, enabling cross-species comparisons of gene function. We anticipate that the use of these tools by the scientific community will accelerate our understanding ofAcinetobacterbiology.
Endocannabinoid regulation of inward rectifier potassium (Kir) channels
Authors: Mayar Sultan , Borbuliak Mariia , Zoumpoulakis Andreas , Bouceba Tahar , Labonté Madeleine M. , Ahrari Ameneh , Sinniah Niveny , Memarpoor-Yazdi Mina , Vénien-Bryan Catherine , Tieleman D. Peter , D’Avanzo Nazzareno 
Published: May 2024

ABSTRACTThe inward rectifier potassium channel Kir2.1 (KCNJ2) is an important regulator of resting membrane potential in both excitable and non-excitable cells. The functions of Kir2.1 channels are dependent on their lipid environment, including the availability of PI(4,5)P2, secondary anionic lipids, cholesterol and long-chain fatty acids acyl coenzyme A (LC-CoA). Endocannabinoids are a class of lipids that are naturally expressed in a variety of cells, including cardiac, neuronal, and immune cells. While these lipids are identified as ligands for cannabinoid receptors (CBRs), there is a growing body of evidence that they can directly regulate the function of numerous ion channels independently of CBRs. Here we examine the effects of a panel of endocannabinoids on Kir2.1 function and demonstrate that a subset of endocannabinoids can alter Kir2.1 conductance to varying degrees independently of CBRs. Using computational and SPR analysis, endocannabinoid regulation of Kir2.1 channels appears to be the result of altered membrane properties, rather than through direct protein-lipid interactions. Furthermore, differences in endocannabinoid effects on Kir4.1 and Kir7.1 channels, indicating that endocannabinoid regulation is not conserved among Kir family members. These findings may have broader implications on the function of cardiac, neuronal and/or immune cells.
Structural and Biophysical Dynamics of Fungal Plasma Membrane Proteins and Implications for Echinocandin Action inCandida glabrata
Authors: Jiang Jennifer , Keniya Mikhail V. , Puri Anusha , Zhan Xueying , Cheng Jeff , Wang Huan , Lin Gigi , Lee Yun-Kyung , Jaber Nora , Hassoun Yasmine , Shor Erika , Shi Zheng , Lee Sang-Hyuk , Xu Min , Perlin David S. , Dai Wei 
Published: May 2024

AbstractFungal plasma membrane proteins represent key therapeutic targets for antifungal agents, yet their structure and spatial distribution in the native context remain poorly characterized. Herein, we employ an integrative multimodal approach to elucidate the structural and functional organization of plasma membrane protein complexes inCandida glabrata, focusing on prominent and essential membrane proteins, the polysaccharide synthase β-(1,3)-glucan synthase (GS) and the proton pump Pma1. Cryo-electron tomography (cryo-ET) and live cell imaging reveal that GS and Pma1 are heterogeneously distributed into distinct plasma membrane microdomains. Treatment with caspofungin, an echinocandin antifungal that targets GS, alters the plasma membrane and disrupts the native distribution of GS and Pma1. Based on these findings, we propose a model for echinocandin action that considers how drug interactions with the plasma membrane environment lead to inhibition of GS. Our work underscores the importance of interrogating the structural and dynamic characteristics of fungal plasma membrane proteinsin situto understand function and facilitate precisely targeted development of novel antifungal therapies.
Non-enzymatic oxylipin production in a mudflat microphytobenthic biofilm: evidence of a diatom response to light
Authors: Doose Caroline , Oger Camille , Mas-Normand Lindsay , Durand Thierry , Hubas Cédric 
Published: May 2024

AbstractThe microphytobenthos (MPB) is a diatom dominated microbial community of primary producers inhabiting the mudflat sediments. In one hand, the benthic diatoms display photo-protective strategies to face extreme light variations susceptible to generate cellular oxidative stress. In the other hand, oxidative stress induces the production of reactive oxygen species (ROS) that generate oxylipins, oxygenated metabolites of polyunsaturated fatty acids (PUFAs), which are among the known chemical mediators in diatoms. However, non-enzymatically generated oxylipins known as isoprostanoids or isofuranoids are poorly studied in diatoms. To better understand the roles of the latter in migrational MPB light response, we investigated the effect of different light irradiances corresponding to dark (D), low light (LL, 50 and 100 µmol. photons. m−2. s−1PAR), medium light (ML, 250 µmol. photons. m−2. s−1PAR), high light (HL, 500, 750 and 1000 µmol. photons. m−2. s−1PAR), on the isoprostanoids production by the biofilm’s organisms. The PUFAs precursors of the varying oxylipins evidenced a diatoms response to light irradiance. Under 1000 PAR condition, the total amount of isoprotanoids increased, indicating an oxidative stress response. Isoprostanes (IsoPs) and prostaglandins (PGs) characterized the HL conditions and evidenced lipid peroxidation probably linked to the higher generation of ROS by the photosynthesis. On the contrary, the phytoprostanes (PhytoPs) characterized the LL and ML where the de-epoxidation state was low and ROS scavengers probably not overwhelmed. This first investigation of non-enzymatic oxylipin production by a microphytobenthic biofilm under different light irradiances highlighted the interest to explore their potential signaling roles related to MPB light responses.
The effects of iron deficient and high iron diets on SARS-CoV-2 lung infection and disease
Authors: Carolin Agnes , Frazer David , Yan Kexin , Bishop Cameron R. , Tang Bing , Nguyen Wilson , Helman Sheridan L. , Horvat Jay , Larcher Thibaut , Rawle Daniel J. , Suhrbier Andreas 
Published: May 2024

