bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibody-mediated delivery of viral epitopes to redirect EBV-specific CD8+ T-cell immunity towards cancer cells
Authors: van der Wulp Willemijn , Remst Dennis F. G. , Kester Michel G. D. , Hagedoorn Renate S. , Parren Paul W. H. I. , van Kasteren Sander I. , Schuurman Janine , Hoeben Rob C. , Ressing Maaike E. , Bleijlevens Boris , Heemskerk Mirjam H. M. 
Published: November 2023

AbstractAntibody-mediated delivery of immunogenic epitopes to redirect virus-specific CD8+ T-cells towards cancer cells is an emerging and promising new therapeutic strategy. These so-called antibody-epitope conjugates (AECs) rely on the proteolytic release of the epitopes close to the tumor surface for presentation by HLA class I molecules to eventually redirect and activate virus-specific CD8+ T-cells towards tumor cells. We fused the immunogenic EBV-BRLF1 epitope preceded by a protease cleavage site to the C-terminus of the heavy and/or light chains of cetuximab and trastuzumab. We evaluated these AECs and found that, even though all AECs were able to redirect the EBV-specific T-cells, AECs with an epitope fused to the C-terminus of the heavy chain resulted in higher levels of T-cell activation compared to AECs with the same epitope fused to the light chain of an antibody. We observed that all AECs were depending on the presence of the antibody target, that the level of T-cell activation correlated with expression levels of the antibody target, and that our AECs could efficiently deliver the BRLF1 epitope to cancer cell lines from different origins (breast, ovarian, lung, and cervical cancer and a multiple myeloma). Moreover, in vivo, the AECs efficiently reduced tumor burden and increased the overall survival, which was prolonged even further in combination with immune checkpoint blockade. We demonstrate the potential of these genetically fused AECs to redirect the potent EBV-specific T-cells towards cancer in vitro and in vivo.
A novel c-Met/TRK inhibitor 1D228 efficiently inhibits tumor growth by targeting angiogenesis and tumor cell proliferation
Authors: An Baijiao , Nie Wenyan , Hu Jinhui , Fan Yangyang , Nie Haoran , Wang Mengxuan , Zhao Yaxuan , Yao Han , Ren Yuanyuan , Zhang Chuanchuan , Wei Mengna , Li Wei , Liu Jiadai , Yang Chunhua , Zhang Yin , Li Xingshu , Tian Geng 
Published: November 2023

AbstractMultiple tumors are synergistically promoted by c-Met and TRK, and blocking their cross-signalling pathway may give better effects. In this study, we developed a tyrosine kinase inhibitor 1D228, which exhibited excellent anti-tumor activity by targeting c-Met and TRK. Models in vitro, 1D228 showed a significant better inhibition on cancer cell proliferation and migration than the positive drug Tepotinib. Models in vivo, 1D228 showed robust anti-tumor effect on gastric and liver tumor growth with 94.8% and 93.4% of the TGI, respectively, comparing 67.61% and 63.9% of Tepotinib. Importantly, compared with the combination of Larotrectinib and Tepotinib, 1D228 monotherapy in MKN45 xenograft tumor models showed stronger antitumor activity and lower toxicity. Mechanistic studies showed that 1D228 can largely inhibit the phosphorylation of TRKB and c-Met. Interestingly, both kinases, TRKs and c-Met, have been found to be co-expressed at high levels in patients with gastric cancer through IHC. Furthermore, bioinformatics analysis has revealed that both genes are abnormally co-expressed in multiple types of cancer. Cell cycle analysis found that 1D228 induced G0/G1 arrest by inhibiting cyclin D1. Additionally, vascular endothelial cells also showed a pronounced response to 1D228 due to its expression of TRKB and c-Met. 1D228 suppressed the migration and tube formation of endothelial cells, which are the key functions of tumor angiogenesis. Taken together, compound 1D228 may be a promising candidate for the next generation of c-Met and TRK inhibitors for cancer treatment, and offers a novel potential treatment strategy for cancer patients with abnormal expressions of c-Met or NTRK, or simultaneous of them.
Gasdermin D promotes hyperinflammation and immunopathology during severe influenza A virus infection
Authors: Rosli Sarah , Harpur Christopher M. , Lam Maggie , West Alison C. , Hodges Christopher , Mansell Ashley , Lawlor Kate E. , Tate Michelle D. 
Published: November 2023

