bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia
Authors: Baran Natalia , Lodi Alessia , Dhungana Yogesh , Herbrich Shelley , Collins Meghan , Sweeney Shannon , Pandey Renu , Skwarska Anna , Patel Shraddha , Tremblay Mathieu , Kuruvilla Vinitha Mary , Cavazos Antonio , Kaplan Mecit , Warmoes Marc O. , Veiga Diogo Troggian , Furudate Ken , Rojas-Sutterin Shanti , Haman Andre , Gareau Yves , Marinier Anne , Ma Helen , Harutyunyan Karine , Daher May , Garcia Luciana Melo , Al-Atrash Gheath , Piya Sujan , Ruvolo Vivian , Yang Wentao , Shanmugavelandy Sriram Saravanan , Feng Ningping , Gay Jason , Du Di , Yang Jun J. , Hoff Fieke W. , Kaminski Marcin , Tomczak Katarzyna , Eric Davis R. , Herranz Daniel , Ferrando Adolfo , Jabbour Elias J. , Emilia Di Francesco M. , Teachey David T. , Horton Terzah M. , Kornblau Steven , Rezvani Katayoun , Sauvageau Guy , Gagea Mihai , Andreeff Michael , Takahashi Koichi , Marszalek Joseph R. , Lorenzi Philip L. , Yu Jiyang , Tiziani Stefano , Hoang Trang , Konopleva Marina 
Published: May 2022

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.
Structural insights into the mechanism of pancreatic KATP channel regulation by nucleotides
Authors: Wang Mengmeng , Wu Jing-Xiang , Ding Dian , Chen Lei 
Published: May 2022

AbstractATP-sensitive potassium channels (KATP) are metabolic sensors that convert the intracellular ATP/ADP ratio to the excitability of cells. They are involved in many physiological processes and implicated in several human diseases. Here we present the cryo-EM structures of the pancreatic KATP channel in both the closed state and the pre-open state, resolved in the same sample. We observe the binding of nucleotides at the inhibitory sites of the Kir6.2 channel in the closed but not in the pre-open state. Structural comparisons reveal the mechanism for ATP inhibition and Mg-ADP activation, two fundamental properties of KATP channels. Moreover, the structures also uncover the activation mechanism of diazoxide-type KATP openers.
The ubiquitin ligase Cul5 regulates CD4+ T cell fate choice and allergic inflammation
Authors: Kumar Binod , Field Natania S. , Kim Dale D. , Dar Asif A. , Chen Yanqun , Suresh Aishwarya , Pastore Christopher F. , Hung Li-Yin , Porter Nadia , Sawada Keisuke , Shah Palak , Elbulok Omar , Moser Emily K. , Herbert De’Broski R. , Oliver Paula M. 
Published: May 2022

AbstractAntigen encounter directs CD4+ T cells to differentiate into T helper or regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern T helper cell versus T regulatory cell fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4+ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells develop Th2 and Th9 inflammation and show pathophysiological features of atopic asthma. Following T cell activation, Cul5 forms a complex with CIS and pJak1. Cul5 deletion reduces ubiquitination and subsequent degradation of pJak1, leading to an increase in pJak1 and pSTAT6 levels and reducing the threshold of IL-4 receptor signaling. As a consequence, Cul5 deficient CD4+ T cells deviate from Treg to Th9 differentiation in low IL-4 conditions. These data support the notion that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma.
PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression
Authors: Lee Keun-Woo , Yeo So-Young , Gong Jeong-Ryeol , Koo Ok-Jae , Sohn Insuk , Lee Woo Yong , Kim Hee Cheol , Yun Seong Hyeon , Cho Yong Beom , Choi Mi-Ae , An Sugyun , Kim Juhee , Sung Chang Ohk , Cho Kwang-Hyun , Kim Seok-Hyung 
Published: May 2022