AbstractThe severity of Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is often dictated by a range of comorbidities. A considerable literature suggests iron deficiency and iron overload may contribute to increased infection, inflammation and disease severity, although direct causal relationships have been difficult to establish. Here we generate iron deficient and iron loaded C57BL/6J mice by feeding low and high iron diets, with mice on a normal iron diet representing controls. All mice were infected with a primary omicron XXB SARS-CoV-2 isolate and lung inflammatory responses were analyzed by histology, immunohistochemistry and RNA-Seq. Compared with controls, iron deficient mice showed no significant changes in lung viral loads or histopathology, whereas, iron loaded mice showed slightly, but significantly, reduced lung viral loads and histopathology. Transcriptional changes were modest, but illustrated widespread dysregulation of inflammation signatures for both iron deficient vs. controls, and iron loaded vs. controls. Some of these changes could be associated with detrimental outcomes, whereas others would be viewed as beneficial. Diet-associated iron deficiency or overload thus induced modest modulations of inflammatory signatures, but no significant histopathologically detectable disease exacerbations.Author summaryA diet deficient in iron can lead to anemia, a widespread problem worldwide. A diet with excessive iron is less common, but can be associated with excessive consumption of iron supplements. We investigate herein using a mouse model, whether low or high iron diets predispose to detrimental outcomes in the lungs after infection with SARS-CoV-2. A considerable literature suggests iron dysregulation would promote infection and inflammation. However, we found, although inflammatory responses showed modest modulations, viral loads were unaffected or slightly reduced, and lung histopathology was either unaffected or indicated slightly less severe disease. These findings do not support a view that low or high iron diets represent comorbidities predisposing to overt detrimental outcomes for acute COVID-19 lung disease.
Attentional propagation of conceptual information in the human brain
Authors: Acunzo David , Grignolio Damiano , Hickey Clayton 
Published: May 2024

AbstractThe visual environment is complicated, and humans and other animals accordingly prioritise some sources of information over others through the deployment of spatial attention. We presume that attention has the ultimate purpose of guiding the abstraction of information from perceptual experience in the development of concepts and categories. However, neuroscientific investigation has focussed closely on identification of the systems and algorithms that support attentional control, or that instantiate the effect of attention on sensation and perception. Much less is known about how attention impacts the acquisition and activation of high-level information in the brain. Here, we use machine learning of EEG and concurrently-recorded EEG/MRI to temporally and anatomically characterise the neural network that abstracts from attended perceptual information to activate and construct semantic and conceptual representations. We find that the trial-wise amplitude of N2pc - an ERP component closely linked to selective attention - predicts the rapid emergence of information about semantic categories in EEG. Similar analysis of EEG/MRI shows that N2pc predicts MRI-derived category information in a network including VMPFC, posterior parietal cortex, and anterior insula. These brain areas appear critically involved in the attention-mediated translation of perceptual information to concepts, semantics, and action plans.
Dual Mechanism of Action: Exosomes from Human iPSC-Cardiomyocytes and Mesenchymal Stem Cells Restore Injured Myocardium
Authors: Tzng Eileen , Bayardo Nathan , Ikeda Gentaro , Takashima Hiroyuki , Lyons Jennifer , Bennett Mihoko , O’Brien Connor G , Yang Phillip C. 
Published: May 2024

AbstractBackgroundTransplantation of mesenchymal stem cells or induced pluripotent stem cell derived cardiomyocytes improve heart function after myocardial infarction in pre-clinical models. Exosomes are extracellular vesicles, 30-150nm in size, which regulate the paracrine signal of the stem cells. We investigated the functional outcomes and biological effects of exosomes from pure populations of human bone marrow derived mesenchymal stem cells (MSCs) and induced pluripotent stem cell derived cardiomyocytes (iCMs) in a porcine acute myocardial infarction model.MethodsYorkshire swine were subject to proximal left anterior descending artery occlusion with a catheter balloon for 1 hour for ischemia-reperfusion injury. Ten 500ul injections containing 5 x 1011exosomes isolated from the tissue culture media of iCMs or MSCs were delivered transendocardially into the peri-infarct region. Cardiac function was assessed by magnetic resonance imaging (MRI). Multi-omic analyses were performed in theex vivoswine peri-infarct specimen to delineate the mechanism of action.ResultsCardiac MRI at weeks 2 and 4 showed significant improvement in heart function in iCM-derived exosomes while MSC-derived exosomes showed a trend towards improvement. A comparative analysis of transcriptomic sequencing of the porcine peri-infarct tissue and Next Generation Sequencing of the exosome cargo confirmed the dual mechanism of action. The marked improvements seen in cardiac function are conferred by miRNA carried by the exosomes, particularly by cardioprotective reduction in metabolism during acute myocardial injury while promoting concurrent cardiomyocyte cell cycle re-entry and proliferation.ConclusionsSignificant reduction in myocardial metabolism and increase in proliferation signal pathways were found in both exosome treatment groups; however, distinct sets of microRNAs were found to underlie the mechanism of action in each population of exosomes.