bluuebunny/crossref_metadata_2025_split huggingface dataset:
PeakPerformance - a tool for Bayesian inference-based fitting of LC-MS/MS peaks
Authors: Nießer Jochen , Osthege Michael , von Lieres Eric , Wiechert Wolfgang , Noack Stephan 
Published: February 2024

AbstractA major bottleneck of chromatography-based analytics has been the elusive fully automated identification and integration of peak data without the need of extensive human supervision. The presented Python packagePeakPerformanceapplies Bayesian inference to chromatographic peak fitting, and provides an automated approach featuring model selection and uncertainty quantification. Currently, its application is focused on data from targeted liquid chromatography tandem mass spectrometry (LC-MS/MS), but its design allows for an expansion to other chromatographic techniques.PeakPerformanceis implemented in Python and the source code is available on GitHub. It is unit-tested on Linux and Windows and accompanied by general introductory documentation, as well as example notebooks.Practical applicationThe presentedPeakPerformancetool performs automated chromatographic peak data fitting using Bayesian methodology. Accordingly, it innovates by delivering built-in uncertainty quantification for each peak, thus taking the measurement noise into account. Using a convergence statistic and based on the determined peak uncertainties, the differentiation of signals into peak and noise was improved and false positives or negatives were largely eliminated. The provided documentation and the implemented convenience functions are meant to lower the barrier of entry for users with little programming experience. Lastly, the modular design of the software enables modification and expansion to data from different chromatographic methods.
Oxygen carrying nanoemulsions and respiratory hyperoxia eliminate tumor hypoxia-induced suppression and improve cancer immunotherapy
Authors: Halpin-Veszeleiova Katarina , Mallouh Michael , Apro Ashley , Romero Nuria , Bahr Camille , Shin Maureen , Ward Kelly , Rosenberg Laura , Sitkovsky Michail V. , Spiess Bruce , Hatfield Stephen M. 
Published: February 2024

AbstractHypoxia-HIF-1α-driven immunosuppressive transcription and cAMP-elevating signaling through A2A-adenosine receptors (A2AR) represent a major tumor-protecting pathway that enables immune evasion. Recent promising clinical outcomes due to the blockade of the adenosine-generating enzyme CD73 and A2AR in patient’s refractory to all other therapies have confirmed the importance of targeting hypoxia-adenosinergic signaling. We report a novel and feasible approach to target the upstream stage of hypoxia-adenosinergic immunosuppression using an oxygen-carrying nanoemulsion (perfluorocarbon blood substitute). It is shown that oxygenation agent therapy i) eliminates tumor hypoxia, ii) improves efficacy of endogenously developed and adoptively transferred T cells, and thereby iii) promotes regression of tumors in different anatomical locations. We show that both T cells and NK cells avoid hypoxic tumor areas and that reversal of hypoxia by oxygenation agent therapy increases intratumoral infiltration of activated T cells and NK cells due to re-programming of the tumor microenvironment (TME). Thus, repurposing oxygenation agents in combination with supplemental oxygen may improve current cancer immunotherapies by preventing hypoxia-adenosinergic suppression, promoting immune cell infiltration and enhancing effector responses. These data also suggest that pretreating patients with oxygenation agent therapy may reprogram the TME from immune-suppressive to immune-permissive prior to adoptive cell therapy, or other forms of immunotherapy.SummaryOxygen delivering nanoemulsions and respiratory hyperoxia address limitations of blood vessel-mediated tumor oxygenation and promote anti-tumor immune responses to enhance immunotherapy.
Hist2Cell: Deciphering Fine-grained Cellular Architectures from Histology Images
Authors: Zhao Weiqin , Liang Zhuo , Huang Xianjie , Huang Yuanhua , Yu Lequan 
Published: February 2024