AbstractExcessive inflammation and tissue damage during severe influenza A virus (IAV) infection can lead to the development of fatal pulmonary disease. Pyroptosis is a lytic and pro-inflammatory form of cell death executed by the pore-forming protein gasdermin D (GSDMD). In this study, we investigated a potential role for GSDMD in promoting the development of severe IAV disease. IAV infection resulted in cleavage of GSDMD in vivo and in vitro in lung epithelial cells. Mice genetically deficient in GSDMD (Gsdmd−/−) developed less severe IAV disease than wildtype mice and displayed improved survival outcomes. GSDMD deficiency significantly reduced neutrophil infiltration into the airways as well as the levels of pro-inflammatory cytokines TNF, IL-6, MCP-1, and IL-1α and neutrophil-attracting chemokines CXCL1 and CXCL2. In contrast, IL-1β and IL-18 responses were not largely impacted by GSDMD deficiency. In addition,Gsdmd−/−mice displayed significantly improved influenza disease resistance with reduced viral burden and less severe pulmonary pathology, including decreased epithelial damage and cell death. These findings indicate a major role for GSDMD in promoting damaging inflammation and the development of severe IAV disease.
Electrocatalytic on-site oxygenation for transplanted cell-based-therapies
Authors: Lee Inkyu , Surendran Abhijith , Fleury Samantha , Gimino Ian , Curtiss Alexander , Fell Cody , Shiwarski Daniel J. , Refy Omar , Rothrock Blaine , Jo Seonghan , Schwartzkopff Tim , Mehta Abijeet Singh , Wang Yingqiao , Sipe Adam , John Sharon , Ji Xudong , Nikiforidis Georgios , Feinberg Adam W. , Hester Josiah , Weber Douglas J. , Veiseh Omid , Rivnay Jonathan , Cohen-Karni Tzahi 
Published: November 2023

AbstractImplantable cell therapies and tissue transplants require sufficient oxygen supply to function and are limited by a delay or lack of vascularization from the transplant host. Previous exogenous oxygenation strategies have been bulky and had limited oxygen production or regulation. Here, we show an electrocatalytic approach that enables bioelectronic control of oxygen generation in complex cellular environments to sustain engineered cell viability and therapy under hypoxic stress and at high cell densities. We find that nanostructured sputtered iridium oxide serves as an ideal catalyst for oxygen evolution reaction at neutral pH. We demonstrate that this approach exhibits a lower oxygenation onset and selective oxygen production without evolution of toxic byproducts. We show that this electrocatalytic on site oxygenator can sustain high cell loadings (>60k cells/mm3) in hypoxic conditions in vitro and in vivo. Our results showcase that exogenous oxygen production devices can be readily integrated into bioelectronic platforms, enabling high cell loadings in smaller devices with broad applicability.
Structures of the DarR transcription regulator reveal unique modes of second messenger and DNA binding
Authors: Schumacher Maria A. , Lent Nicholas , Chen Vincent B. , Salinas Raul 
Published: November 2023

AbstractThe mycobacterial repressor, DarR, a TetR family regulator (TFR), was the first transcription regulator shown to bind c-di-AMP. However, the molecular basis for this interaction and the mechanism involved in DNA binding by DarR remain unknown. Here we describe DarR-c-di-AMP and DarR-DNA structures and complementary biochemical assays. The DarR-c-di-AMP structure reveals a unique effector binding site for a TFR, located between DarR dimer subunits. Strikingly, we show this motif also binds cAMP. The location of the adenine nucleotide binding site between subunits suggests this interaction may facilitate dimerization and hence DNA binding. Indeed, biochemical assays show cAMP enhances DarR DNA binding. Finally, DarR-DNA structures reveal a distinct TFR DNA-binding mechanism involving two interacting dimers on the DNA. Thus, the combined data unveil a newly described second messenger binding motif and DNA binding mode for this important family of regulators.
The transcriptional legacy of developmental stochasticity
Authors: Ballouz Sara , Kawaguchi Risa Karakida , Pena Maria T. , Fischer Stephan , Crow Megan , French Leon , Knight Frank M. , Adams Linda B. , Gillis Jesse 
Published: November 2023

