bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reassessment of Hydrate Destabilization Mechanisms Offshore West Svalbard Confirms Link to Recent Ocean Warming
Authors: Trivedi Akash , Sarkar Sudipta , Marin‐Moreno Hector , Minshull Timothy A. , Whitehouse Pippa L. , Singh Utpal 
Published: October 2022

AbstractThe stability of methane hydrates at the feather edge of hydrate stability on the upper continental slope (UCS) is prone to ocean warming and relative sea level (RSL) change. West of Svalbard, methane seeps on the UCS were initially proposed to result from hydrate destabilization resulting from four decades of warming of Atlantic bottom water. Alternatively, it has been proposed that hydrate dissociation was triggered by RSL fall due to isostatic rebound over the past 8,000 yr rather than recent bottom water temperature (BWT) rise. Here, we address these two contrasting hypotheses by simulating the impact of 11,000 yr of BWT and RSL change on hydrates located at the UCS off west Svalbard. Our numerical simulation considers multiphase fluid and heat flow coupled with hydrate formation and dissociation. We used two reconstructions of local ice history (UiT and ICE‐6G_C) that predict contrasting results for the local sea level history. Over the past 8,000 yr, the UiT model predicts a fall in RSL on the UCS, while the ICE‐6G_C model, which provides a better fit to nearby coastal RSL observations, predicts a continuous rise. Our modeling shows that whilst long‐term RSL fall would progressively thin the region of hydrate stability, the abrupt rise in BWT enhances hydrate dissociation. Even in the model with an RSL rise, the increase in BWT causes hydrate destabilization and pore water freshening that matches observations. We conclude that recent ocean warming plays a critical role in hydrate dissociation west of Svalbard regardless of the longer‐term sea level history.
Intraseasonal Variability of Surface Circulation in the Indo‐Pacific Warm Pool Induced by Summer Monsoon Intraseasonal Oscillations
Authors: Song Lina , Wang Fan , Li Yuanlong , Lee June‐Yi 
Published: October 2022

AbstractThe Indian summer monsoon intraseasonal oscillation (MISO) is the most influential mode of tropical atmospheric intraseasonal variability in boreal summer (May–October). This study investigates how the MISO drives the intraseasonal variability (ISV) of zonal currents (U) in the Indo‐Pacific warm pool (IPWP) region. An analysis of satellite observations confirms a close association between U ISV and the MISO, with MISO‐induced surface U anomalies reaching 16–19 cm s−1 near the equator and 4–5 cm s−1 in the Northern Hemisphere portion of the IPWP. These ISVs account for 15%–35% of the intensity changes in the major zonal currents. The spatial distribution of U ISV shows coherent enhancement and suppression of MISO convections with a lag of approximately 7 days as a delayed response to the tropical wind forcing. ISV anomalies show northward emanation following propagation of the MISO. Ocean model experiments confirm that large‐scale ISV in surface U is primarily caused by the wind forcing of the MISO. Owing to the convergence/divergence of MISO‐induced U ISV, significant warm water volume anomalies occur in the western‐to‐central equatorial Pacific.
Influence of UGT1A1 and SLC22A6 polymorphisms on the population pharmacokinetics and pharmacodynamics of raltegravir in HIV-infected adults: a NEAT001/ANRS143 sub-study
Authors: Gurjar Rohan , Dickinson Laura , Carr Daniel , Stöhr Wolfgang , Bonora Stefano , Owen Andrew , D’Avolio Antonio , Cursley Adam , De Castro Nathalie , Fätkenheuer Gerd , Vandekerckhove Linos , Di Perri Giovanni , Pozniak Anton , Schwimmer Christine , Raffi François , Boffito Marta ,   the NEAT001/ANRS143 Study Group
Published: October 2022

