bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability
Authors: Patterson Michael T. , Xu Yingzheng , Hillman Hannah , Osinski Victoria , Schrank Patricia R. , Kennedy Ainsley E. , Zhu Alisha , Tollison Samuel , Shekhar Sia , Stromnes Ingunn M. , Tassi Ilaria , Wu Dick , Binstadt Bryce A. , Williams Jesse W. 
Published: September 2023

AbstractObjectiveTrem2, a surface lipid receptor, is expressed on foamy macrophages within atherosclerotic lesions and regulates cell survival, proliferation, and anti-inflammatory responses. Studies examining the role of Trem2 in atherosclerosis have shown that deletion of Trem2 leads to impaired foamy macrophage lipid uptake, proliferation, survival, and cholesterol efflux. Thus, we tested the hypothesis that administration of a validated Trem2 agonist antibody (AL002a) to atherogenic mice could drive macrophage survival and decrease necrotic core formation to improve plaque stability.Approach and ResultsTo model a therapeutic intervention approach, atherosclerosis-prone mice (Ldlr-/-) were fed a high fat diet (HFD) for 8 weeks, then transitioned to treatment with AL002a or isotype control for an additional 8 weeks while continuing on an HFD. AL002a-treated mice had increased lesion size in both the aortic sinus and whole mount aorta, which correlated with an expansion of plaque macrophage area. This expansion was due to increased macrophage survival and proliferation in plaques. Importantly, plaques from AL002a-treated mice showed improved features of plaque stability, including smaller necrotic cores, increased fibrous caps, and greater collagen deposition. Single cell RNA sequencing of whole aorta suspensions from isotype and AL002a-treated atherosclerotic mice revealed that Trem2 agonism dramatically altered foamy macrophage transcriptome. This included upregulation of oxidative phosphorylation and increased expression of collagen genes. In vitro studies validated that Trem2-agonism with AL002a promoted foamy macrophage oxLDL uptake, survival, and cholesterol efflux in culture.ConclusionsTrem2 agonist expands plaque macrophages by promoting cell survival and proliferation but improves features of plaque stability by rewiring foamy macrophage function to enhance collagen deposition.
Comparative analysis of the RNA-chromatin interactions data. Completeness and accuracy
Authors: Ryabykh Grigory , Vasilyev Artem , Garkul Lidia , Shatskiy Vladimir , Mironov Andrey 
Published: September 2023

AbstractNon-coding RNAs play an essential role in a wide variety of biological processes. We have previously developed RNA-Chrom, an analytical database containing uniformly processed RNA-chromatin interactions data. Here, we analyzed the consistency of these data with each other and performed a comparative analysis of human and mouse datasets from “all-to-all” experiments (interactome of all possible RNAs in a cell) and “one-to-all” experiments (individual RNA interactome). We analyzed the dependence of RNA cis-contacts density as a function of distance to the RNA source gene and found that in all experiments, density of cis-contacts decreases with distance. We tested whether the most contacting RNAs of one “all-to-all” experiment (“RNA-leaders”) are the same for the other “all-to-all” experiments. Our analysis shows that “all-to-all” experiments are not complete and require substantially deeper sequencing, and conclusions can only be drawn for highly contacting RNAs. We noted that for “all-to-all” experiments, sequencing depth and the type of cell treatment give a significant impact on the contact map, while the cell line does not have as much of an impact.
The predictive value of microfilariae-based stop-MDA thresholds after triple drug therapy with IDA in treatment-naive Indian settings
Authors: James Ananthu , Coffeng Luc E. , Blok David J. , King Jonathan D. , de Vlas Sake J. , Stolk Wilma A. 
Published: September 2023