AbstractGenetic and environmental variation are key contributors during organism development, but the influence of minor perturbations or noise is difficult to assess. This study focuses on the stochastic variation in allele-specific expression that persists through cell divisions in the nine-banded armadillo (Dasypus novemcinctus). We investigated the blood transcriptome of five wild monozygotic quadruplets over time to explore the influence of developmental stochasticity on gene expression. We identify an enduring signal of autosomal allelic variability that distinguishes individuals within a quadruplet despite their genetic similarity. This stochastic allelic variation, akin to X-inactivation but broader, provides insight into non-genetic influences on phenotype. The presence of stochastically canalized allelic signatures represents a novel axis for characterizing organismal variability, complementing traditional approaches based on genetic and environmental factors. We also developed a model to explain the inconsistent penetrance associated with these stochastically canalized allelic expressions. By elucidating mechanisms underlying the persistence of allele-specific expression, we enhance understanding of development’s role in shaping organismal diversity.
Tailoring chemical composition of solid electrolyte interphase by selective dissolution for long-life micron-sized silicon anode
Authors: Tian Yi-Fan , Tan Shuang-Jie , Yang Chunpeng , Zhao Yu-Ming , Xu Di-Xin , Lu Zhuo-Ya , Li Ge , Li Jin-Yi , Zhang Xu-Sheng , Zhang Chao-Hui , Tang Jilin , Zhao Yao , Wang Fuyi , Wen Rui , Xu Quan , Guo Yu-Guo 
Published: November 2023

AbstractMicron-sized Si anode promises a much higher theoretical capacity than the traditional graphite anode and more attractive application prospect compared to its nanoscale counterpart. However, its severe volume expansion during lithiation requires solid electrolyte interphase (SEI) with reinforced mechanical stability. Here, we propose a solvent-induced selective dissolution strategy to in situ regulate the mechanical properties of SEI. By introducing a high-donor-number solvent, gamma-butyrolactone, into conventional electrolytes, low-modulus components of the SEI, such as Li alkyl carbonates, can be selectively dissolved upon cycling, leaving a robust SEI mainly consisting of lithium fluoride and polycarbonates. With this strategy, raw micron-sized Si anode retains 87.5% capacity after 100 cycles at 0.5 C (1500 mA g−1, 25°C), which can be improved to >300 cycles with carbon-coated micron-sized Si anode. Furthermore, the Si||LiNi0.8Co0.1Mn0.1O2 battery using the raw micron-sized Si anode with the selectively dissolved SEI retains 83.7% capacity after 150 cycles at 0.5 C (90 mA g−1). The selective dissolution effect for tailoring the SEI, as well as the corresponding cycling life of the Si anodes, is positively related to the donor number of the solvents, which highlights designing high-donor-number electrolytes as a guideline to tailor the SEI for stabilizing volume-changing alloying-type anodes in high-energy rechargeable batteries.
Essential gene complement of Planctopirus limnophila from the bacterial phylum Planctomycetes
Authors: Rivas-Marin Elena , Moyano-Palazuelo David , Henriques Valentina , Merino Enrique , Devos Damien P. 
Published: November 2023

AbstractPlanctopirus limnophilabelongs to the bacterial phylumPlanctomycetes, a relatively understudied lineage with remarkable cell biology features. Here, we report a genome-wide analysis of essential gene content inP. limnophila. We show that certain genes involved in peptidoglycan synthesis or cell division, which are essential in most other studied bacteria, are not essential for growth under laboratory conditions in this species. We identify essential genes likely involved in lipopolysaccharide biosynthesis, consistent with the view of Planctomycetes as diderm bacteria, and highlight other essential genes of unknown functions. Furthermore, we explore potential stages of evolution of the essential gene repertoire inPlanctomycetesand the related phylaVerrucomicrobiaandChlamydiae. Our results provide insights into the divergent molecular and cellular biology ofPlanctomycetes.
Low circulating adropin levels in late-middle aged African Americans with poor cognitive performance
Authors: Aggarwal Geetika , Malmstrom Theodore K. , Morley John E. , Miller Douglas K. , Nguyen Andrew D. , Butler Andrew A. 
Published: November 2023

