bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination CDC-like kinase inhibition (CLK)/Dual-specificity tyrosine-regulated kinase (DYRK) and taxane therapy inCTNNB1-mutated endometrial cancer
Authors: Corr Bradley R , Moroney Marisa R , Woodruff Elizabeth , Watson Zachary L , Jordan Kimberly R. , Danhorn Thomas , Bailey Courtney , Wolsky Rebecca J , Bitler Benjamin G 
Published: April 2023

ABSTRACTSM08502 (cirtuvivint) is a novel pan CDC-like kinase (CLK) and Dual specificity tyrosine kinase (DYRK) inhibitor that targets mRNA splicing and is optimized for Wnt pathway inhibition. Previous evaluation of single agent CLK/DYRK inhibition (SM04690) demonstrated inhibition of tumor progression and β-catenin/TCF transcriptional activity inCTNNB1-mutant endometrial cancer (EC).In-vitroanalysis of SM08502 similarly decreases Wnt transcriptional activity and cellular proliferation while increasing cellular apoptosis. SM08502 is an active single-agent therapy with IC50’s in the nanomolar range for all EC cell lines evaluated. Combination of SM08502 with paclitaxel has synergistic effectin vitro, as demonstrated by Combination Index <1, and inhibits tumor progression in four endometrial cancer models (HEC265, Ishikawa, Ishikawa-S33Y, and SNGM). In ourin vivomouse models, Ishikawa demonstrated significantly lower tumor volumes of combination vs SM08502 alone (Repeated Measures one-way ANOVA, p = 0.04), but not vs paclitaxel alone. HEC265, SNGM, and Ishikawa-S33Y tumors all had significantly lower tumor volumes with combination SM08502 and paclitaxel compared to single-agent paclitaxel (Repeated Measures one-way ANOVA, p = 0.01, 0.004, and 0.0008, respectively) or single-agent SM08502 (Repeated Measures one-way ANOVA, p = 0.002, 0.005, and 0.01, respectively) alone. Mechanistically, treatment with SM08502 increases alternative splicing (AS) events compared to treatment with paclitaxel. AS regulation is an important post-transcriptional mechanism associated with the oncogenic process in many cancers, including EC. Results from these studies have led to a Phase I evaluation of this combination in recurrent EC.
Cell surface proteomics reveal a strategy for targeting myeloma through combinatorial targeting of TNFRSF8 and TMPRSS11E
Authors: Anderson Georgina S.F. , Walker Ieuan G. , Roy James P. , Chapman Michael A. 
Published: April 2023

AbstractChimeric antigen receptor (CAR) T-cell therapy is a highly effective novel treatment in haematological malignancies that has shown promise as a therapeutic option in multiple myeloma. However, widespread adoption of CAR T-cell therapy in myeloma has been hindered by the challenge of unbiased target antigen identification and selection. As activation of CAR T-cells requires minimal antigen on the cell surface, a major risk of toxicity is destruction of healthy tissue expressing the target protein, i.e. on-target, off-tumour toxicity. Indeed, examination of the myeloma surface proteome demonstrated that there was no single target that was completely unique to myeloma cells. One approach to achieve target specificity is to require simultaneous expression of two proteins on the target cells, so-called AND-gate targeting. To identify potential AND-gate combinations for myeloma, we devised an algorithm to prioritise pairings that exhibited pan-myeloma expression and no overlapping expression in vital healthy tissue, as predicted by proteomics. Through this approach, we identified over 600 combinations. To minimise the risk of exhaustion or priming by CAR T-cells, any combination whereby one of the two antigens was expressed in T-cells was also excluded, leading to the prioritisation of 144 candidate pairings. This demonstrates the potential for AND-gating to expand the repertoire of CAR T-cell targets for myeloma. We evaluated one of these candidate pairings, TMPRSS11E and TNFRSF8,in vitro. Activation in the Jurkat cell line co-expressing a suboptimal CAR against TNFRSF8 and a chimeric costimulatory receptor (CCR) against TMPRSS11E was markedly enhanced following co-culture with a dual-target positive myeloma cell line compared with single-target positive K562, demonstrating improved discrimination between tumour and non-tumour cells.
Telling mutualistic and antagonistic ecological networks apart by learning their multiscale structure
Authors: Pichon Benoît , Goff Rémy Le , Morlon Hélène , Perez-Lamarque Benoît 
Published: April 2023