AbstractHistology images, with low cost, are unleashing great power of predicting cellular phenotypes in tissue, thanks to the emerging spatial transcriptomics serving as annotations. Recent efforts aimed to predict individual gene expression, suffering from low accuracy and high variability, while no methods are tailored to predict fine-grained transcriptional cell types -the most critical phenotype. Here, we present Hist2Cell, a Vision Graph-Transformer framework, to accurately resolve fine-grained transcriptional cell types (up to 40 cell types) directly from histology images and further create cellular maps of diverse tissues at a customizable resolution. Specifically, trained on human lung and breast cancer spatial transcriptome datasets, Hist2Cell accurately predicts the abundance of each cell type across space in new patient samples with Pearson Correlation Coefficient of biological informative cell types over 0.80, and effectively capturing their colocalization directly from histology images. Moreover, without re-training, it robustly generalizes to large-scale histology cancer cohorts from TCGA, highlighting recurrent cell co-localization and supporting precise survival prediction by revealing distinct tissue micro-environments and insightful cell type-patient mortality relationship. Therefore, Hist2Cell enables cost-efficient histology analysis for large-scale studies of spatial biology and precise cancer prognosis in real-world clinical diagnostics.
Multiplexed dynamic control of temperature to probe and observe mammalian cells
Authors: Benman William , Iyengar Pavan , Mumford Thomas , Huang Zikang , Bugaj Lukasz J. 
Published: February 2024

AbstractTemperature is aa critical parameter for biological function, yet there is a lack of approaches to modulate the temperature of biological specimens in a dynamic and high-throughput manner. We present the thermoPlate, a device for programmable control of temperature in each well of a 96-well plate, in a manner compatible with mammalian cell culture and live cell imaging. The thermoPlate maintains precise feedback control of temperature patterns independently in each well, with minutes-scale heating and cooling through ΔT ∼15-20°C. A computational model that predicts thermal diffusion guides optimal design of heating protocols. The thermoPlate allowed systematic characterization of both synthetic and natural thermo-responsive systems. We first used the thermoPlate in conjunction with live-cell microscopy to characterize the rapid temperature-dependent phase separation of a synthetic elastin-like polypeptide (ELP53). We then measured stress granule (SG) formation in response to heat stress, observing differences in SG dynamics with each increasing degree of stress. We observed adaptive formation of SGs, whereby SGs formed but then dissolved in response to persistent heat stress (> 42°C). SG adaptation revealed a biochemical memory of stress that depended on both the time and temperature of heat shock. Stress memories continued to form even after the removal of heat and persisted for 6-9 hours before dissipating. The capabilities and open-source nature of the thermoPlate will empower the study and engineering of a wide range of thermoresponsive phenomena.
Polygenic risk for depression and resting state functional connectivity of subgenual anterior cingulate cortex in young adults
Authors: Chen Yu , Li Huey-Ting , Luo Xingguang , Li Guangfei , Ide Jaime S. , Li Chiang-Shan R. 
Published: February 2024

AbstractGenetic variants may confer risks for depression by modulating brain structure and function. Prior evidence has underscored a key role of the subgenual anterior cingulate cortex (sgACC) in depression. Here, we built on the literature and examined how the resting state functional connectivity (rsFC) of the sgACC was associated with polygenic risks for depression. We followed published routines and computed seed-based whole-brain sgACC rsFC and polygenic risk scores (PRS) of 717 young adults curated from the Human Connectome Project. We performed whole-brain regression against PRS and severity of depression symptoms in a single model for all subjects and for men and women alone, controlling for age, sex (for all), race, severity of alcohol use, and household income, and evaluated the results at a corrected threshold. We found lower sgACC rsFC with the default mode network and frontal regions in association with PRS and lower sgACC-cerebellar rsFC in association with depression severity. We also noted sex differences in the connectivity correlates of PRS and depression severity. In an additional set of analyses, we observed a significant correlation between PRS and somatic complaints score and altered sgACC-somatosensory cortical connectivity in link with the severity of somatic complaints. Our findings collectively highlighted the pivotal role of distinct sgACC-based networks in the genetic predisposition to depression and the clinical manifestation of depression. Distinguishing the risk from severity markers of depression may have implications in developing early and effective treatments for individuals at risk for depression.
Intrinsic Disorder and Salt-dependent Conformational Changes of the N-terminal Region of TFIP11 Splicing Factor
Authors: Juniku Blinera , Mignon Julien , Carême Rachel , Genco Alexia , Obeid Anna Maria , Mottet Denis , Monari Antonio , Michaux Catherine 
Published: February 2024

