bluuebunny/crossref_metadata_2025_split huggingface dataset:
CRACD suppresses neuroendocrinal plasticity of lung adenocarcinoma
Authors: Kim Bongjun , Zhang Shengzhe , Huang Yuanjian , Ko Kyung-Pil , Zou Gengyi , Zhang Jie , Jun Sohee , Kim Kee-Beom , Jung Youn-Sang , Park Kwon-Sik , Park Jae-Il 
Published: April 2023

AbstractTumor cell plasticity contributes to intratumoral heterogeneity and therapy resistance. Through cell plasticity, lung adenocarcinoma (LUAD) cells transform into neuroendocrinal (NE) tumor cells. However, the mechanisms of NE cell plasticity remain unclear. CRACD, a capping protein inhibitor, is frequently inactivated in cancers.CRACDknock-out (KO) de-represses NE-related gene expression in the pulmonary epithelium and LUAD cells. In LUAD mouse models,CracdKO increases intratumoral heterogeneity with NE gene expression. Single-cell transcriptomic analysis showed thatCracdKO-induced NE plasticity is associated with cell de-differentiation and activated stemness-related pathways. The single-cell transcriptomes of LUAD patient tumors recapitulate that the distinct LUAD NE cell cluster expressing NE genes is co-enriched with SOX2, OCT4, and NANOG pathway activation, and impaired actin remodeling. This study reveals an unexpected role of CRACD in restricting NE cell plasticity that induces cell de-differentiation, providing new insights into cell plasticity of LUAD.
A millisecond coarse-grained simulation approach to decipher allosteric cannabinoid binding at the glycine receptorα1
Authors: Bartocci Alessio , Grazzi Andrea , Awad Nour , Corringer Pierre-Jean , Souza Paulo C.T. , Cecchini Marco 
Published: April 2023

AbstractGlycine receptors (GlyR) are regulated by small-molecule binding at several allosteric sites. Cannabinoids like tetrahydrocannabinol (THC) and N-arachidonyl-ethanol-amide (AEA) potentiate GlyR but their mechanism of action is not fully established. By combining millisecond coarse-grained MD simulations powered by Martini 3 with backmapping to all-atom representations, we characterize the cannabinoid-binding sites at zebrafish GlyR-α1 with atomic resolution. Based on hundreds of thousand ligand-binding events, we find that cannabinoids bind to the transmembrane domain of the receptor at both intrasubunit and intersubunit sites. For THC, the intrasubunit binding mode predicted in simulation is in excellent agreement with recent cryo-EM structures, while intersubunit binding recapitulates in full previous mutagenesis experiments. Intriguingly, AEA is predicted to bind at the same intersubunit site despite the strikingly different chemistry. Statistical analyses of the receptor-ligand interactions highlight potentially relevant residues for GlyR potentiation, offering experimentally testable predictions. The predictions for AEA are validated by electrophysiology recordings of rationally designed mutants. The results highlight the existence of multiple cannabinoid-binding sites for the allosteric regulation of GlyR and put forward an effective strategy for the identification and structural characterization of allosteric sites in transmembrane proteins.
The ATP-exporting channel Pannexin-1 promotes CD8+T cell effector and memory responses
Authors: Vardam-Kaur Trupti , Banuelos Alma , Gabaldon-Parish Maria , Macedo Bruna Gois , Salgado Caio Loureiro , Wanhainen Kelsey Marie , Zhou Maggie Hanqi , van Dijk Sarah , Santiago-Carvalho Igor , Beniwal Angad S. , Leff Chloe L. , Peng Changwei , Tran Nhan L. , Jameson Stephen C. , Borges da Silva Henrique 
Published: April 2023