AbstractCharacterizing and understanding the processes that shape the structure of ecological networks, which represent who interacts with whom in a community, has many implications in ecology, evolutionary biology, and conservation. A highly debated question is whether and how the structure of a bipartite ecological network differs between antagonistic (e.g., herbivory) and mutualistic (e.g., pollination) interaction types.Here, we tackle this question by using a multiscale characterization of network structure, machine learning tools, and a large database of empirical and simulated bipartite networks.Contrary to previous studies focusing on global structural metrics, such as nestedness and modularity, which concluded that antagonistic and mutualistic networks cannot be told apart from only their structure, we find that they can be told apart by combining a meso-scale characterization of their structure and supervised machine learning. Motif frequencies appear particularly informative, with an over-representation of densely connected motifs in antagonistic networks and of motifs with asymmetrical specialization in mutualistic networks. These characteristics can be used to predict interaction types with relatively good confidence. Beyond this classical mutualism/antagonism dichotomy, we also find significant structural uniqueness linked to specific ecologies (e.g., pollination, parasitism).Our results clarify structural differences between antagonistic and mutualistic networks and suggest the investigation of the structural uniqueness of specific ecologies as a promising approach for characterizing interactions beyond the coarse antagonistic/mutualistic dichotomy.
Lead (Pb) Inhibits-PMA Induced Microglia Multinucleation
Authors: Nicholson Stacia M. , Chen Karie , Schanne Francis A.X. 
Published: April 2023

AbstractMultinucleated Microglia are formed in response to aging, inflammation, the presence of some pathogens, and are a histological feature of several CNS pathologies. Multinucleated microglia may be involved with increased clearance of CNS debris and whole cells. The present study has sought to determine the best model by which to study multinucleation in microgliain vitro, in order to investigate whether the known neurotoxicant metal lead (Pb) impacts the formation of multinucleated microglia. It was determined that isolated rat microglia (Sprague-Dawley), compared to murine (BV2) and human (HMC3) microglia cell-lines, when induced by Phorbol-myristate-acetate (PMA) results in the greatest amount of cell multinucleation and multinuclearity. In this model, it was shown that long-term exposure to Pb inhibited microglia cell proliferation, multinucleation, and multinuclearity in a dose-dependent manner. Pb appears to inhibit multinucleation in microglia by induction of multinuclear regression (karyolysis, pyknosis, or karyorrhexis) resulting in large mononuclear cells. The mechanism by which PMA induces multinucleation may involve p38/MAPK activity and Pb interferes with this activation.
Quantification of extracellular matrix components in immunolabeled tissue samples
Authors: Rubi-Sans Gerard , Cler Marina , Valls-Lacalle Laura , Nyga Agata , Pérez-Amodio Soledad , Mateos-Timoneda Miguel A. , Engel Elisabeth , Rebollo Elena 
Published: April 2023

ABSTRACTIn recent years, the interaction between cells and the extracellular matrix (ECM) has become a new focus in understanding tissue morphogenesis, regeneration, and disease. However, the lack of specific techniques to study the ECM composition in preserved tissue structures remains a major obstacle to explaining ECM changes in response to extrinsic stimuli. To overcome this, we propose a novel strategy that uses multidimensional fluorescence microscopy and computational tools to quantify ECM composition in immunolabeled tissues and/or cell-derived matrices (CDM). This approach includes a detailed protocol for densitometric fluorescence calibration and procedures for image acquisition, processing, and automated quantification. Using this method, we present new data comparing collagen types I, III, and IV, and fibronectin contents in various tissues. These results emphasize the importance of studying ECM compositionin situunder both normal homeostatic and disease conditions.Graphical abstract
Agent-Based Modelling shows that Operation of Fisher’s Principle does not explain Zero Heritability in Human Offspring Sex Ratio
Authors: Harper Kaitlyn T. , Sidari Morgan J. , Zietsch Brendan P. 
Published: April 2023