AbstractUsing concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p = 0.012), even after adjusting for baseline CD4 count (p = 0.048), but not when adjusted for baseline HIV-1 viral load (p = 0.082) or both (p = 0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir’s characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.
Impact of the selective A2AR and A2BR dual antagonist AB928/etrumadenant on CAR T cell function
Authors: Seifert Matthias , Benmebarek Mohamed-Reda , Briukhovetska Daria , Märkl Florian , Dörr Janina , Cadilha Bruno L. , Jobst Jakob , Stock Sophia , Andreu-Sanz David , Lorenzini Theo , Grünmeier Ruth , Oner Arman , Obeck Hannah , Majed Lina , Dhoqina Dario , Feinendegen Manouk , Gottschlich Adrian , Zhang Jin , Schindler Ulrike , Endres Stefan , Kobold Sebastian 
Published: October 2022

Abstract
Background
Chimeric antigen receptor (CAR) T cell therapy has been successfully translated to clinical practice for the treatment of B cell malignancies. The suppressive microenvironment of many malignancies is a bottleneck preventing treatment success of CAR T cells in a broader range of tumours. Among others, the immunosuppressive metabolite adenosine is present in high concentrations within many tumours and dampens anti-tumour function of immune cells and consequently therapeutic response.

Methods
Here, we present the impact of the selective adenosine A2A and A2B receptor antagonist AB928/etrumadenant on CAR T cell cytokine secretion, proliferation, and cytotoxicity. Using phosphorylation-specific flow cytometry, we evaluated the capability of AB928 to shield CAR T cells from adenosine-mediated signalling. The effect of orally administered AB928 on CAR T cells was assessed in a syngeneic mouse model of colon carcinoma.

Results
We found that immunosuppressive signalling in CAR T cells in response to adenosine was fully blocked by the small molecule inhibitor. AB928 treatment enhanced CAR T cell cytokine secretion and proliferation, granted efficient cytolysis of tumour cells in vitro and augmented CAR T cell activation in vivo.

Conclusions
Together our results suggest that combination therapy with AB928 represents a promising approach to improve adoptive cell therapy.
Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development
Authors: Madden Stephen F. , Cremona Mattia , Farrelly Angela M. , Low Weng Hei , McBryan Jean 
Published: October 2022

AbstractTo prevent the development of endocrine-resistant breast cancer, additional targeted therapies are increasingly being trialled in combination with endocrine therapy. The molecular mechanisms facilitating cancer cell survival during endocrine treatment remain unknown but could help direct selection of additional targeted therapies. We present a novel proteomic timecourse dataset, profiling potential drug targets in a population of MCF7 cells during 1 year of tamoxifen treatment. Reverse phase protein arrays profiled >70 proteins across 30 timepoints. A biphasic response to tamoxifen was evident, which coincided with changes in growth rate. Tamoxifen strongly impeded cell growth for the first 160 days, followed by gradual growth recovery and eventual resistance development. The growth-impeded phase was distinguished by the phosphorylation of Stat3 (y705) and Src (y527). Tumour tissue from patients treated with neo-adjuvant endocrine therapy (<4 months) also displayed increased Stat3 and Src signalling. Inhibitors of Stat3 (napabucasin) and Src (dasatinib), were effective at killing tamoxifen-treated MCF7 and T47D cells. Sensitivity to both drugs was significantly enhanced once tamoxifen had induced the growth-impeded phase. This novel proteomic resource identifies key mechanisms enabling cell survival during tamoxifen treatment. It provides valuable insight into potential drug combinations and timing that may prevent the development of endocrine resistance.
Pyruvate carboxylase promotes malignant transformation of papillary thyroid carcinoma and reduces iodine uptake
Authors: Liu Yang , Liu Chang , Pan Yu , Zhou Jinxin , Ju Huijun , Zhang Yifan 
Published: October 2022