AbstractWe recently reported accelerated cognitive decline in Europeans aged > 70 years with low circulating adropin levels. Adropin is a small, secreted peptide that is highly expressed in the human nervous system. Expression profiling indicate relationships between adropin expression in the human brain and pathways that affect dementia risk. Moreover, increased adropin expression or treatment using synthetic adropin improves cognition in mouse models of aging. Here we report that low circulating adropin concentrations associate with poor cognition (worst quintile for a composite score derived from the MMSE and semantic fluency test) in late-middle aged community-dwelling African Americans (OR = 0.775, P < 0.05; age range 45–65 y, n = 352). The binomial logistic regression controlled for sex, age, education, cardiometabolic disease risk indicators, and obesity. Previous studies using cultured cells from the brains of human donors suggest high expression in astrocytes. In snRNA-seq data from the middle temporal gyrus (MTG) of human donors, adropin expression is higher in astrocytes relative to other cell types. Adropin expression in all cell-types declines with advance age, but is not affected by dementia status. In cultured human astrocytes, adropin expression also declines with donor age. Additional analysis indicated positive correlations between adropin and transcriptomic signatures of energy metabolism and protein synthesis that are adversely affected by donor age. Adropin expression is also suppressed by pro-inflammatory factors. Collectively, these data indicate low circulating adropin levels are a potential early risk indicator of cognitive impairment. Declining adropin expression in the brain is a plausible link between aging, neuroinflammation, and risk of cognitive decline.
Recent co-evolution of two pandemic plant diseases in a multi-hybrid swarm
Authors: Rahnama Mostafa , Condon Bradford , Ascari João P. , Dupuis Julian R. , Del Ponte Emerson M. , Pedley Kerry F. , Martinez Sebastián , Valent Barbara , Farman Mark L. 
Published: November 2023

AbstractMost plant pathogens exhibit host specificity but when former barriers to infection break down, new diseases can rapidly emerge. For a number of fungal diseases, there is increasing evidence that hybridization plays a major role in driving host jumps. However, the relative contributions of existing variation versus new mutations in adapting to new host(s) is unclear. Here we reconstruct the evolutionary history of two recently emerged populations of the fungus Pyricularia oryzae that are responsible for two new plant diseases: wheat blast and grey leaf spot of ryegrasses. We provide evidence that wheat blast/grey leaf spot evolved through two distinct mating episodes: the first occurred ~60 years ago, when a fungal individual adapted to Eleusine mated with another individual from Urochloa. Then, about 10 years later, a single progeny from this cross underwent a series of matings with a small number of individuals from three additional host-specialized populations. These matings introduced non-functional alleles of two key host-specificity factors, whose recombination in a multi-hybrid swarm probably facilitated the host jump. We show that very few mutations have arisen since the founding event and a majority are private to individual isolates. Thus, adaptation to the wheat or Lolium hosts appears to have been instantaneous, and driven entirely by selection on repartitioned standing variation, with no obvious role for newly formed mutations.
Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens
Authors: McCutcheon Sean R. , Swartz Adam M. , Brown Michael C. , Barrera Alejandro , McRoberts Amador Christian , Siklenka Keith , Humayun Lucas , ter Weele Maria A. , Isaacs James M. , Reddy Timothy E. , Allen Andrew S. , Nair Smita K. , Antonia Scott J. , Gersbach Charles A. 
Published: November 2023

AbstractClinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapies. Here we developed pooled, epigenetic CRISPR screening approaches to systematically profile the effects of activating or repressing 120 transcriptional and epigenetic regulators on human CD8+ T cell state. We found that BATF3 overexpression promoted specific features of memory T cells and attenuated gene programs associated with cytotoxicity, regulatory T cell function, and exhaustion. Upon chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. Moreover, BATF3 enhanced the potency of CAR T cells in both in vitro and in vivo tumor models and programmed a transcriptional profile that correlates with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens that defined cofactors and downstream mediators of the BATF3 gene network.
Three-dimensional dental microwear in type-Maastrichtian mosasaur teeth (Reptilia, Squamata)
Authors: Holwerda Femke M. , Bestwick Jordan , Purnell Mark A. , Jagt John W. M. , Schulp Anne S. 
Published: November 2023

AbstractMosasaurs (Squamata, Mosasauridae) were large aquatic reptiles from the Late Cretaceous that filled a range of ecological niches within marine ecosystems. The type-Maastrichtian strata (68–66 Ma) of the Netherlands and Belgium preserve remains of five species that seemed to have performed different ecological roles (carnivores, piscivores, durophages). However, many interpretations of mosasaur diet and niche partitioning are based on qualitative types of evidence that are difficult to test explicitly. Here, we apply three-dimensional dental microwear texture analysis (DMTA) to provide quantitative dietary constraints for type-Maastrichtian mosasaurs, and to assess levels of niche partitioning between taxa. DMTA indicates that these mosasaurs did not exhibit neatly defined diets or strict dietary partitioning. Instead, we identify three broad groups: (i) mosasaurs Carinodens belgicus and Plioplatecarpus marshi plotting in the space of modern reptiles that are predominantly piscivorous and/or consume harder invertebrate prey, (ii) Prognathodon saturator and Prognathodon sectorius overlapping with extant reptiles that consume larger amounts of softer invertebrate prey items, and (iii) Mosasaurus hoffmanni spanning a larger plot area in terms of dietary constraints. The clear divide between the aforementioned first two groups in texture-dietary space indicates that, despite our small sample sizes, this method shows the potential of DMTA to test hypotheses and provide quantitative constraints on mosasaur diets and ecological roles.
A cost-effective smart metering approach towards affordable deployment strategy
Authors: Ezhilarasi P. , Ramesh L. , Sanjeevikumar P. , Khan Baseem 
Published: November 2023