AbstractSensing of extracellular ATP (eATP) controls CD8+T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin-1 (Panx1). Whether Panx1 controls CD8+T cell immune responsesin vivo, however, has not been previously addressed. Here, we report that T cell-specific Panx1 is needed for CD8+T cell responses to viral infections and cancer. We found that CD8-specific Panx1 promotes both effector and memory CD8+T cell responses. Panx1 favors initial effector CD8+T cell activation through extracellular ATP (eATP) export and subsequent P2RX4 activation, which helps promote full effector differentiation through extracellular lactate accumulation and its subsequent recycling. In contrast, Panx1 promotes memory CD8+T cell survival primarily through ATP export and subsequent P2RX7 engagement, leading to improved mitochondrial metabolism. In summary, Panx1-mediated eATP export regulates effector and memory CD8+T cells through distinct purinergic receptors and different metabolic and signaling pathways.
Pharmacological Induction of mesenchymal-epithelial transition chemosensitizes breast cancer cells and prevents metastatic progression
Authors: Bagheri Meisam , Mohamed Gadisti Aisha , Ashick Mohammed , Saleem Mohamed , Ognjenovic Nevena B. , Lu Hanxu , Kolling Fred W. , Wilkins Owen M. , Das Subhadeep , Croix Ian S. La , Nagaraj Shivashankar H. , Muller Kristen E. , Gerber Scott A. , Miller Todd W. , Pattabiraman Diwakar R. 
Published: April 2023

AbstractThe epithelial-mesenchymal transition (EMT) is a developmental program co-opted by tumor cells that aids the initiation of the metastatic cascade. Tumor cells that undergo EMT are relatively chemoresistant, and there are currently no therapeutic avenues specifically targeting cells that have acquired mesenchymal traits. We show that treatment of mesenchymal-like triple-negative breast cancer (TNBC) cells with the microtubule-destabilizing chemotherapeutic eribulin, which is FDA-approved for the treatment of advanced breast cancer, leads to a mesenchymal-epithelial transition (MET). This MET is accompanied by loss of metastatic propensity and sensitization to subsequent treatment with other FDA-approved chemotherapeutics. We uncover a novel epigenetic mechanism of action that supports eribulin pretreatment as a path to MET induction that curtails metastatic progression and the evolution of therapy resistance.SummaryWhile the advent of targeted therapy has led to vast improvements in outcomes for certain types of breast cancer, a mainstay for triple-negative breast cancer (TNBC) remains cytotoxic chemotherapy. A major clinical hurdle in successfully managing this disease is the eventual development of therapeutic resistance and disease relapse in more aggressive forms. Our data reveal that epigenetic modulation of EMT state using the FDA-approved therapeutic eribulin curtails metastatic propensity of breast tumors and, when administered in the treatment-naïve setting, sensitizes to subsequent treatment with other chemotherapeutics.
Individual vocal recognition in the black-headed spider monkey (Ateles fusciceps)
Authors: Nagle D. , Power T. , Quinn J. L. , Troisi C. A. 
Published: April 2023

AbstractIndividual vocal recognition – the ability to discriminate between individuals based on sound – is thought to be particularly useful for social species that regularly lose visual contact between group members. For instance, individuals living in a fission-fusion group that feed on patchily distributed food in a complex physical environment (e.g., dense forest) are likely to depend heavily on vocalisation to identify individuals that are good at finding food. Spider monkeys (Ateles spp.) live in such environments and have distinctive individual contact calls (whinnies). We used a habituation-dishabituation playback-paradigm to investigate whether black-headed spider monkeys (A. fusciceps) are able to discriminate between female individuals in their group. We found that a group of captive spider monkeys was able to discriminate between individuals using those contact calls. Although many primate species have been found to have individual characteristics in their calls, this is one of the few direct experimental evidence of vocal recognition using a habituation-dishabituation paradigm.
Mapping rhodopsin trafficking in rod photoreceptors with quantitative super-resolution microscopy
Authors: Haggerty Kristen N. , Eshelman Shannon C. , Sexton Lauren A. , Frimpong Emmanuel , Rogers Leah M. , Agosto Melina A. , Robichaux Michael A. 
Published: April 2023

ABSTRACTPhotoreceptor cells in the vertebrate retina have a highly compartmentalized morphology for efficient long-term phototransduction. Rhodopsin, the visual pigment in rod photoreceptors, is densely packaged into the rod outer segment sensory cilium and continuously renewed through essential synthesis and trafficking pathways housed in the rod inner segment. Despite the importance of this region for rod health and maintenance, the subcellular organization of rhodopsin and its trafficking regulators in the mammalian rod inner segment remain undefined. We used super-resolution fluorescence microscopy with optimized retinal immunolabeling techniques to perform a single molecule localization analysis of rhodopsin in the inner segments of mouse rods. We found that a significant fraction of rhodopsin molecules was localized at the plasma membrane in an even distribution along the entire length of the inner segment, where markers of transport vesicles also colocalized. Thus, our results collectively establish a model of rhodopsin trafficking through the inner segment plasma membrane as an essential subcellular pathway in mouse rod photoreceptors.SUMMARYPhotoreceptor cells of the retina are maintained through a complex protein trafficking network. This study applies quantitative super-resolution microscopy to uncover localization details about the trafficking of the essential visual pigment rhodopsin in the inner segment region of rod photoreceptors.
A multi-scale digital twin for adiposity-driven insulin resistance in humans: diet and drug effects
Authors: Herrgårdh Tilda , Simonsson Christian , Ekstedt Mattias , Lundberg Peter , Stenkula Karin G. , Nyman Elin , Gennemark Peter , Cedersund Gunnar 
Published: April 2023