AbstractPrevious studies have shown that pyruvate carboxylase (PC) plays a key role in the occurrence and progression of thyroid cancer (TC); however, the relationship between PC and iodine-refractory TC is unclear. Therefore, the present study aimed to investigate the molecular mechanism of PC in the malignant progression and loss of iodine uptake in papillary TC (PTC) and to explore the potential therapeutic effect of PC inhibitors in iodine-refractory PTC. PC increased cell proliferation, invasion, and metastasis, inhibited expression of the iodine metabolism-related genes TSHR, NIS, TPO, and TG, and decreased the iodine-uptake capacity by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway in PTC cell lines. Furthermore, the PC inhibitor ZY-444 effectively inhibited the activation of PC, reduced the malignant invasiveness, and restored the expression of iodine metabolism-related genes and the iodine-uptake capacity in PTC cells. These findings suggest that PC activation is involved in the progression of iodine-refractory TC and that PC inhibitors may represent a potentially novel targeted therapy for iodine-refractory TC.
Technology readiness levels for machine learning systems
Authors: Lavin Alexander , Gilligan-Lee Ciarán M. , Visnjic Alessya , Ganju Siddha , Newman Dava , Ganguly Sujoy , Lange Danny , Baydin Atílím Güneş , Sharma Amit , Gibson Adam , Zheng Stephan , Xing Eric P. , Mattmann Chris , Parr James , Gal Yarin 
Published: October 2022

AbstractThe development and deployment of machine learning systems can be executed easily with modern tools, but the process is typically rushed and means-to-an-end. Lack of diligence can lead to technical debt, scope creep and misaligned objectives, model misuse and failures, and expensive consequences. Engineering systems, on the other hand, follow well-defined processes and testing standards to streamline development for high-quality, reliable results. The extreme is spacecraft systems, with mission critical measures and robustness throughout the process. Drawing on experience in both spacecraft engineering and machine learning (research through product across domain areas), we’ve developed a proven systems engineering approach for machine learning and artificial intelligence: the Machine Learning Technology Readiness Levels framework defines a principled process to ensure robust, reliable, and responsible systems while being streamlined for machine learning workflows, including key distinctions from traditional software engineering, and a lingua franca for people across teams and organizations to work collaboratively on machine learning and artificial intelligence technologies. Here we describe the framework and elucidate with use-cases from physics research to computer vision apps to medical diagnostics.
Incorporating social knowledge structures into computational models
Authors: Frolichs Koen M. M. , Rosenblau Gabriela , Korn Christoph W. 
Published: October 2022

AbstractTo navigate social interactions successfully, humans need to continuously learn about the personality traits of other people (e.g., how helpful or aggressive is the other person?). However, formal models that capture the complexities of social learning processes are currently lacking. In this study, we specify and test potential strategies that humans can employ for learning about others. Standard Rescorla-Wagner (RW) learning models only capture parts of the learning process because they neglect inherent knowledge structures and omit previously acquired knowledge. We therefore formalize two social knowledge structures and implement them in hybrid RW models to test their usefulness across multiple social learning tasks. We name these concepts granularity (knowledge structures about personality traits that can be utilized at different levels of detail during learning) and reference points (previous knowledge formalized into representations of average people within a social group). In five behavioural experiments, results from model comparisons and statistical analyses indicate that participants efficiently combine the concepts of granularity and reference points—with the specific combinations in models depending on the people and traits that participants learned about. Overall, our experiments demonstrate that variants of RW algorithms, which incorporate social knowledge structures, describe crucial aspects of the dynamics at play when people interact with each other.
Dynamical control of quantum heat engines using exceptional points
Authors: Zhang J.-W. , Zhang J.-Q. , Ding G.-Y. , Li J.-C. , Bu J.-T. , Wang B. , Yan L.-L. , Su S.-L. , Chen L. , Nori F. , Özdemir Ş. K. , Zhou F. , Jing H. , Feng M. 
Published: October 2022