AbstractRevamping the power grid into a smart grid and modernizing it with advanced metering infrastructure are essential steps in addressing ongoing energy challenges. Smart meters play a pivotal role in power grid modernization by providing real-time energy-related data which fuels the control activities of modern grid. While the advantages of smart meters are evident, their deployment necessitates a comprehensive redesign of the grid architecture, involving smart end devices for monitoring and communication networks for efficient data exchange. Yet, achieving cost-effective and widespread adoption of these technologies poses a challenge, particularly in developing and underdeveloped nations due to high capital costs, technological constraints and uneconomical deployment strategies. Moreover, the prevailing research often advocates a complete transition to new smart meters to achieve 'smartness,' neglecting the potential of existing metering infrastructure upgrades. To address these concerns, this study proposes and simulates the design of a low-cost Smart Network Meter. Notably, this meter upgrades the existing meter infrastructure while validating a cost-effective deployment strategy. Furthermore, a consumer opinion survey was also conducted to compelling evidence supporting the adoption of the proposed low-cost smart metering solution.
The genetics of falling susceptibility and identification of causal risk factors
Authors: Smith Matt C. , O’Loughlin Jessica , Karageorgiou Vasileios , Casanova Francesco , Williams Genevieve K. R. , Hilton Malcolm , Tyrrell Jessica 
Published: November 2023

AbstractFalls represent a huge health and economic burden. Whilst many factors are associated with fall risk (e.g. obesity and physical inactivity) there is limited evidence for the causal role of these risk factors. Here, we used hospital and general practitioner records in UK Biobank, deriving a balance specific fall phenotype in 20,789 cases and 180,658 controls, performed a Genome Wide Association Study (GWAS) and used Mendelian Randomisation (MR) to test causal pathways. GWAS indicated a small but significant SNP-based heritability (4.4%), identifying one variant (rs429358) inAPOEat genome-wide significance (P < 5e-8). MR provided evidence for a causal role of higher BMI on higher fall risk even in the absence of adverse metabolic consequences. Depression and neuroticism predicted higher risk of falling, whilst higher hand grip strength and physical activity were protective. Our findings suggest promoting lower BMI, higher physical activity as well as psychological health is likely to reduce falls.
Localization of early infarction on non-contrast CT images in acute ischemic stroke with deep learning approach
Authors: Mohapatra Sulagna , Lee Tsong-Hai , Sahoo Prasan Kumar , Wu Ching-Yi 
Published: November 2023

AbstractLocalization of early infarction on first-line Non-contrast computed tomogram (NCCT) guides prompt treatment to improve stroke outcome. Our previous study has shown a good performance in the identification of ischemic injury on NCCT. In the present study, we developed a deep learning (DL) localization model to help localize the early infarction sign on NCCT. This retrospective study included consecutive 517 ischemic stroke (IS) patients who received NCCT within 12 h after stroke onset. A total of 21,436 infarction patches and 20,391 non-infarction patches were extracted from the slice pool of 1,634 NCCT according to brain symmetricity property. The generated patches were fed into different pretrained convolutional neural network (CNN) models such as Visual Geometry Group 16 (VGG16), GoogleNet, Residual Networks 50 (ResNet50), Inception-ResNet-v2 (IR-v2), Inception-v3 and Inception-v4. The selected VGG16 model could detect the early infarction in both supratentorial and infratentorial regions to achieve an average area under curve (AUC) 0.73 after extensive customization. The properly tuned-VGG16 model could identify the early infarction in the cortical, subcortical and cortical plus subcortical areas of supratentorial region with the mean AUC > 0.70. Further, the model could attain 95.6% of accuracy on recognizing infarction lesion in 494 out of 517 IS patients.