bluuebunny/crossref_metadata_2025_split huggingface dataset:
Artificial environment impact: O2 concentration changes between IVM and IVF alter embryo production, metabolism, and epigenetic marks
Authors: Cruz Jessica B , Nogueira Carolina M , Sangalli Juliano R , Nociti Ricardo P , Ambrizi Dewison R , Bridi Alessandra , Pinzon Jorge , Alves Maira BR , de Lima Vera FMH , Watanabe Yeda F , Bressan Fabiana F , Meirelles Flavio V , Sampaio Rafael V 
Published: November 2023

ABSTRACTCreating an optimal in vitro cell culture environment requires careful simulation of all critical components, especially the gaseous atmosphere. Although it is well-documented that embryonic culture under low oxygen tension promotes embryonic development, little is known about the effect of changes in in vitro maturation (IVM) and fertilization (IVF) on the epigenome. This study explores the role of oxygen tension variation in the early stages of in vitro production of bovine embryos and its impact on oxidative stress and epigenetic remodeling. We initially validated our system by scrutinizing the epigenetic effects on bovine fibroblasts. We observed that cell cultures under 20% O2 exhibited reduced H3K9me2 levels in early passages, which stabilized with prolonged cultivation and elevated gene expression of HIF2a and KDM5C. Our results reveal that oocytes maturing in 20% O2 environments have heightened levels of reactive oxygen species (ROS) and glutathione (GSH), whereas blastocyst embryos maturing under reduced oxygen tension exhibit increased oxidative stress markers (NRF2,SOD1,SOD2), with upregulated transcripts observed in epigenetic remodelers (KDM5A,TET1). Elevated O2 levels in both IVM and IVF processes showcase improved embryo production. Maintaining consistent O2 levels at either 5% or 20% between IVM and IVF results in heightened GSH, reduced ROS, and increased levels of H3K9me2/3 in embryos. Finally, distinct DNA methylation patterns emerge, indicating higher levels in groups matured under low O2 tension and increased DNA hydroxymethylation in groups fertilized under low O2 tension. In conclusion, our comprehensive investigation underscores the critical role of oxygen concentration in shaping the epigenetic landscape during the early stages of in vitro culture. These findings provide valuable insights for optimizing conditions in assisted reproductive technologies.
Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations
Authors: Abecunas Cara , Kidd Audrey D. , Jiang Ying , Zong Hui , Fallahi-Sichani Mohammad 
Published: November 2023

SummaryTargeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges in identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tumor lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings via analysis of data from patient-derived tumors and pharmacological screens, and by performing new genetic and pharmacological experiments. Our analysis uncovers new synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating the mechanisms underlying these relationships can inform the development of more precise and context-specific, metabolism-targeted cancer therapies.
A reappraisal of the default mode and frontoparietal networks in the common marmoset brain
Authors: Okuno Takuto , Ichinohe Noritaka , Woodward Alexander 
Published: November 2023

AbstractIn recent years the common marmoset homologue of the human default mode network (DMN) has been a hot topic of discussion in the marmoset research field. Previously, the posterior cingulate cortex regions (PGM, A19M) and posterior parietal cortex regions (LIP, MIP) were defined as the DMN, but some studies claim that these form the frontoparietal network (FPN). We restarted from a neuroanatomical point of view and identified two DMN candidates: Comp-A (which has been called both the DMN and FPN) and Comp-B. We performed GLM analysis on auditory task-fMRI and found Comp-B to be more appropriate as the DMN, and Comp-A as the FPN. Additionally, through fingerprint analysis, a DMN and FPN in the tasking human was closer to the resting common marmoset. The human DMN appears to have an advanced function that may be underdeveloped in the common marmoset brain.
Robust diagnosis of infectious disease, autoimmunity and cancer from the paratope networks of adaptive immune receptors
Authors: Xu Zichang , Ismanto Hendra S , Saputri Dianita S , Haruna Soichiro , Sun Guanqun , Wilamowski Jan , Teraguchi Shunsuke , Sengupta Ayan , Li Songling , Standley Daron M 
Published: November 2023