AbstractA quantum thermal machine is an open quantum system coupled to hot and cold thermal baths. Thus, its dynamics can be well understood using the concepts and tools from non-Hermitian quantum systems. A hallmark of non-Hermiticity is the existence of exceptional points where the eigenvalues of a non-Hermitian Hamiltonian or a Liouvillian superoperator and their associated eigenvectors coalesce. Here, we report the experimental realization of a single-ion heat engine and demonstrate the effect of Liouvillian exceptional points on the dynamics and the performance of a quantum heat engine. Our experiments have revealed that operating the engine in the exact- and broken-phases, separated by a Liouvillian exceptional point, respectively during the isochoric heating and cooling strokes of an Otto cycle produces more work and output power and achieves higher efficiency than executing the Otto cycle completely in the exact phase where the system has an oscillatory dynamics and higher coherence. This result opens interesting possibilities for the control of quantum heat engines and will be of interest to other research areas that are concerned with the role of coherence and exceptional points in quantum processes and in work extraction by thermal machines.
p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition
Authors: Murai Kasumi , Dentro Stefan , Ong Swee Hoe , Sood Roshan , Fernandez-Antoran David , Herms Albert , Kostiou Vasiliki , Abnizova Irina , Hall Benjamin A. , Gerstung Moritz , Jones Philip H. 
Published: October 2022

AbstractAging normal human oesophagus accumulates TP53 mutant clones. These are the origin of most oesophageal squamous carcinomas, in which biallelic TP53 disruption is almost universal. However, how p53 mutant clones expand and contribute to cancer development is unclear. Here we show that inducing the p53R245W mutant in single oesophageal progenitor cells in transgenic mice confers a proliferative advantage and clonal expansion but does not disrupt normal epithelial structure. Loss of the remaining p53 allele in mutant cells results in genomically unstable p53R245W/null epithelium with giant polyaneuploid cells and copy number altered clones. In carcinogenesis, p53 mutation does not initiate tumour formation, but tumours developing from areas with p53 mutation and LOH are larger and show extensive chromosomal instability compared to lesions arising in wild type epithelium. We conclude that p53 has distinct functions at different stages of carcinogenesis and that LOH within p53 mutant clones in normal epithelium is a critical step in malignant transformation.
Hemisphere-specific spatial representation by hippocampal granule cells
Authors: Cholvin Thibault , Bartos Marlene 
Published: October 2022

AbstractThe dentate gyrus (DG) output plays a key role in the emergence of spatial and contextual map representation within the hippocampus during learning. Differences in neuronal network activity have been observed between left and right CA1-3 areas, implying lateralization in spatial coding properties. Whether bilateral differences of DG granule cell (GC) assemblies encoding spatial and contextual information exist remains largely unexplored. Here, we employed two-photon calcium imaging of the left or the right DG to record the activity of GC populations over five consecutive days in head-fixed mice navigating through familiar and novel virtual environments. Imaging revealed similar mean GC activity on both sides. However, spatial tuning, context-selectivity and run-to-run place field reliability was markedly higher for DG place cells in the left than the right hemisphere. Moreover, the proportion of GCs reconfiguring their place fields between contexts was greater in the left DG. Thus, our data suggest that contextual information is differentially processed by GC populations depending on the hemisphere, with higher context discrimination in the left but a bias towards generalization in the right DG.
Cryogenic contrast-enhanced microCT enables nondestructive 3D quantitative histopathology of soft biological tissues
Authors: Maes Arne , Pestiaux Camille , Marino Alice , Balcaen Tim , Leyssens Lisa , Vangrunderbeeck Sarah , Pyka Grzegorz , De Borggraeve Wim M. , Bertrand Luc , Beauloye Christophe , Horman Sandrine , Wevers Martine , Kerckhofs Greet 
Published: October 2022