AbstractMass drug administration (MDA) of antifilarial drugs is the main strategy towards the elimination of lymphatic filariasis (LF). Recent clinical trials indicated that the triple drug therapy with ivermectin, diethylcarbamazine and albendazole (IDA) is much more effective against LF than the widely used two-drug combinations (albendazole plus either ivermectin or diethylcarbamazine). For IDA-based MDA, the stop-MDA decision is taken based on microfilariae (mf) prevalence in adults. In this study, we assess how the probability of eventually reaching elimination of transmission depends on the critical threshold used in transmission assessment surveys (TAS-es) to define whether transmission was successfully suppressed and triple-drug MDA can be stopped. This analysis focuses on treatment-naive Indian settings. We do this for a range of epidemiological and programmatic contexts, using the established LYMFASIM model for transmission and control of LF. Based on our simulations, a single TAS one year after the last MDA round provides limited predictive value of having achieved suppressed transmission, while a higher MDA coverage increases elimination probability, thus leading to a higher predictive value. Every additional TAS, conditional on previous TAS-es being passed with the same threshold, further improves predictive value for low values of stop-MDA thresholds. An mf prevalence threshold of 0.5% corresponding to TAS-3 results in ≥95% predictive value even when the MDA coverage is relatively low.
A combined risk model shows viability for personalized breast cancer risk assessment in the Indonesian population
Authors: Rabbani Bijak , Tanu Sabrina Gabriel , Ramanto Kevin Nathanael , Audrienna Jessica , Aldila Fatma , Fernandez Eric Aria , Gonzalez-Porta Mar , Valeska Margareta Deidre , Haruman Jessline , Ulag Lorina Handayani , Maulana Yusuf , Junusmin Kathleen Irena , Amelia Margareta , Gabriella Gabriella , Soetyono Feilicia , Fajarrahman Aulian , Hasan Salma Syahfani Maudina , Agatha Faustina Audrey , Wijaya Marco , Sormin Stevany Tiurma Br , Sani Levana , Ali Soegianto , Irwanto Astrid , Haryono Samuel J 
Published: September 2023

AbstractBreast cancer remains a significant concern worldwide, with a rising incidence in Indonesia. This study aims to evaluate the applicability of risk-based screening approaches in the Indonesian demographic through a case-control study involving 305 women. We developed a personalized breast cancer risk assessment workflow that integrates multiple risk factors, including clinical (Gail) and polygenic (Mavaddat) risk predictions, into a consolidated risk category. By evaluating the area under the receiver operating characteristic curve (AUC) of each single-factor risk model, we demonstrate that they retain their predictive accuracy in the Indonesian context (AUC for clinical risk: 0.67 [0.61,0.74]; AUC for genetic risk: 0.67 [0.61,0.73]). Notably, our combined risk approach enhanced the AUC to 0.70 [0.64,0.76], highlighting the advantages of a multifaceted model. Our findings demonstrate for the first time the applicability of the Mavaddat and Gail models to Indonesian populations, and show that within this demographic, combined risk models provide a superior predictive framework compared to single-factor approaches.
Total-body Dynamic Imaging and Kinetic Modeling of18F-AraG in Healthy Individuals and a Non-Small Cell Lung Cancer Patient Undergoing Anti-PD-1 Immunotherapy
Authors: Omidvari Negar , Levi Jelena , Abdelhafez Yasser G , Wang Yiran , Nardo Lorenzo , Daly Megan E , Wang Guobao , Cherry Simon R 
Published: September 2023

ABSTRACTImmunotherapies, especially the checkpoint inhibitors such as anti-PD-1 antibodies, have transformed cancer treatment by enhancing immune system’s capability to target and kill cancer cells. However, predicting immunotherapy response remains challenging.18F-AraG is a molecular imaging tracer targeting activated T cells, which may facilitate therapy response assessment by non-invasive quantification of immune cell activity within tumor microenvironment and elsewhere in the body. The aim of this study was to obtain preliminary data on total-body pharmacokinetics of18F-AraG, as a potential quantitative biomarker for immune response evaluation.MethodsThe study consisted of 90-min total-body dynamic scans of four healthy subjects and one non-small cell lung cancer (NSCLC) patient, scanned before and after anti-PD-1 immunotherapy. Compartmental modeling with Akaike information criterion model selection were employed to analyze tracer kinetics in various organs. Additionally, seven sub-regions of the primary lung tumor and four mediastinal lymph nodes were analyzed. Practical identifiability analysis was performed to assess reliability of kinetic parameter estimation. Correlations of SUVmean, SUVR (tissue-to-blood ratio), and Logan plot slope (KLogan) with total volume-of-distribution (VT) were calculated to identify potential surrogates for kinetic modeling.ResultsStrong correlations were observed betweenKLoganand SUVR values withVT, suggesting that they can be used as promising surrogates forVT, especially in organs with low blood-volume fraction. Moreover, the practical identifiability analysis suggests that the dynamic18F-AraG PET scans could potentially be shortened to 60 minutes, while maintaining quantification accuracy for all organs-of-interest. The study suggests that although18F-AraG SUV images can provide insights on immune cell distribution, kinetic modeling or graphical analysis methods may be required for accurate quantification of immune response post-therapy. While SUVmean showed variable changes in different sub-regions of the tumor post-therapy, the SUVR,KLogan, andVTshowed consistent increasing trends in all analyzed sub-regions of the tumor with high practical identifiability.ConclusionOur findings highlight the promise of18F-AraG dynamic imaging as a non-invasive biomarker for quantifying the immune response to immunotherapy in cancer patients. The promising total-body kinetic modeling results also suggest potentially wider applications of the tracer in investigating the role of T cells in the immunopathogenesis of diseases.
TRENDS IN CLINICAL STAGE AT PRESENTATION FOR FOUR COMMON ADULT CANCERS IN IBADAN, NIGERIA
Authors: Omigbodun Akinyinka O. , Agboola Adebayo D. , Fayehun Olufunke A , Ajisola Motunrayo , Oladejo Abiola , Popoola Omolara , Lilford Richard 
Published: September 2023