AbstractAimsThe increased prevalence of insulin resistance is one of the major health risks in society today. Insulin resistance involves both short-term dynamics, such as altered meal responses, and long-term dynamics, such as development of type 2 diabetes. Insulin resistance also occurs on different physiological levels, ranging from disease phenotypes to organ-organ communication and intracellular signaling. To better understand the progression of insulin resistance, an analysis method is needed that can combine different timescales and physiological levels. One such method is digital twins, consisting of combined mechanistic multi-scale and multi-level mathematical models. We have previously developed a multi-level model for short-term glucose homeostasis and intracellular insulin signaling, and there exists long-term weight regulation models. However, no one has combined these kinds of models into an interconnected, multi-level and multi-timescale digital twin model. Herein, we present a first such multi-scale digital twin for the progression of insulin resistance in humans.MethodsThe model is based on ordinary differential equations representing biochemical and physiological processes, in which unknown parameters were fitted to data using a MATLAB toolbox.ResultsThe connected twin correctly predicts independent data from a weight increase study, both for weight-changes, for fasting plasma insulin and glucose levels, as well as for intracellular insulin signaling. Similarly, the model can predict independent weight-change data in a weight loss study, involving diet and the weight loss drug topiramate. These independent validation tests are confirmed by a chi-square test (𝑉(𝜃) = 4.8 < 21 = 𝜒2𝑐𝑢𝑚,𝑖𝑛𝑣(12,0.05)). In both these cases, the model can also predict non-measured variables, such as activity of intracellular intermediaries, glucose tolerance responses, and organ fluxes.ConclusionsWe present a first multi-level and multi-timescale model, describing dynamics on the whole-body, organ and cellular levels, ranging from minutes to years. This model constitutes the basis for a new digital twin technology, which in the future could potentially be used to aid medical pedagogics and increase motivation and compliance and thus aid in prevention and treatment of insulin resistance.
Dosimetric and biologic intercomparison between electron and proton FLASH beams
Authors: Almeida A , Togno M , Ballesteros-Zebadua P , Franco-Perez J , Geyer R , Schaefer R , Petit B , Grilj V , Meer D , Safai S , Lomax T , Weber DC , Bailat C , Psoroulas S , Vozenin MC 
Published: April 2023

AbstractBackground and purposeThe FLASH effect has been validated in different preclinical experiments with electrons (eFLASH) and protons (pFLASH) operating at a mean dose rate above 40 Gy/s. However, no systematic intercomparison of the FLASH effect produced by evs. pFLASH has yet been performed and constitutes the aim of the present study.Materials and methodsThe electron eRT6/Oriatron/CHUV/5.5 MeV and proton Gantry1/PSI/170 MeV were used to deliver conventional (0.1 Gy/s eCONV and pCONV) and FLASH (≥100 Gy/s eFLASH and pFLASH) irradiation. Protons were delivered in transmission. Dosimetric and biologic intercomparisons were performed with previously validated models.ResultsDoses measured at Gantry1 were in agreement (± 2.5%) with reference dosimeters calibrated at CHUV/IRA. The neurocognitive capacity of e and pFLASH irradiated mice was indistinguishable from the control while both e and pCONV irradiated cohorts showed cognitive decrements. Complete tumor response was obtained with the two beams and was similar between e and pFLASHvs. e and pCONV. Tumor rejection was similar indicating that T-cell memory response is beam-type and dose-rate independent.ConclusionDespite major differences in the temporal microstructure, this study shows that dosimetric standards can be established. The sparing of brain function and tumor control produced by the two beams were similar, suggesting that the most important physical parameter driving the FLASH effect is the overall time of exposure which should be in the range of hundreds of milliseconds for WBI in mice. In addition, we observed that immunological memory response is similar between electron and proton beams and is independent off the dose rate.
Tuning social interactions’ strength drives collective response to light intensity in schooling fish
Authors: Xue Tingting , Li Xu , Lin GuoZheng , Escobedo Ramón , Han Zhangang , Chen Xiaosong , Sire Clément , Theraulaz Guy 
Published: April 2023