AbstractLiquid biopsies based on peripheral blood offer a minimally invasive alternative to solid tissue biopsies for the detection of diseases, primarily cancers. However, such tests currently consider only the serum component of blood, overlooking a potentially rich source of biomarkers: adaptive immune receptors (AIRs) expressed on circulating B and T cells. Machine learning-based classifiers trained on AIRs have been reported to accurately identify not only cancers, but also autoimmune and infectious diseases as well. However, when using the conventional “clonotype cluster” representation of AIRs, donors within a disease or healthy cohort exhibit vastly different features, limiting the generalizability of these classifiers. This paper addresses the challenge of classifying specific diseases from circulating B or T cells by developing a novel representation of AIRs based on similarity networks constructed from their antigen-binding regions (paratopes). Features based on this novel representation, paratope cluster occupancies (PCOs), significantly improved disease classification performance for infectious disease, autoimmunity and cancer. Under identical methodological conditions, classifiers trained on PCOs achieved a mean ROC AUC of 0.893 when applied to new donors, compared to clonotype cluster-based classifiers (0.714) or the best-performing published classifier (0.777). Surprisingly, for cancer patients, we observed that some of the AIRs that were important for classification were significantly more abundant in healthy controls than in individuals with disease. These “healthy-biased” AIRs were predicted to target known cancer-associated antigens at dramatically higher rates than healthy AIRs as a whole (Z scores > 75), suggesting the existence of an overlooked reservoir of cancer-targeting immune cells that are diagnostic and identifiable from a routine blood test. Consequently, PCOs not only enhance classification of a broad range of diseases but also identify immune cells with therapeutic potential.
Sensory uncertainty influences motor learning differently in blocked versus interleaved trial contexts when both feedforward and feedback processes are engaged
Authors: Crossley Matthew J. , Hewitson Christopher L. , Kaplan David M. 
Published: November 2023

AbstractTheories of human motor learning commonly assume that the degree to which movement plans are adjusted in response to movement errors scales with the precision of sensory feedback received regarding their success. However, support for such error-scaling models has mainly come from experiments that limit the amount of correction that can occur within an ongoing movement. In contrast, we have recently shown that when this restriction is relaxed, and both within-movement and between-movement corrections co-occur, movement plans undergo large and abrupt changes that are strongly correlated with the degree of sensory uncertainty present on the previous trial and are insensitive to the magnitude and direction of the experienced movement error. Here, we show that the presence of these abrupt and error-insensitive changes can only be reliably detected when different levels of sensory precision are interleaved pseudo randomly on a trial-by-trial basis. These results augment our earlier findings and suggest that the co-occurrence of within-movement and between-movement corrections is not the only important aspect of our earlier study that challenged the error-scaling models of motor learning under uncertainty.Author summaryA large body of literature shows that sensory uncertainty inversely scales the degree of error-driven corrections made to motor plans from one trial to the next. However, by limiting sensory feedback to the endpoint of movements, these studies prevent corrections from taking place during the movement. We have recently shown that when such corrections are promoted, sensory uncertainty punctuates between-trial movement corrections with abrupt changes that closely track the degree of sensory uncertainty but are insensitive to the magnitude and direction of movement error. Here, we show that this result requires different levels of sensory uncertainty to be mixed on a trial-by-trial basis. This carries important implications for how previous studies of motor learning under uncertainty are interpreted, and what future studies will likely constitute progress for the field.
Erythrovirus B19 (B19V) in patients with acute febrile illness suspected of arboviruses in Mato Grosso do Sul, Brazil
Authors: Lichs Gislene Garcia C. , Fernandez Grillo Zoraida del Carmen , Alves do Nascimento Valdinete , Alcantara Daniel Maximo Corrêa , Lemos Everton Ferreira , Espínola Carvalho Cristiano M. , Ferraz Demarchi Luiz Henrique , Maymone Gonçalves Crhistinne Carvalho , Naveca Felipe Gomes , Rodrigues de Mendonça Favacho Alexsandra 
Published: November 2023

AbstractHuman Erythrovirus (parvovirus) B19 infection can produce symptoms similar to those produced by Dengue, Chikungunya, and Zika viruses, making clinical diagnosis difficult. The importance of erythrovirus B19 in human pathology has been increased and reported in numerous studies published globally. The B19V infection was investigated by real-time PCR in samples from patients with signs and symptoms related to classic arboviral symptoms. This study was conducted to provide information on the genetic diversity of Human Erythrovirus B19 (B19V) circulating in the state of Mato Grosso do Sul, Midwest region of Brazil, from 2017 to 2022. A total of 773 sera samples of patients with negative diagnostic results for Dengue, Chikungunya, and Zika, during the study period were analyzed. Erythrovirus DNA was found in 10.6% (82/773) of patients, among them 10 were pregnant women. Four samples were completely sequenced, and the other five partially, to genotype by phylogenetic reconstruction. All samples belong to worldwide dispersed genotype 1, subgenotype 1a. These results demonstrate the importance of including B19V in differential laboratory diagnosis for epidemiological purposes and appropriate patient management. The diagnosis for B19V should be performed, particularly among pregnant women, immunocompromised patients, and individuals with hemolytic diseases, as the infection is more severe in these cases.
Land use density, land use mix, and walking: insight from a simple theoretical model
Authors: Yang Yong 
Published: November 2023