AbstractTuftelin Interacting Protein 11 (TFIP11) was recently identified as a critical human spliceosome assembly regulator, interacting with multiple spliceosome proteins and localises in several membrane-less organelles. However, there is a lack of structural information on TFIP11, limiting the rationalisation of its biological role. TFIP11 has been predicted as a highly disordered protein, and more specifically concerning its N-terminal (N-TER) region. Intrinsically disordered proteins (IDPs) lack a defined tertiary structure, existing as a dynamic conformational ensemble, favouring their role as hubs in protein-protein and protein-RNA interaction networks. Furthermore, IDPs are involved in liquid-liquid phase separation (LLPS), driving the formation of subnuclear compartments.Combining disorder prediction, molecular dynamics, and spectroscopy methods, this contribution shows the first evidence TFIP11 N-TER may be described as a polyampholytic IDP, exhibiting a structural duality with the coexistence of ordered and disordered assemblies, depending on the ionic strength of the protein environment. Increasing the salt concentration enhances the protein conformational flexibility, presenting a fuzzier conformational landscape, a more globule-like shape, and an unstructured arrangement that could favour LLPS segregation and protein-RNA interaction. The regions mostly composed of charged and hydrophilic residues are the most impacted, including the G-Patch domain which is of crucial importance to TFIP11 function.
Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells
Authors: Santiappillai Nancy T , Cao Yue , Hakeem-Sanni Mariam F , Yang Jean , Quek Lake-Ee , Hoy Andrew J 
Published: February 2024

ABSTRACTLarge-scale metabolomic analyses of pan-cancer cell line panels have provided significant insights into the relationships between metabolism and cancer cell biology. Here, we took a pathway-centric approach by transforming targeted metabolomic data into ratios to study associations between reactant and product metabolites in a panel of cancer and non-cancer cell lines. We identified five clusters of cells from various tissue origins. Of these, cells in Cluster 4 had high ratios of TCA cycle metabolites relative to pyruvate, produced more lactate yet consumed less glucose and glutamine, and greater OXPHOS activity compared to Cluster 3 cells with low TCA cycle metabolite ratios. This was due to more glutamine cataplerotic efflux and not glycolysis in cells of Cluster 4.In silicoanalyses of loss-of-function and drug sensitivity screens showed that Cluster 4 cells were more susceptible to gene deletion and drug targeting of lactate and glutamine metabolism, and OXPHOS than cells in Cluster 3. Our results highlight the potential of pathway-centric approaches to reveal new aspects of cellular metabolism from metabolomic data.
Single-cell multimodal profiling of monocytes reveals diverse phenotypes and alterations linked to cardiovascular disease risks
Authors: Bashore Alexander C. , Xue Chenyi , Kim Eunyoung , Yan Hanying , Zhu Lucie Y. , Pan Huize , Kissner Michael , Ross Leila S. , Zhang Hanrui , Li Mingyao , Reilly Muredach P. 
Published: February 2024

AbstractMonocytes are a critical innate immune system cell type that serves homeostatic and immunoregulatory functions. The Cell surface expression of CD14 and CD16 has historically identified them, however, recent single-cell studies have uncovered that they are much more heterogeneous than previously realized. We utilized cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing (scRNA-seq) to describe the comprehensive transcriptional and phenotypic landscape of 437,126 monocytes. This high-dimensional multimodal approach identified vast phenotypic diversity and functionally distinct subsets, including IFN-responsive, MHCIIhi, monocyte-platelet aggregates, and non-classical, as well as several subpopulations of classical monocytes. Using flow cytometry, we validated the existence of MHCII+CD275+MHCIIhi, CD42b+monocyte-platelet aggregates, CD16+CD99-non-classical monocytes, and CD99+classical monocytes. Each subpopulation exhibited unique functions, developmental trajectories, transcriptional regulation, and tissue distribution. Moreover, we revealed alterations associated with cardiovascular disease (CVD) risk factors, including race, smoking, and hyperlipidemia, and the effect of hyperlipidemia was recapitulated in mouse models of elevated cholesterol. This integrative and cross-species comparative analysis provides a unique resource to compare alterations in monocytes in pathological conditions and offers insights into monocyte-driven mechanisms in CVD and the potential for targeted therapies.SummaryMultimodal profiling provides a comprehensive phenotypic and transcriptional understanding of monocytes in health and cardiovascular disease risk states.
Unveiling the genes and pathways that are dysregulated in dopaminergic neurons during both familial and sporadic Parkinson’s disease
Authors: Padhan PK , Verma S. 
Published: February 2024