AbstractSchooling fish heavily rely on visual cues to interact with neighbors and avoid obstacles. The availability of sensory information is influenced by environmental conditions and changes in the physical environment that can alter the sensory environment of the fish, which in turn affects individual and group movements. In this study, we combine experiments and data-driven modeling to investigate the impact of varying levels of light intensity on social interactions and collective behavior in rummy-nose tetra fish. The trajectories of single fish and groups of fish swimming in a tank under different lighting conditions were analyzed to quantify their movements and spatial distribution. Interaction functions between two individuals and the fish interaction with the tank wall were reconstructed and modeled for each light condition. Our results demonstrate that light intensity strongly modulates social interactions between fish and their reactions to obstacles, which then impact collective motion patterns that emerge at the group level.
Key common genes and pathways in ulcerative colitis and ankylosing spondylitis based on bioinformatics analysis
Authors: Li Lin , Li Fuzhen , Xie Kunpeng , Zhou Pengyi , Zhu Haiyan , Du Liping , Yang Peizeng , Jin Xuemin 
Published: April 2023

AbstractAssociations between ulcerative colitis (UC) and ankylosing spondylitis (AS) have been observed in multiple studies, but the common etiology of UC and AS remain unknown. Thus, the current research was conducted to investigate the shared genes and relevant mechanisms in UC and AS. GSE87466 and GSE25101 datasets were used to identify DEGs involved in UC and AS, respectively. The clusterProfiler R package was utilized to detect the biological processes of DEGs in UC and AS. The performance of common DEGs in distinguishing UC or AS samples from control ones were evaluated by ROC curves. The miRWalk, Cistrome and TransmiR database were utilized to construct the network of TF-miRNA-diagnostic biomarker. GSEA method and CTD database were used to investigate the common KEGG pathways shared by UC and AS. In addition, CTD database was also used to detect the interaction score between diagnostic biomarkers and diseases associated with UC or AS. Moreover, prospective diagnostic biomarker-targeting drugs were identified using the DGIdb database. A total of 20 common DEGs were obtained by analyzing data in GSE97466 and GSE25101 datasets. ROC curves revealed that GMFG, GNG11, CLEC4D, CMTM2, VAMP5, S100A8, S100A12 and DGKQ may serve as diagnostic biomarkers for the individuals with AS and UC. A network of TF-miRNA-diagnostic biomarker, composed of 212 nodes and 721 edges, was constructed and visualized by Cytoscape software. Toll-like receptor signaling pathway, antigen processing and presentation, allograft rejection, viral myocarditis, pathways in cancer, graft versus host disease and natural killer cell mediated cytotoxicity were identified as common pathways in UC and AS. For the first time, our study identified 8 common key genes and 7 common pathways in UC and AS. These findings may help to clarify the relationship between UC and AS, and provide guidance in the diagnosis and treatment of UC and AS patients.Author SummaryAnkylosing spondylitis (AS) and Ulcerative colitis (UC) are two types of autoimmune diseases that often co-occur. The simultaneous onset of both diseases often results in severe clinical manifestations and limited therapeutic efficacy. So there is an urgent need to gain a deeper understanding of the causes of UC and AS in order to develop more effective treatment strategies. In this study, we explored the genes and pathways commonly involved in two diseases, constructed a transcriptional network, and further investigated potential drugs. The discoveries could potentially offer insights into the connection between UC and AS, and assist in identifying and managing patients with UC and AS.
Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation
Authors: Zhou Mengmeng , Han Yuhong , Jiang Jin 
Published: April 2023