AbstractBiological tissues comprise a spatially complex structure, composition and organization at the microscale, named the microstructure. Given the close structure-function relationships in tissues, structural characterization is essential to fully understand the functioning of healthy and pathological tissues, as well as the impact of possible treatments. Here, we present a nondestructive imaging approach to perform quantitative 3D histo(patho)logy of biological tissues, termed Cryogenic Contrast-Enhanced MicroCT (cryo-CECT). By combining sample staining, using an X-ray contrast-enhancing staining agent, with freezing the sample at the optimal freezing rate, cryo-CECT enables 3D visualization and structural analysis of individual tissue constituents, such as muscle and collagen fibers. We applied cryo-CECT on murine hearts subjected to pressure overload following transverse aortic constriction surgery. Cryo-CECT allowed to analyze, in an unprecedented manner, the orientation and diameter of the individual muscle fibers in the entire heart, as well as the 3D localization of fibrotic regions within the myocardial layers. We foresee further applications of cryo-CECT in the optimization of tissue/food preservation and donor banking, showing that cryo-CECT also has clinical and industrial potential.
Role of mucus-bacteria interactions in Enterotoxigenic Escherichia coli (ETEC) H10407 virulence and interplay with human microbiome
Authors: Sauvaitre Thomas , Van Landuyt Josefien , Durif Claude , Roussel Charlène , Sivignon Adeline , Chalancon Sandrine , Uriot Ophélie , Van Herreweghen Florence , Van de Wiele Tom , Etienne-Mesmin Lucie , Blanquet-Diot Stéphanie 
Published: October 2022

AbstractThe intestinal mucus layer has a dual role in human health constituting a well-known microbial niche that supports gut microbiota maintenance but also acting as a physical barrier against enteric pathogens. Enterotoxigenic Escherichia coli (ETEC), the major agent responsible for traveler’s diarrhea, is able to bind and degrade intestinal mucins, representing an important but understudied virulent trait of the pathogen. Using a set of complementary in vitro approaches simulating the human digestive environment, this study aimed to describe how the mucus microenvironment could shape different aspects of the human ETEC strain H10407 pathophysiology, namely its survival, adhesion, virulence gene expression, interleukin-8 induction and interactions with human fecal microbiota. Using the TNO gastrointestinal model (TIM-1) simulating the physicochemical conditions of the human upper gastrointestinal (GI) tract, we reported that mucus secretion and physical surface sustained ETEC survival, probably by helping it to face GI stresses. When integrating the host part in Caco2/HT29-MTX co-culture model, we demonstrated that mucus secreting-cells favored ETEC adhesion and virulence gene expression, but did not impede ETEC Interleukin-8 (IL-8) induction. Furthermore, we proved that mucosal surface did not favor ETEC colonization in a complex gut microbial background simulated in batch fecal experiments. However, the mucus-specific microbiota was widely modified upon the ETEC challenge suggesting its role in the pathogen infectious cycle. Using multi-targeted in vitro approaches, this study supports the major role played by mucus in ETEC pathophysiology, opening avenues in the design of new treatment strategies.
Micropattern-based nerve guidance conduit with hundreds of microchannels and stem cell recruitment for nerve regeneration
Authors: Park DoYeun , Kim Donghak , Park Su Jeong , Choi Jeong Ho , Seo Yoojin , Kim Dong-Hwee , Lee Sang-Hoon , Hyun Jung Keun , Yoo Jin , Jung Youngmee , Kim Soo Hyun 
Published: October 2022

AbstractGuiding the regrowth of thousands of nerve fibers within a regeneration-friendly environment enhances the regeneration capacity in the case of peripheral nerve injury (PNI) and spinal cord injury (SCI). Although clinical treatments are available and several studies have been conducted, the development of nerve guidance conduits (NGCs) with desirable properties, including controllable size, hundreds of nerve bundle-sized microchannels, and host stem-cell recruitment, remains challenging. In this study, the micropattern-based fabrication method was combined with stem-cell recruitment factor (substance P, SP) immobilization onto the main material to produce a size-tunable NGC with hundreds of microchannels with stem-cell recruitment capability. The SP-immobilized multiple microchannels aligned the regrowth of nerve fibers and recruited the host stem cells, which enhanced the functional regeneration capacity. This method has wide applicability in the modification and augmentation of NGCs, such as bifurcated morphology or directional topographies on microchannels. Additional improvements in fabrication will advance the regeneration technology and improve the treatment of PNI/SCI.