AbstractIdentification of shared dysregulated genes and molecular mechanisms responsible for dopaminergic (DA) neuronal death in familial and sporadic forms of Parkinson’s disease (PD) can offer the potential for common therapies in both types of PD. The gene expression profiles of DA neurons with sporadic and familial PD backgrounds and healthy DA neurons were obtained from the Gene Expression Omnibus database. Overlapping differentially expressed genes and hub genes were identified. These genes were subjected to Gene Ontology and Reactome pathway enrichment analyses. The roles of a select few differentially expressed genes inC. elegansDA neuron health were assessed. 40 genes, including 12 hub genes, were found dysregulated in DA neurons with sporadic and familial PD. Altering the expression of some of these genes in wild-typeCaenorhabditis eleganspromoted DA neuron degeneration and function. The study unveils shared molecular mechanisms in DA neurons for familial and sporadic PD, potentially driving DA neuron degeneration. Understanding their roles may lead to targeted therapies, early detection, and intervention.In vivoexperiments support our hypothesis, suggesting the implication of these genes in PD neurodegeneration and neuroprotection.
Aedes albopictusis not an arbovirus aficionado – Impacts of sylvatic flavivirus infection in vectors and hosts on mosquito engorgement on non-human primates
Authors: Cecilia Hélène , Althouse Benjamin M. , Azar Sasha R. , Moehn Brett A. , Yun Ruimei , Rossi Shannan L. , Vasilakis Nikos , Hanley Kathryn A. 
Published: February 2024

AbstractThe contact structure between vertebrate hosts and arthropod vectors plays a key role in the spread of arthropod-borne viruses (arboviruses); thus, it is important to determine whether arbovirus infection of either host or vector alters vector feeding behavior. Here we leveraged a study of the replication dynamics of two arboviruses isolated from their ancestral cycles in paleotropical forests, sylvatic dengue-2 (DENV-2) and Zika (ZIKV), in one non-human primate (NHP) species from the paleotropics (cynomolgus macaques,Macaca fascicularis) and one from the neotropics (squirrel monkeys,Saimiri boliviensis) to test the effect of both vector and host infection with each virus on completion of blood feeding (engorgement) of the mosquitoAedes albopictus. Although mosquitoes were starved and given no choice of hosts, engorgement rates varied dramatically, from 0% to 100%. While neither vector nor host infection systematically affected engorgement, NHP species and body temperature at the time of feeding did. We also interrogated the effect of repeated mosquito bites on cytokine expression and found that epidermal growth factor (EGF) and macrophage migration inhibitory factor (MIF) concentrations were dynamically associated with exposure to mosquito bites. This study highlights the importance of incorporating individual-level heterogeneity of vector biting in arbovirus transmission models.
Host 5-HT affectsPlasmodiumtransmission in mosquitoes via modulating mosquito mitochondrial homeostasis
Authors: Gao Li , Zhang Benguang , Feng Yuebiao , Yang Wenxu , Zhang Shibo , Wang Jingwen 
Published: February 2024

SUMMARYMalaria parasites hijack the metabolism of their mammalian host during the blood-stage cycle.Anophelesmosquitoes depend on mammalian blood to survive and to transmit malaria parasites. However, it remains understudied whether changes in host metabolism affect parasite transmission in mosquitoes. In this study, we discovered thatPlasmodiuminfection significantly decreased the levels of the tryptophan metabolite, 5-hydroxytryptamine (5-HT), in both humans and mice. The reduction led to the decrease of 5-HT in mosquitoes. Oral supplementation of 5-HT toAnopheles stephensienhanced its resistance toPlasmodium bergheiinfection by promoting the generation of mitochondrial reactive oxygen species. This effect was due to the accumulation of dysfunctional mitochondria caused by 5-HT-mediated inhibition of mitophagy. Elevating 5-HT levels in mouse serum significantly suppressed parasite infection in mosquitoes. In summary, our data highlight the critical role of metabolites in animal blood in determining the capacity of mosquitoes to control parasite infection.
GATAD2B containing NuRD complex drives R-loop dependent chromatin boundary formation at double strand breaks
Authors: Liu Zhichao , Ajit Kamal , Wu Yupei , Zhu Wei-Guo , Gullerova Monika 
Published: February 2024