AbstractThe evolutionary basis of the ratio of male to female births has been a focus of research for over a century. Fisher’s principle suggests that offspring sex ratios remain roughly equal due to negative frequency-dependent balancing selection: individuals with alleles that produce the rarer sex have greater fitness, increasing these alleles’ frequency until the sex ratio is balanced. However, recent analysis of Swedish births since 1932 reveals that offspring sex ratio is not heritable, challenging Fisher’s principle’s application to humans. Here, we test the hypothesis that Fisher’s principle uniquely depletes offspring sex ratio heritability at equilibrium. We used agent-based modelling to simulate Fisher’s principle over 5000 generations and found that Fisher’s principle at equilibrium does not eliminate genetic variation. These findings, along with evidence of non-heritable offspring sex ratios in humans, suggest Fisher’s principle is not a suitable explanatory framework for human offspring sex ratio.
The purinergic receptor P2X7 and the NLRP3 inflammasome are druggable host factors required for SARS-CoV-2 infection
Authors: Lécuyer Déborah , Nardacci Roberta , Tannous Désirée , Gutierrez-Mateyron Emie , Deva-Nathan Aurélia , Subra Frédéric , Primio Cristina Di , Quaranta Paola , Petit Vanessa , Richetta Clémence , Mostefa-Kara Ali , Nonno Franca Del , Falasca Laura , Marlin Romain , Maisonnasse Pauline , Delahousse Julia , Pascaud Juliette , Deprez Eric , Naigeon Marie , Chaput Nathalie , Paci Angelo , Saada Véronique , Ghez David , Mariette Xavier , Costa Mario , Pistello Mauro , Allouch Awatef , Delelis Olivier , Piacentini Mauro , Le Grand Roger , Perfettini Jean-Luc 
Published: April 2023

AbstractPurinergic receptors and NOD-like receptor protein 3 (NLRP3) inflammasome regulate inflammation and viral infection, but their effects on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain poorly understood. Here, we report that the purinergic receptor P2X7 and NLRP3 inflammasome are cellular host factors required for SARS-CoV-2 infection. Lung autopsies from patients with severe coronavirus disease 2019 (COVID-19) reveal that NLRP3 expression is increased in host cellular targets of SARS-CoV-2 including alveolar macrophages, type II pneumocytes and syncytia arising from the fusion of infected macrophages, thus suggesting a potential role of NLRP3 and associated signaling pathways to both inflammation and viral replication. In vitro studies demonstrate that NLRP3-dependent inflammasome activation is detected upon macrophage abortive infection. More importantly, a weak activation of NLRP3 inflammasome is also detected during the early steps of SARS-CoV-2 infection of epithelial cells and promotes the viral replication in these cells. Interestingly, the purinergic receptor P2X7, which is known to control NLRP3 inflammasome activation, also favors the replication of D614G and alpha SARS-CoV-2 variants. Altogether, our results reveal an unexpected relationship between the purinergic receptor P2X7, the NLRP3 inflammasome and the permissiveness to SARS-CoV-2 infection that offers novel opportunities for COVID-19 treatment.
Early consequences of the phospholamban mutation PLN-R14del+/-in a transgenic mouse model
Authors: Maniezzi Claudia , Eskandr Marem , Florindi Chiara , Ferrandi Mara , Barassi Paolo , Sacco Elena , Pasquale Valentina , Maione Angela S. , Pompilio Giulio , Oliveira Nunes Teixeira Vivian , de Boer Rudolf A , Silljé Herman H W , Lodola Francesco , Zaza Antonio 
Published: April 2023

ABSTRACTAimsThe heterozygous phospholamban (PLN) mutation R14del (PLN R14del+/-) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. “Superinhibition” of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to 1) to evaluate Ca2+dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; 2) to test whether they are causally connected.Methods and ResultsCa2+dynamics, energy metabolism parameters, reporters of mitochondrial integrity, energy and redox homeostasis were measured in ventricular myocytes of 8-12 weeks-old, phenotypically silent, TG mice. Mutation effects were compared to pharmacological PLN antagonism and analysed during modulation of sarcoplasmic reticulum (SR) and cytosolic Ca2+compartments. Transcripts and proteins of relevant signalling pathways were evaluated. The mutation was characterized by hyperdynamic Ca2+handling, similar to that induced by PLN antagonism. Albeit all components of energy metabolism were depressed at rest, functional signs of mitochondrial damage or energy starvation were absent and cell energy charge was preserved. The response of mitochondrial O2consumption to SERCA2a blockade was lost in mutant myocytes (SR-mitochondrial uncoupling) and ER-stress signalling was activated.Conclusions1) PLN R14del+/-loses its ability to inhibit SERCA2a, which argues against SERCA2a superinhibition as a mechanism of ACM; 2) depression of resting energy metabolism may at least partly reflect impairment of SR-mitochondrial coupling; 3) ER-stress may be an early factor in the pathogenesis.
N-linked glycosylation of the M-protein variable region: Glycoproteogenomics reveals a new layer of personalized complexity in multiple myeloma
Authors: Langerhorst Pieter , Baerenfaenger Melissa , Kulkarni Purva , Nadal Simon , Wijnands Charissa , Post Merel A. , Noori Somayya , vanDuijn Martijn M. , Joosten Irma , Dejoie Thomas , van Gool Alain J. , Gloerich Jolein , Lefeber Dirk J. , Wessels Hans J.C.T. , Jacobs Joannes F.M. 
Published: April 2023