AbstractAlthough stromal fibroblasts play a critical role in cancer progression, their identities remain unclear as they exhibit high heterogeneity and plasticity. Here, a master transcription factor (mTF) constructing core-regulatory circuitry, PRRX1, which determines the fibroblast lineage with a myofibroblastic phenotype, is identified for the fibroblast subgroup. PRRX1 orchestrates the functional drift of fibroblasts into myofibroblastic phenotype via TGF-β signaling by remodeling a super-enhancer landscape. Such reprogrammed fibroblasts have myofibroblastic functions resulting in markedly enhanced tumorigenicity and aggressiveness of cancer. PRRX1 expression in cancer-associated fibroblast (CAF) has an unfavorable prognosis in multiple cancer types. Fibroblast-specific PRRX1 depletion induces long-term and sustained complete remission of chemotherapy-resistant cancer in genetically engineered mice models. This study reveals CAF subpopulations based on super-enhancer profiles including PRRX1. Therefore, mTFs, including PRRX1, provide another opportunity for establishing a hierarchical classification system of fibroblasts and cancer treatment by targeting fibroblasts.
Anomalous size effect on yield strength enabled by compositional heterogeneity in high-entropy alloy nanoparticles
Authors: Yan Jingyuan , Yin Sheng , Asta Mark , Ritchie Robert O. , Ding Jun , Yu Qian 
Published: May 2022

AbstractHigh-entropy alloys (HEAs), although often presumed to be random solid solutions, have recently been shown to display nanometer-scale variations in the arrangements of their multiple chemical elements. Here, we study the effects of this compositional heterogeneity in HEAs on their mechanical properties using in situ compression testing in the transmission electron microscope (TEM), combined with molecular dynamics simulations. We report an anomalous size effect on the yield strength in HEAs, arising from such compositional heterogeneity. By progressively reducing the sample size, HEAs initially display the classical “smaller-is-stronger” phenomenon, similar to pure metals and conventional alloys. However, as the sample size is decreased below a critical characteristic length (~180 nm), influenced by the size-scale of compositional heterogeneity, a transition from homogeneous deformation to a heterogeneous distribution of planar slip is observed, coupled with an anomalous “smaller-is-weaker” size effect. Atomic-scale computational modeling shows these observations arise due to compositional fluctuations over a few nanometers. These results demonstrate the efficacy of influencing mechanical properties in HEAs through control of local compositional variations at the nanoscale.
High-performance photocatalytic nonoxidative conversion of methane to ethane and hydrogen by heteroatoms-engineered TiO2
Authors: Zhang Wenqing , Fu Cenfeng , Low Jingxiang , Duan Delong , Ma Jun , Jiang Wenbin , Chen Yihong , Liu Hengjie , Qi Zeming , Long Ran , Yao Yingfang , Li Xiaobao , Zhang Hui , Liu Zhi , Yang Jinlong , Zou Zhigang , Xiong Yujie 
Published: May 2022

AbstractNonoxidative coupling of methane (NOCM) is a highly important process to simultaneously produce multicarbons and hydrogen. Although oxide-based photocatalysis opens opportunities for NOCM at mild condition, it suffers from unsatisfying selectivity and durability, due to overoxidation of CH4 with lattice oxygen. Here, we propose a heteroatom engineering strategy for highly active, selective and durable photocatalytic NOCM. Demonstrated by commonly used TiO2 photocatalyst, construction of Pd–O4 in surface reduces contribution of O sites to valence band, overcoming the limitations. In contrast to state of the art, 94.3% selectivity is achieved for C2H6 production at 0.91 mmol g–1 h–1 along with stoichiometric H2 production, approaching the level of thermocatalysis at relatively mild condition. As a benchmark, apparent quantum efficiency reaches 3.05% at 350 nm. Further elemental doping can elevate durability over 24 h by stabilizing lattice oxygen. This work provides new insights for high-performance photocatalytic NOCM by atomic engineering.
DVL1 and DVL3 require nuclear localisation to regulate proliferation in human myoblasts
Authors: Pruller Johanna , Figeac Nicolas , Zammit Peter S. 
Published: May 2022