SummaryThe Hedgehog (Hh) family of secreted proteins governs embryonic development and adult tissue homeostasis through the Gli family of transcription factors. Gli is thought to be activated at the tip of primary cilium, but the underlying mechanism has remained poorly understood. Here, we show thatUnc-51-likekinase 4 (Ulk4), a pseudokinase and a member of the Ulk kinase family, acts in conjunction with another Ulk family member Stk36 to promote Gli2 phosphorylation and Hh pathway activation. Ulk4 interacts with Stk36 through its N-terminal region containing the pseudokinase domain and Gli2 via its regulatory domain to bridge the kinase and substrate. Although dispensable for Hh-induced Stk36 kinase activation, Ulk4 is essential for Stk36 ciliary tip localization, Gli2 phosphorylation and activation. In response to Hh, both Ulk4 and Stk36 colocalize with Gli2 at ciliary tip, and Ulk4 and Stk36 depend on each other for their ciliary tip accumulation. We further show that ciliary localization of Ulk4 depends on Stk36 kinase activity and phosphorylation of Ulk4 on Thr1023, and that ciliary tip accumulation of Ulk4 is essential for its function in the Hh pathway. Taken together, our results suggest that Ulk4 regulates Hh signaling by promoting Stk36-mediated Gli2 phosphorylation and activation at ciliary tip.
Single-cell temporal dynamics reveals the relative contributions of transcription and degradation to cell-type specific gene expression in zebrafish embryos
Authors: Fishman Lior , Nechooshtan Gal , Erhard Florian , Regev Aviv , Farrell Jeffrey A. , Rabani Michal 
Published: April 2023

AbstractDuring embryonic development, pluripotent cells assume specialized identities by adopting particular gene expression profiles. However, systematically dissecting the underlying regulation of mRNA transcription and degradation remains a challenge, especially within whole embryos with diverse cellular identities. Here, we collect temporal cellular transcriptomes of zebrafish embryos, and decompose them into their newly-transcribed (zygotic) and pre-existing (maternal) mRNA components by combining single-cell RNA-Seq and metabolic labeling. We introduce kinetic models capable of quantifying regulatory rates of mRNA transcription and degradation within individual cell types during their specification. These reveal different regulatory rates between thousands of genes, and sometimes between cell types, that shape spatio-temporal expression patterns. Transcription drives most cell-type restricted gene expression. However, selective retention of maternal transcripts helps to define the gene expression profiles of germ cells and enveloping layer cells, two of the earliest specified cell-types. Coordination between transcription and degradation restricts expression of maternal-zygotic genes to specific cell types or times, and allows the emergence of spatio-temporal patterns when overall mRNA levels are held relatively constant. Sequence-based analysis links differences in degradation to specific sequence motifs. Our study reveals mRNA transcription and degradation events that control embryonic gene expression, and provides a quantitative approach to study mRNA regulation during a dynamic spatio-temporal response.
Dynamic calcium-mediated stress response and recovery signatures in the fungal pathogen,Candida albicans
Authors: Giuraniuc CV , Parkin C , Almeida MC , Fricker M , Shadmani P , Nye S , Wehmeier S , Chawla S , Bedekovic T , Lehtovirta-Morley L , Richards D , Gow NA , Brand AC 
Published: April 2023

AbstractCalcium (Ca2+) is an important second messenger for activating stress response signalling and cell adaptation in eukaryotic cells yet intracellular Ca2+-dynamics in fungi is poorly understood due to lack of effective real-time Ca2+reporters. We engineered the GCaMP6f construct for use in the fungal pathogen,Candida albicans, and used live-cell imaging to observe dynamic Ca2+spiking as well as slower changes in ambient Ca2+-GCaMP levels elicited by stress or gene deletion. Short-term exposure to membrane, osmotic or oxidative stress generated immediate stress-specific responses and repeated exposure revealed differential recovery signatures. Osmotic stress caused yeast cell shrinkage and no adaptation response, where Ca2+-GCaMP spiking was inhibited by 1 M NaCl but not by 0.66 M CaCl2.Treatment with SDS caused a spike-burst, raised ambient Ca2+-GCaMP levels and significant cell death, but surviving cells adapted over subsequent exposures. Treatment with 5 mM H2O2abolished spiking and caused transient autofluorescence but cells adapted such that spiking returned and autofluorescence diminished on repeated exposure. Adaptation to H2O2was dependent on Cap1, extracellular Ca2+and calcineurin, but not on its downstream target, Crz1. Ca2+-dynamics were not affected by H2O2in thehog1Δ oryvc1Δ mutants, suggesting a pre-adapted, resistant state, possibly due to changes in membrane permeability. Live-cell imaging of Ca2+-GCaMP responses in individual cells has therefore revealed the dynamics of Ca2+-influx, signalling and homeostasis and their role in the temporal stress response signatures ofC. albicans.