ABSTRACTIntroductionCancer outcome is largely determined by stage at diagnosis. We hypothesised that people living in Low- and Middle-Income Countries may be reaching diagnosis at an early stage, reflecting growth in awareness of the disease and its symptoms. We examined stage at diagnosis for four common cancers presenting at a referral centre in Nigeria.MethodsA retrospective review of case-records from cases treated for four common cancers (colorectal, uterine cervix, breast and prostate) at University College Hospital, Ibadan over two epochs: 2012-2013 and 2017-2018.ResultsThere is no evidence that cases were diagnosed at an earlier stage in the later epoch. Seventy-five percent of cases were diagnosed at late stage (III or IV) in the second epoch, vs seventy percent in the first epoch.ConclusionThere is no evidence in the data that the problem of late presentation of common cancers is reducing in Oyo State, Nigeria.
Investigation of singlet oxygen sensitive genes in the cyanobacteriumSynechocystisPCC 6803
Authors: Patyi Gábor , Hódi Barbara , Mallick Ivy , Maróti Gergely , Kós Péter B. , Vass Imre 
Published: September 2023

SummarySinglet oxygen (1O2) is an important reactive oxygen species whose formation by the type-II, light-dependent, photodynamic reaction is inevitable during photosynthetic processes. In the last decades, the recognition that1O2is not only a damaging agent, but can also affect gene expression and participates in signal transduction pathways has received increasing attention. However, contrary to several other taxa,1O2-specific genes have not been identified in the important cyanobacterial model organismSynechocystisPCC 6803. By using global transcript analysis we have identified a large set of1O2-responsiveSynechocystisgenes, whose transcript levels were either enhanced or repressed in the presence of1O2. Characteristic1O2responses were observed in several light-inducible genes ofSynechocystis, especially in thehli(orscp) family encoding HLIP/SCP proteins involved in photoprotection. Other important1O2-induced genes include components of the Photosystem II repair machinery (psbA2andftsH2,ftsH3), iron homeostasis genesisiAandidiA, the Group-2 sigma factorsigD, some components of the transcriptomes induced by salt-, hyperosmotic and cold-stress, as well as several genes of unknown function. One of the most pronounced1O2-induced upregulation was observed for thehliBgene, whose deletion provided tolerance against1O2-mediated light damage. A bioreporterSynechocystisstrain was created by fusing thehliBpromoter to the bacterial luciferase (lux), which showed its utility for continuous monitoring of1O2concentrations inside the cell.
Variability in the phytoplankton response to upwelling across an iron limitation mosaic within the California Current System
Authors: Lin YuanYu , Torano Olivia , Whitehouse Logan , Pierce Emily , Till Claire P. , Hurst Matthew , Freiberger Robert , Mellett Travis , Maldonado Maria T. , Guo Jian , Sutton Mariam , Zeitz David , Marchetti Adrian 
Published: September 2023