AbstractWNT signalling is essential for regulating a diverse range of cellular processes. In skeletal muscle, the WNT pathway plays crucial roles in maintenance of the stem cell pool and myogenic differentiation. Focus is usually directed at examining the function of central components of the WNT pathway, including β-CATENIN and the GSK3β complex and TCF/LEF transcription factors, in tissue homeostasis and cancer. Other core components of the WNT pathway though, are three dishevelled (DVL) proteins: membrane associated proteins that propagate WNT signalling from membrane to nucleus. Here we examined DVL function in human myogenesis and the muscle-related cancer alveolar rhabdomyosarcoma. We demonstrate that DVL1 and DVL3 are necessary for efficient proliferation in human myoblasts and are important for timely myogenic differentiation. DVL1 and DVL3 also contribute to regulation of proliferation in rhabdomyosarcoma. DVL1 or DVL3 must be present in the nucleus to regulate proliferation, but they operate through different protein domains: DVL3 requires the DIX and PDZ domains, while DVL1 does not. Importantly, DVL1 and DVL3 activity is independent of markedly increased translocation of β-CATENIN to the nucleus, normally a hallmark of active canonical WNT signalling.
Preprocess dependence of optical properties of ensembles and single siphonaxanthin-containing major antenna from the marine green alga Codium fragile
Authors: Brotosudarmo Tatas Hardo Panintingjati , Wittmann Bernd , Seki Soichiro , Fujii Ritsuko , Köhler Jürgen 
Published: May 2022

AbstractThe siphonaxanthin-siphonein-Chl-a/b-protein (SCP) is the light-harvesting complex of the marine alga Codium fragile. Its structure resembles that of the major light-harvesting complexes of higher plants, LHC II, yet it features a reversed Chl a:Chl b ratio and it accommodates other variants of carotenoids. We have recorded the fluorescence emission spectra and fluorescence lifetimes from ensembles and single SCP complexes for three different scenarios of handling the samples. While the data obtained from ensembles of SCP complexes yield equivalent results, those obtained from single SCP complexes featured significant differences as a function of the sample history. We ascribe this discrepancy to the different excitation intensities that have been used for ensemble and single complex spectroscopy, and conclude that the SCP complexes undergo an aging process during storage. This process is manifested as a lowering of energetic barriers within the protein, enabling thermal activation of conformational changes at room temperature. This in turn leads to the preferential population of a red-shifted state that features a significant decrease of the fluorescence lifetime.
Freshwater influx to the Eastern Mediterranean Sea from the melting of the Fennoscandian ice sheet during the last deglaciation
Authors: Vadsaria Tristan , Zaragosi Sébastien , Ramstein Gilles , Dutay Jean-Claude , Li Laurent , Siani Giuseppe , Revel Marie , Obase Takashi , Abe-Ouchi Ayako 
Published: May 2022

AbstractBetween the Last Glacial Maximum and the mid-Holocene, the Mediterranean Sea experienced major hydrological changes. The deposition of the last sapropel, S1, during the Early Holocene is a consequence of these changes. In order to cause anoxia in the Eastern Mediterranean Sea (EMS) bottom water, a long preconditioning period of a few thousand years would need to occur throughout the deglaciation prior to S1. It is generally believed that this freshwater was of North Atlantic origin, later supplemented by the African Humid period (AHP). Here, we investigate another potentially important source of freshwater to the EMS: the Fennoscandian ice sheet (FIS) meltwater, running into the Caspian and Black Seas. A few scenarios of continental hydrologic perturbation have been developed to drive a high-resolution Mediterranean Sea general circulation model. We demonstrate that, during the last deglaciation, FIS meltwater flowing into the Black Sea reduced surface salinity and ventilation over the main convection areas in the EMS. By including continental hydrological changes, a more consistent framework is produced to characterize the hydrology of the Mediterranean Sea during the last deglaciation and the Early Holocene.
Vibration velocity and frequency characteristics of surrounding rock of adjacent tunnel under blasting excavation
Authors: Luo Yi , Gong Hangli , Qu Dengxing , Zhang Xueping , Tao Yuhang , Li Xinping 
Published: May 2022