ABSTRACTMultiple Myeloma (MM) is a plasma cell malignancy characterized by a monoclonal expansion of plasma cells that secrete a characteristic M-protein. This M-protein is crucial for diagnosis and monitoring of MM in the blood of patients. Recent evidence has emerged suggesting that N-glycosylation of the M-protein variable (Fab) region contributes to M-protein pathogenicity, and that it is a risk factor for disease progression of plasma cell disorders. Current methodologies lack the specificity to provide a site-specific glycoprofile of the Fab regions of M-proteins. Here, we introduce a novel glycoproteogenomics method that allows detailed M-protein glycoprofiling by integrating patient specific Fab region sequences (genomics) with glycoprofiling by glycoproteomics. Genomic analysis uncovered a more than two-fold increase in the Fab Light Chain N-glycosylation of M-proteins of patients with Multiple Myeloma compared to Fab Light Chain N-glycosylation of polyclonal antibodies from healthy individuals. Subsequent glycoproteogenomics analysis of 41 patients enrolled in the IFM 2009 clinical trial revealed that the majority of the Fab N-glycosylation sites were fully occupied with complex type glycans, distinguishable from Fc region glycans due to high levels of sialylation, fucosylation and bisecting structures. Together, glycoproteogenomics is a powerful tool to studyde novoFab N-glycosylation in plasma cell dyscrasias.
The super-enhancer landscape reflects molecular subgroups of adrenocortical carcinoma
Authors: Gunz Samuel , Kerdivel Gwenneg , Meirer Jonas , Shapiro Igor , Ragazzon Bruno , Amrouche Floriane , Calmejane Marie-Ange , Hamroune Juliette , Sigala Sandra , Berruti Alfredo , Bertherat Jérôme , Assié Guillaume , Hantel Constanze , Boeva Valentina 
Published: April 2023

AbstractAdrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland with generally very unfavourable outcome. Two molecular subgroups, C1A and C1B, have been previously identified with a significant association with patient survival. In this work, we study chromatin state organization characterized by histone modifications using ChIP-sequencing in adult ACC. We describe the super-enhancer landscape of ACC, characterized by H3K27ac, and identify super-enhancer regulated genes that play a significant role in tumorigenesis. We show that the super-enhancer landscape reflects differences between the molecular sub-groups C1A and C1B and identify networks of master transcription factors mirroring these differences. Additionally, we study the effects of molecules THZ1 and JQ1 previously reported to affect super-enhancer-driven gene expression in ACC cell lines. Our results reveal that the landscape of histone modifications in ACC is linked to its molecular subgroups and thus provide the groundwork for future analysis of epigenetic reprogramming in ACC.
A supervised data-driven spatial filter denoising method for speech artifacts in intracranial electrophysiological recordings
Authors: Peterson Victoria , Vissani Matteo , Luo Shiyu , Rabbani Qinwan , Crone Nathan E. , Bush Alan , Richardson R. Mark 
Published: April 2023

AbstractNeurosurgical procedures that enable direct brain recordings in awake patients offer unique opportunities to explore the neurophysiology of human speech. The scarcity of these opportunities and the altruism of participating patients compel us to apply the highest rigor to signal analysis. Intracranial electroencephalography (iEEG) signals recorded during overt speech can contain a speech artifact that tracks the fundamental frequency (F0) of the participant’s voice, involving the same high-gamma frequencies that are modulated during speech production and perception. To address this artifact, we developed a spatial-filtering approach to identify and remove acoustic-induced contaminations of the recorded signal. We found that traditional reference schemes jeopardized signal quality, whereas our data-driven method denoised the recordings while preserving underlying neural activity.
Neutral Drift and Threshold Selection Promote Phenotypic Variation
Authors: Erdoğan Ayşe N. , Dasmeh Pouria , Socha Raymond D. , Chen John Z. , Life Ben , Jun Rachel , Kiritchkov Linda , Kehila Dan , Serohijos Adrian W.R. , Tokuriki Nobuhiko 
Published: April 2023