AbstractBackgroundLand use density and land use mix are the two most studied characteristics of the built environment and generally, it is believed that higher land use density and higher level of land use mix are associated with more walking, especially for utilitarian purposes. However, although a large number of studies including population density and land use mix have been conducted over the last two decades, overall, the result is still not very clear.MethodsI developed a simple computer model to simulate the influence of land use density and land use mix on walking. It includes a hypothetical city with a grid space and a number of households and non-residential places located across the city. Eventually, we varied the contexts to explore the corresponding results of the walking trips and walking distance across the population.ResultsOnly at a very low level, increased land use density may increase walking trips. At the same time, increased land use density may decrease the total distance of walking trips. A higher level of land use mix is associated with higher walking trips. However, a higher level of land use mix level may be not associated with a higher total distance of walking trips. The relationship between land use and walking is significantly modified by other factors.ConclusionThe relationship between land use and walking is complicated because multiple factors at multiple levels could contribute to this relationship and the conclusions from the most existing practical studies may apply only to a specific population in a specific context. Computer models will be supplemental because they provide a method to disentangle the complex relationship by separating and removing confounding factors and focusing on the interested factors.
Wastewater-Based Analysis of Antihistamines to Investigate Pollinosis Symptom Burden at Population-Scale
Authors: Baumgartner Stephan , Salvisberg Michelle , Clot Bernard , Crouzy Benoît , Schmid-Grendelmeier Peter , Singer Heinz , Ort Christoph 
Published: November 2023

AbstractBackgroundPollinosis, or hay fever, is the most prevalent allergic disorder. Assessing the impact of real-world pollen exposure on symptoms remains challenging due to the extensive efforts required at the patient level.ObjectivesWe explore the potential of wastewater-based epidemiology (WBE) to investigate the impact of exposure to specific pollen taxa on symptoms and to assess self-medication patterns of second-generation antihistamines at a population-scale.MethodsIn Zurich (Switzerland), 279 wastewater samples were collected from 2021-2023. Each sample represents a 24-hour period with excreta from approximately 471,000 individuals. Eleven antihistamine markers were analyzed in the samples using liquid chromatography high-resolution mass spectrometry. The relationship between antihistamine loads in wastewater and concentrations of airborne pollen (47 taxa) was investigated using multivariate linear regression analysis.ResultsThe loads of three second-generation antihistamines in wastewater showed strong day-to-day variation correlating with airborne pollen patterns. About 50% of the annual fexofenadine consumption was linked to acute pollen exposure, 20% to baseline consumption during pollen season, and 30% was independent of pollen. Alder, birch, grasses, hornbeam, plane, and plantain explained most of the variance in consumption (R2= 0.82), with grass pollen alone causing a quarter of the annual consumption. Increased fexofenadine consumption during periods without elevated concentrations of common allergenic pollen suggests the presence of additional triggers for allergy symptoms, potentially yew pollen.ConclusionsOur study demonstrates that WBE can effectively capture substantial day-to-day variation in antihistamine consumption caused by pollen exposure symptoms. As such, WBE is an objective, cost-effective, and questionnaire-independent method for investigating pollinosis at a population-scale.
Optogenetic confirmation of transverse-tubular membrane excitability in intact cardiac myocytes
Authors: Scardigli M. , Pásek M. , Santini L. , Palandri C. , Conti E. , Crocini C. , Campione M. , Loew L. , de Vries A. A. F. , Pijnappels D. A. , Pavone F. S. , Poggesi C. , Cerbai E. , Coppini R. , Kohl P. , Ferrantini C. , Sacconi L. 
Published: November 2023

ABSTRACTT-tubules (TT) form a complex network of sarcolemmal membrane invaginations, essential for well-coordinated excitation-contraction coupling (ECC) and, thus, homogeneous mechanical activation of cardiomyocytes. ECC is initiated by rapid depolarization of the sarcolemmal membrane. Whether TT membrane depolarisation is active (local generation of action potentials; AP) or passive (following depolarisation of the outer cell surface sarcolemma; SS) has not been experimentally assessed in cardiomyocytes. Based on the assessment of ion flux pathways needed for AP generation, we hypothesise that TT are excitable. We therefore explored TT excitability experimentally, using an all-optical approach to stimulate and record trans-membrane potential changes in TT that were electrically insulated from the SS membrane by transient osmotic shock. Our results establish that cardiomyocyte TT can generate AP. These AP show electrical features that differ substantially from those observed in SS, consistent with differences in the density of ion channels and transporters in the two different membrane domains. We propose that TT-generated AP represent a safety mechanism for TT AP propagation and ECC, which may be particularly relevant in pathophysiological settings where morpho-functional changes reduce the electrical connectivity between SS and TT membranes.KEY POINTSCardiomyocytes are characterized by a complex network of membrane invaginations (the T-tubular system) that propagate action potentials to the core of the cell, ensuring synchronous and uniform cell contraction.In this study, we investigate whether the T-tubular system is able to generate action potentials autonomously, rather than following depolarization of the outer cell surface sarcolemma.For this purpose, we developed a fully optical platform to probe and manipulate the electrical dynamics of sub-cellular membrane domains.Our findings demonstrate that T-tubules are intrinsically excitable, revealing distinct characteristics of self-generated T-tubular action potentials.This active electrical capability may serve as a protective mechanism against voltage drops occurring within the T-tubular network.
Kinetic and structural characterization of human NUDIX hydrolases NUDT15 and NUDT18 as catalysts of isoprene pyrophosphate hydrolysis
Authors: Scaletti Emma R. , Unterlass Judith E. , Almlöf Ingrid , Koolmeister Tobias , Vallin Karl S. , Kapsitidou Despina , Helleday Thomas , Stenmark Pål , Jemth Ann-Sofie 
Published: November 2023