AbstractThe aim of this study is to improve the accuracy of response prediction and safety evaluation of blasting vibration of a deeply-buried tunnel group. For this purpose, the expression of frequency-domain and blasting vibration velocity spectra for the equivalent blasting load in multiple holes was derived through theoretical analysis, and propagation and attenuation of the primary frequency of blasting vibration of multiple cutting holes and caving holes in the infinite rock mass were explored. Response characteristics of vibration frequency spectra in rock surrounding of the adjacent tunnel induced by full-section blasting excavation of the tunnel under the high in situ stress were studied using the dynamic finite element method. The research indicates that blasting vibration waves have the greatest influences on the adjacent tunnel at the haunch in the side facing the blasting, where the vibration velocity is inversely proportional to the spacing between tunnels and directly proportional to the tunnel diameter. The centroid frequency increases with the increase of the spacing between tunnels and tunnel diameter. Furthermore, vibration velocity spectra at the most affected location (namely the haunch) in the side facing blasting of the adjacent tunnel under different conditions were derived. The coincidence of the theoretical formula was verified by comparing measured data of blasting of diversion tunnels in Pubugou Hydropower Station (Sichuan Province, China). The research results can provide theoretical guidance and reference for the prediction of blasting vibration response of similar projects in the future.
Structure-guided affinity maturation of a novel human antibody targeting the SARS-CoV-2 nucleocapsid protein
Authors: Wang Zhihong , Hu Naijing , Zhou Yangyihua , Shi Ning , Shen Beifen , Luo Longlong , Feng Jiannan 
Published: May 2022

AbstractThe continuous mutation of SARS-CoV-2 has presented enormous challenges to global pandemic prevention and control. Recent studies have shown evidence that the genome sequence of SARS-CoV-2 nucleocapsid proteins is relatively conserved, and their biological functions are being confirmed. There is increasing evidence that the N protein will not only provide a specific diagnostic marker but also become an effective treatment target. In this study, 2G4, which specifically recognizes the N protein, was identified by screening a human phage display library. Based on the computer-guided homology modelling and molecular docking method used, the 3-D structures for the 2G4 scFv fragment (VH-linker-VL structure, with (G4S)3 as the linker peptide in the model), SARS-CoV-2 N protein and its complex were modelled and optimized with a suitable force field. The binding mode and key residues of the 2G4 and N protein interaction were predicted, and three mutant antibodies (named 2G4-M1, 2G4-M2 and 2G4-M3) with higher affinity were designed theoretically. Using directed point mutant technology, the three mutant antibodies were prepared, and their affinity was tested. Their affinity constants of approximately 0.19 nM (2G4-M1), 0.019 nM (2G4-M2) and 0.075 nM (2G4-M3) were at least one order of magnitude lower than that of the parent antibody (3 nM; 2G4, parent antibody), as determined using a biolayer interferometry (BLI) assay. It is expected that high-affinity candidates will be used for diagnosis and even as potential therapeutic drugs for the SARS-CoV-2 pandemic.
Anxiety among pregnant women during the first wave of the COVID-19 pandemic in Poland
Authors: Ilska Michalina , Brandt-Salmeri Anna , Kołodziej-Zaleska Anna , Preis Heidi , Rehbein Emily , Lobel Marci 
Published: May 2022

AbstractAlthough anxiety is common because of the transitional nature of the perinatal period, particularly high levels of anxiety have been observed in some studies of pregnant women during the pandemic. The purpose of this study was to evaluate the severity of anxiety among pregnant women during the first wave of the COVID-19 pandemic in Poland, and factors associated with it. Cross-sectional study with a total of 1050 pregnant women recruited via social media in Poland during the first wave of the COVID-19 pandemic, from March 1 until June 1, 2020. The survey included validated psychological measures: the GAD-7 (anxiety), the PREPS (pandemic stress), with two subscales: preparedness and infection stress, and obstetric, sociodemographic and COVID-19 related variables. T-tests, ANOVAs, and hierarchical binary logistic regression for dichotomized GAD-7 scores (minimal or mild vs. moderate or severe) were used. Over a third of respondents experienced moderate or severe levels of anxiety. Predictors of moderate or severe anxiety were non-pandemic related factors like unplanned pregnancy and emotional and psychiatric problems, as well as pandemic related pregnancy stress. Levels of anxiety among pregnant women during the first wave of the COVID-19 pandemic in Poland exceeded pre-pandemic norms. Findings suggest that prior psychiatric conditions, unplanned pregnancy, and elevated pandemic-related pregnancy stress due to concerns about infection or poor preparation for birth contributed to the risk of high anxiety in Polish pregnant women during the pandemic onset. Given the harmful effects of antenatal anxiety on the health and well-being of mothers and their children, psychotherapeutic interventions, efforts to alleviate pregnant women’s stress, and training in adaptive ways to cope with stress are vital to reduce the prevalence of maternal anxiety and its potential consequences during this global crisis.
In silico assessment of electrophysiological neuronal recordings mediated by magnetoelectric nanoparticles
Authors: Bok Ilhan , Haber Ido , Qu Xiaofei , Hai Aviad 
Published: May 2022