AbstractCoastal upwelling currents such as the California Current System (CCS) comprise some of the most productive biological systems on the planet. Diatoms, a distinct taxon of phytoplankton, dominate these upwelling events in part due to their rapid response to nutrient entrainment. In this region, they may also be limited by the micronutrient iron (Fe), an important trace element primarily involved in photosynthesis and nitrogen assimilation. The mechanisms behind how diatoms physiologically acclimate to the different stages of the upwelling conveyor belt cycle with respect to Fe limitation remains largely uncharacterized. Here, we explore their physiological and metatranscriptomic response to the upwelling cycle with respect to the Fe limitation mosaic that exists in the CCS. Subsurface, natural plankton assemblages that would potentially seed surface blooms were examined over wide and narrow shelf regions. The initial biomass and physiological state of the phytoplankton community had a large impact on the overall response to simulated upwelling. Following on-deck incubation under varying Fe physiological states, our results suggest that diatoms quickly dominated the blooms by “frontloading” nitrogen assimilation genes prior to upwelling. However, diatoms subjected to induced Fe limitation exhibited reductions in carbon and nitrogen uptake and decreasing biomass accumulation. Simultaneously, they exhibited a distinct gene expression response which included increased expression of Fe-starvation induced proteins and decreased expression of nitrogen assimilation and photosynthesis genes. These findings may have significant implications for upwelling events in future oceans, where changes in ocean conditions are projected to amplify the gradient of Fe limitation in coastal upwelling regions.
Exposure to aldehyde cherry e-liquid flavouring and its vape by-product disrupts pulmonary surfactant biophysical function
Authors: Martin Alexia , Tempra Carmelo , Yu Yuefan , Liekkinen Juho , Thakker Roma , Lee Hayoung , de Santos Moreno Berta , Vattulainen Ilpo , Rossios Christos , Javanainen Matti , Bernardino de la Serna Jorge 
Published: September 2023

AbstractOver the last decade there has been a surge in vaping device usage, especially among adolescents, raising concerns for potentially related lung damage. Notoriously, there have been many e-cigarette or vaping-related lung injury (EVALI) cases resulting in hospitalisations and deaths. Although the vaping component vitamin E acetate has been linked to a large proportion of EVALI cases resulting in its widespread banning, one fifth of the cases remain unexplained. Furthermore, the overall long-term impact of vaping on respiratory health is poorly understood. A likely driver behind EVALI is pulmonary surfactant disruption, as it is the first point of contact for any inhaled toxicant in the alveoli, and abnormalities of its function are linked to some symptoms presented in EVALI cases. Aberrant biophysical function of the surfactant results in alveolar surface tension increase, causing alveolar collapse. Vaping chemicals with the potential to disrupt surfactant function must be hydrophobic molecules able to interact with surfactant components at the alveolar air–liquid interface. Recent findings have recorded the synthesis of highly hydrophobic acetal by-products of the base vaping chemical propylene glycol and common flavouring aldehydes, including the cherry flavouring benzaldehyde, not identified in preliminary e-liquid safety tests. This study provides evidence that benzaldehyde and its by-product, benzaldehyde propylene glycol acetal, have the potential to significantly disrupt surfactant biophysical functionviainteractions with surfactant proteins SP-B and/or SP-C, which may provide stable interactions within the surfactant film by forming associations with the sublayer of surfactant three-dimensional structure present at high lateral compression,i.e., expiration breathing. Data also suggest considerable vaping chemical loss to the experimental subphase, indicating potential further implications to the alveolar epithelial layer beneath.
NF-κB dependent expression of A20 controls IKK repression of RIPK1 dependent cell death in activated T cells
Authors: Layzell Scott , Barbarulo Alessandro , Seddon Benedict 
Published: September 2023