ABSTRACTIsoprene pyrophosphates play a crucial role in the synthesis of a diverse array of essential nonsterol and sterol biomolecules, and serve as substrates for post-translational isoprenylation of proteins, enabling specific anchoring to cellular membranes. Hydrolysis of isoprene pyrophosphates would be a means to modulate their levels, downstream products, and protein isoprenylation. While NUDIX hydrolases from plants have been reported to catalyze the hydrolysis of isoprene pyrophosphates, homologous enzymes with this function in animals have not yet been identified. In this study, we screened an extensive panel of human NUDIX hydrolases for activity in hydrolyzing isoprene pyrophosphates. We found that human NUDT15 and NUDT18 efficiently catalyze the hydrolysis of several physiologically relevant isoprene pyrophosphates. Notably, we demonstrate that geranyl pyrophosphate is an excellent substrate for NUDT18, which displays a catalytic efficiency of 2.1·105M-1s-1, thus making it the best substrate identified for NUDT18 to date. Similarly, geranyl pyrophosphate proved to be the best isoprene pyrophosphate substrate for NUDT15, with a catalytic efficiency of 4.0·104M-1s-1. LC-MS analysis of NUDT15 and NUDT18 catalyzed isoprene pyrophosphate hydrolysis revealed the generation of the corresponding monophosphates and inorganic phosphate. Furthermore, we solved the crystal structure of NUDT15 in complex with the hydrolysis product geranyl phosphate at a resolution of 1.70 Å. This structure revealed that the active site nicely accommodates the hydrophobic isoprenoid moiety and aided in identifying key binding residues. By overexpressing NUDT15 and NUDT18 in cells, we demonstrated a decrease in cellular cholesterol levels. Collectively, our findings strongly imply that isoprene pyrophosphates are endogenous substrates of NUDT15 and NUDT18, and support their involvement in animal isoprene pyrophosphate metabolism.
Oligomerisation mediated by the D2 domain of DTX3L is critical for DTX3L-PARP9 reading function of mono-ADP-ribosylated androgen receptor
Authors: Vela-Rodríguez Carlos , Yang Chunsong , Alanen Heli I. , Eki Rebeka , Abbas Tarek A. , Maksimainen Mirko M. , Glumoff Tuomo , Duman Ramona , Wagner Armin , Paschal Bryce M. , Lehtiö Lari 
Published: November 2023

AbstractDeltex proteins are a family of E3 ubiquitin ligases that encode C-terminal RING and DTC domains that mediate interactions with E2 ubiquitin-conjugating enzymes and recognise ubiquitination substrates. DTX3L is unique among the Deltex proteins based on its N-terminal domain architecture. The N-terminal D1 and D2 domains of DTX3L mediate homo-oligomerisation, and the D3 domain interacts with PARP9, a protein that contains tandem macrodomains with ADP-ribose reader function. While DTX3L and PARP9 are known to heterodimerize, they assemble into a high molecular weight oligomeric complex, but the nature of the oligomeric structure, including whether this contributes to the ADP-ribose reader function is unknown. Here, we report a crystal structure of the DTX3L N-terminal D2 domain and show that it forms a tetramer with, conveniently, D2 symmetry. We identified two interfaces in the structure: a major, conserved interface with a surface of 973 Å2and a smaller one of 415 Å2. Using native mass spectrometry, we observed molecular species that correspond to monomers, dimers and tetramers of the D2 domain. Reconstitution of DTX3L knockout cells with a D1-D2 deletion mutant showed the domain is dispensable for DTX3L-PARP9 heterodimer formation, but necessary to assemble an oligomeric complex with efficient reader function for ADP-ribosylated androgen receptor. Our results suggest that homo-oligomerisation of DTX3L is important for mono-ADP-ribosylation reading by the DTX3L-PARP9 complex and to a ligand-regulated transcription factor.