AbstractPhenotypic variations within a population exist on different scales of biological organization and play a central role in evolution by providing adaptive capacity at the population-level. Thus, the question of how evolution generates phenotypic variation within an evolving population is fundamental in evolutionary biology. Here we address this question by performing experimental evolution of an antibiotic resistance gene, VIM-2 β-lactamase, combined with diverse biochemical assays and population genetics. We found that neutral drift,i.e., evolution under a static environment, with a low antibiotic concentration can promote and maintain significant phenotypic variation within the population with >100-fold differences in resistance strength. We developed a model based on the phenotype-environment-fitness landscape generated with >5,000 VIM-2 variants, and demonstrated that the combination of “mutation-selection balance” and “threshold-like fitness-phenotype relationship” is sufficient to explain the generation of large phenotypic variation within the evolving population. Importantly, high-resistance conferring variants can emerge during neutral drift, without being a product of adaptation. Our findings provide a novel and simple mechanistic explanation for why most genes in nature, and by extension, systems and organisms, inherently exhibit phenotypic variation, and thus, population-level evolvability.
A cell atlas of the developing human outflow tract of the heart and its adult derivatives
Authors: Leshem Rotem , Baker Syed Murtuza , Mallen Joshua , Wang Lu , Dark John , Sharrocks Andrew D , Hanley Karen Piper , Hanley Neil A , Rattray Magnus , Bamforth Simon D , Bobola Nicoletta 
Published: April 2023

AbstractThe outflow tract (OFT) of the heart carries blood away from the heart into the great arteries. During embryogenesis, the OFT divides to form the aorta and pulmonary trunk, creating the double circulation present in mammals. Defects in this area account for one-third of all congenital heart disease cases. Here, we present comprehensive transcriptomic data on the developing OFT at two distinct timepoints (embryonic and fetal) and its adult derivatives, the aortic valves, and use spatial transcriptomics to define the distribution of cell populations. We uncover that distinctive embryonic signatures persist in adult cells and can be used as labels to retrospectively attribute relationships between cells separated by a large time scale. Our findings define the cellular and molecular signatures of the OFT and its distinct cell lineages, which is critical for understanding congenital heart defects and developing cardiac tissue for regenerative medicine.
Evaluating drought tolerance stability in soybean by the response of irrigation change captured from time-series multispectral data
Authors: Sakurai Kengo , Toda Yusuke , Hamazaki Kosuke , Ohmori Yoshihiro , Yamasaki Yuji , Takahashi Hirokazu , Takanashi Hideki , Tsuda Mai , Tsujimoto Hisashi , Kaga Akito , Nakazono Mikio , Fujiwara Toru , Iwata Hiroyoshi 
Published: April 2023

AbstractThis study investigated a method to evaluate the drought tolerance stability of a genotype in a single environmental trial by capturing the plant response to irrigation changes. Genotypes that exhibit stable phenotypes under various drought stress conditions are required for stable crop production. However, considerable time and money are required to evaluate the environmental stability of a genotype through multiple environmental trials. As an index of drought tolerance stability, we calculated the coefficient of variation (CV) of shoot fresh weight of 178 soybean (Glycine max(L.) Merr.) accessions in a total of nine types of drought treatments, including changing irrigation treatments (every five or ten days) over 3-year trials. To capture the plant responses to irrigation changes, time-series multispectral (MS) data were collected, including the timings of the irrigation/non-irrigation switch in the changing irrigation treatments. We built a random regression model (RRM) for each of the nine treatments using the time-series MS data. We built a genomic prediction model (MTRRMmodel) using the genetic random regression coefficients of RRM as secondary traits and evaluated the accuracy of each model for predicting CV. In two out of the three years, the prediction accuracy of MTRRMmodels built in the changing irrigation treatment was higher than that in the continuous drought treatment in the same year. When the CV was predicted using the MTRRMmodel across years in the changing irrigation treatment, the prediction accuracy was 61% higher than that of the simple genomic prediction model. These results suggest that drought tolerance stability can be evaluated in a single environmental trial, which may reduce the time and cost of selecting genotypes with high drought tolerance stability.