AbstractThe Inhibitor of Kappa B Kinase (IKK) complex is a critical regulator of canonical NF-κB activation. More recently, RIPK1 has also been identified as a phosphorylation target of the IKK complex, resulting in repression of extrinsic cell death pathways. Our previous work shows that normal thymocyte development is exclusively reliant on repression of TNF triggered cell death pathways by IKK, and that NF-κB signalling is in fact redundant for development. The role of IKK signalling in activated T cells is unclear. To investigate this, we analysed activation of IKK2 deficient TCR transgenic T cells with cognate peptide. While early activation events were normal, proliferation of blasts was impaired. Surprisingly, cell cycle progression in IKK2 KO T cells was unperturbed. Instead, dividing cells were more sensitive to apoptosis triggered by extrinsic cell death pathways, since inhibition of RIPK1 kinase activity almost completely rescued cell survival. Transcriptomic analysis of activated IKK2 deficient T cells revealed defective expression of several NF-κB targets, including Tnfaip3, that encodes A20, a negative regulator of NF-κB in T cells. To test whether A20 expression was required to protect IKK2 deficient T cells from cell death, we generated mice with T cells lacking both A20 and IKK2. Conditional deletion of bothIkk2andTnfaip3in T cells resulted in near complete ablation of peripheral naïve T cells, in contrast to mice lacking one or other gene. Strikingly, this phenotype was completely reversed by inhibition of RIPK1 kinase activity in vivo. Therefore, our data suggests that IKK signalling in T cells protects against RIPK1 dependent death, both by direct phosphorylation of RIPK1 and through NF-κB mediated induction of A20, that we identify for the first time as a modulator of RIPK1 function in T cells.
Gene regulatory Networks Reveal Sex Difference in Lung Adenocarcinoma
Authors: Saha Enakshi , Guebila Marouen Ben , Fanfani Viola , Fischer Jonas , Shutta Katherine H. , Mandros Panagiotis , DeMeo Dawn L. , Quackenbush John , Lopes-Ramos Camila M. 
Published: September 2023

SummaryLung adenocarcinoma (LUAD) has been observed to have significant sex differences in incidence, prognosis, and response to therapy. However, the molecular mechanisms responsible for these disparities have not been investigated extensively. Sample-specific gene regulatory network methods were used to analyze RNA sequencing data from non-cancerous human lung samples from The Genotype Tissue Expression Project (GTEx) and lung adenocarcinoma primary tumor samples from The Cancer Genome Atlas (TCGA); results were validated on independent data. We observe that genes associated with key biological pathways including cell proliferation, immune response and drug metabolism are differentially regulated between males and females in both healthy lung tissue, as well as in tumor, and that these regulatory differences are further perturbed by tobacco smoking. We also uncovered significant sex bias in transcription factor targeting patterns of clinically actionable oncogenes and tumor suppressor genes, includingAKT2andKRAS. Using differentially regulated genes between healthy and tumor samples in conjunction with a drug repurposing tool, we identified several small-molecule drugs that might have sex-biased efficacy as cancer therapeutics and further validated this observation using an independent cell line database. These findings underscore the importance of including sex as a biological variable and considering gene regulatory processes in developing strategies for disease prevention and management.
Cooperative Membrane Binding of HIV-1 Matrix Proteins
Authors: Banerjee Puja , Monje-Galvan Viviana , Voth Gregory A. 
Published: September 2023

AbstractThe HIV-1 assembly process begins with a newly synthesized Gag polyprotein being targeted to the inner leaflet of the plasma membrane of the infected cells to form immature viral particles. Gag-membrane interactions are mediated through the myristoylated(Myr) N-terminal matrix (MA) domain of Gag which eventually multimerize on the membrane to form trimers and higher-order oligomers. The study of the structure and dynamics of peripheral membrane proteins like MA has been challenging for both experimental and computational studies due to the complex dynamics of protein-membrane interactions. Although the roles of anionic phospholipids (PIP2, PS) and the Myr group in the membrane targeting and stable membrane binding of MA are now well-established, the cooperative interactions between MA monomers and MA-membrane still remain elusive. Our present study focuses on the membrane binding dynamics of a higher-order oligomeric structure of MA protein (a dimer of trimers), which has not been explored before. Employing time-lagged independent component analysis (tICA) to our microsecond-long trajectories, we investigate conformational changes of the matrix protein induced by membrane binding. Interestingly, the Myr switch of a MA monomer correlates with the conformational switch of adjacent monomers in the same trimer. Together, our findings suggest that MA trimerization facilitates Myr insertion, but MA trimer-trimer interactions in the lattice of immature HIV-1 particles can hinder the same. Additionally, local lipid density patterns of different lipid species provide a signature of the initial stage of lipid-domain formation upon membrane binding of the protein complex.TOC