AbstractDouble-strand breaks (DSBs) are the most lethal form of DNA damage. Transcriptional activity at DSBs, as well as transcriptional repression around DSBs, are both required for efficient DNA repair. The chromatin landscape defines and coordinates these two opposing events. However, the regulation of the open and condensed chromatin architecture is still unclear. In this study, we show that the GATAD2B-NuRD complex associates with DSBs in a transcription- and R-loop-dependent manner, to promote histone deacetylation and chromatin condensation, creating a temporal boundary between open and closed chromatin. This boundary is necessary for correct DNA end resection termination. The lack of the GATAD2B-NuRD complex leads to chromatin hyper-relaxation and extended DNA end resection, resulting in HR repair failure. Our results suggest that the GATAD2B-NuRD complex is a key coordinator of the dynamic interplay between transcription and chromatin landscape and underscore its biological significance in the RNA-dependent DNA damage response.
Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition
Authors: Flower Cameron T. , Liu Chunmei , Chuang Hui-Yu , Ye Xiaoyang , Cheng Hanjun , Heath James R. , Wei Wei , White Forest M. 
Published: February 2024

AbstractA major contributor to poor sensitivity to anti-cancer kinase inhibitor therapy is drug-induced cellular adaptation, whereby remodeling of signaling and gene regulatory networks permits a drug-tolerant phenotype. Here, we resolve the scale and kinetics of critical subcellular events following oncogenic kinase inhibition and preceding cell cycle re-entry, using mass spectrometry-based phosphoproteomics and RNA sequencing to capture molecular snapshots within the first minutes, hours, and days of BRAF kinase inhibitor exposure in a humanBRAF-mutant melanoma model of adaptive therapy resistance. By enriching specific phospho-motifs associated with mitogenic kinase activity, we monitored the dynamics of thousands of growth- and survival-related protein phosphorylation events under oncogenic BRAF inhibition and drug removal. We observed early and sustained inhibition of the BRAF-ERK axis, gradual downregulation of canonical cell cycle-dependent signals, and three distinct and reversible phase transitions toward quiescence. Statistical inference of kinetically-defined signaling and transcriptional modules revealed a concerted response to oncogenic BRAF inhibition and a dominant compensatory induction of SRC family kinase (SFK) signaling, which we found to be at least partially driven by accumulation of reactive oxygen species via impaired redox homeostasis. This induction sensitized cells to co-treatment with an SFK inhibitor across a panel of patient-derived melanoma cell lines and in an orthotopic mouse xenograft model, underscoring the translational potential for measuring the early temporal dynamics of signaling and transcriptional networks under therapeutic challenge.
Heat Stable and Intrinsically Sterile Liquid Protein Formulations
Authors: Lawanprasert Atip , Pimcharoen Sopida , Singh Harminder , González Vargas Mariangely , Dewan Arshiya , Kirimanjeswara Girish S. , Medina Scott 
Published: February 2024

AbstractOver 80% of biologic drugs, and 90% of vaccines, require temperature-controlled conditions throughout the supply chain to minimize thermal inactivation and contamination. This cold chain is costly, requires stringent oversight, and is impractical in remote environments. Here, we report chemical dispersants that non-covalently solvate proteins within fluorous liquids to alter their thermodynamic equilibrium and reduce conformational flexibility. This generates non-aqueous, fluorine-based liquid protein formulations that biochemically rigidify protein structure to yield thermally stable biologics at extreme temperatures (up to 90°C). These non-aqueous formulations are impervious to contamination by microorganismal pathogens, degradative enzymes, and environmental impurities, and display comparable pre-clinical serum half-life and safety profiles to standard saline protein samples. As a result, we deliver a fluorochemical formulation paradigm that may limit the need for cold chain logistics of protein reagents and biopharmaceuticals.