AbstractMagnetoelectric materials hold untapped potential to revolutionize biomedical technologies. Sensing of biophysical processes in the brain is a particularly attractive application, with the prospect of using magnetoelectric nanoparticles (MENPs) as injectable agents for rapid brain-wide modulation and recording. Recent studies have demonstrated wireless brain stimulation in vivo using MENPs synthesized from cobalt ferrite (CFO) cores coated with piezoelectric barium titanate (BTO) shells. CFO–BTO core–shell MENPs have a relatively high magnetoelectric coefficient and have been proposed for direct magnetic particle imaging (MPI) of brain electrophysiology. However, the feasibility of acquiring such readouts has not been demonstrated or methodically quantified. Here we present the results of implementing a strain-based finite element magnetoelectric model of CFO–BTO core–shell MENPs and apply the model to quantify magnetization in response to neural electric fields. We use the model to determine optimal MENPs-mediated electrophysiological readouts both at the single neuron level and for MENPs diffusing in bulk neural tissue for in vivo scenarios. Our results lay the groundwork for MENP recording of electrophysiological signals and provide a broad analytical infrastructure to validate MENPs for biomedical applications.
Neuro-molecular characterization of fish cleaning interactions
Authors: Ramírez-Calero S. , Paula J. R. , Otjacques E. , Rosa R. , Ravasi T. , Schunter C. 
Published: May 2022

AbstractCoral reef fish exhibit a large variety of behaviours crucial for fitness and survival. The cleaner wrasseLabroides dimidiatusdisplays cognitive abilities during interspecific interactions by providing services of ectoparasite cleaning, thus serving as a good example to understand the processes of complex social behaviour. However, little is known about the molecular underpinnings of cooperative behaviour betweenL. dimidiatusand a potential client fish (Acanthurus leucosternon). Therefore, we investigated the molecular mechanisms in three regions of the brain (Fore-, Mid-, and Hindbrain) during the interaction of these fishes. Here we show, using transcriptomics, that most of the transcriptional response in both species was regulated in the Hindbrain and Forebrain regions and that the interacting behaviour responses ofL. dimidiatusinvolved immediate early gene alteration, dopaminergic and glutamatergic pathways, the expression of neurohormones (such as isotocin) and steroids (e.g. progesterone and estrogen). In contrast, in the client, fewer molecular alterations were found, mostly involving pituitary hormone responses. The particular pathways found suggested synaptic plasticity, learning and memory processes in the cleaner wrasse, while the client indicated stress relief.
Combined treatment of graft versus host disease using donor regulatory T cells and ruxolitinib
Authors: Rodríguez-Gil Alfonso , Escamilla-Gómez Virginia , Nufer Melanie , Andújar-Sánchez Félix , Lopes-Ramos Teresa , Bejarano-García José Antonio , García-Guerrero Estefanía , Calderón-Cabrera Cristina , Caballero-Velázquez Teresa , García-Calderón Clara Beatriz , Hernández-Díaz Paola , Reguera-Ortega Juan Luis , Rodríguez-Torres Nancy , Martínez-Cibrián Nuria , Rodríguez-Barbosa José Ignacio , Villadiego Javier , Pérez-Simón José Antonio 
Published: May 2022

AbstractDonor derived regulatory T lymphocytes and the JAK1/2 kinase inhibitor ruxolitinib are currently being evaluated as therapeutic options in the treatment of chronic graft versus host disease (cGvHD). In this work, we aimed to determine if the combined use of both agents can exert a synergistic effect in the treatment of GvHD. For this purpose, we studied the effect of this combination both in vitro and in a GvHD mouse model. Our results show that ruxolitinib favors the ratio of thymic regulatory T cells to conventional T cells in culture, without affecting the suppressive capacity of these Treg. The combination of ruxolitinib with Treg showed a higher efficacy as compared to each single treatment alone in our GvHD mouse model in terms of GvHD incidence, severity and survival without hampering graft versus leukemia effect. This beneficial effect correlated with the detection in the bone marrow of recipient mice of the infused donor allogeneic Treg after the adoptive transfer.