bluuebunny/crossref_metadata_2025_split huggingface dataset:
LIMP-2 enhances cancer stem-like cell properties by promoting autophagy-induced GSK3β degradation in head and neck squamous cell carcinoma
Authors: Liu Yuantong , Li Shujin , Wang Shuo , Yang Qichao , Wu Zhizhong , Zhang Mengjie , Chen Lei , Sun Zhijun 
Published: June 2023

AbstractCancer stem cell-like cells (CSCs) play an integral role in the heterogeneity, metastasis, and treatment resistance of head and neck squamous cell carcinoma (HNSCC) due to their high tumor initiation capacity and plasticity. Here, we identified a candidate gene named LIMP-2 as a novel therapeutic target regulating HNSCC progression and CSC properties. The high expression of LIMP-2 in HNSCC patients suggested a poor prognosis and potential immunotherapy resistance. Functionally, LIMP-2 can facilitate autolysosome formation to promote autophagic flux. LIMP-2 knockdown inhibits autophagic flux and reduces the tumorigenic ability of HNSCC. Further mechanistic studies suggest that enhanced autophagy helps HNSCC maintain stemness and promotes degradation of GSK3β, which in turn facilitates nuclear translocation of β-catenin and transcription of downstream target genes. In conclusion, this study reveals LIMP-2 as a novel prospective therapeutic target for HNSCC and provides evidence for a link between autophagy, CSC, and immunotherapy resistance.
Promotion effect of TGF-β-Zfp423-ApoD pathway on lip sensory recovery after nerve sacrifice caused by nerve collateral compensation
Authors: Ma Pingchuan , Zhang Gaowei , Chen Su , Miao Cheng , Cao Yubin , Wang Meng , Liu Wenwen , Shen Jiefei , Tang Patrick Ming-Kuen , Men Yi , Ye Li , Li Chunjie 
Published: June 2023

AbstractResection of oral and maxillofacial tumors is often accompanied by the inferior alveolar nerve neurectomy, resulting in abnormal sensation in lower lip. It is generally believed that spontaneous sensory recovery in this nerve injury is difficult. However, during our follow-up, patients with inferior alveolar nerve sacrifice showed different degrees of lower lip sensory recovery. In this study, a prospective cohort study was conducted to demonstrate this phenomenon and analyze the factors influencing sensory recovery. A mental nerve transection model of Thy1-YFP mice and tissue clearing technique were used to explore possible mechanisms in this process. Gene silencing and overexpression experiments were then conducted to detect the changes in cell morphology and molecular markers. In our follow-up, 75% of patients with unilateral inferior alveolar nerve neurectomy had complete sensory recovery of the lower lip 12 months postoperatively. Patients with younger age, malignant tumors, and preservation of ipsilateral buccal and lingual nerves had a shorter recovery time. The buccal nerve collateral sprouting compensation was observed in the lower lip tissue of Thy1-YFP mice. ApoD was demonstrated to be involved in axon growth and peripheral nerve sensory recovery in the animal model. TGF-β inhibited the expression of STAT3 and the transcription of ApoD in Schwann cells through Zfp423. Overall, after sacrificing the inferior alveolar nerve, the collateral compensation of the ipsilateral buccal nerve could innervate the sensation. And this process was regulated by TGF-β-Zfp423-ApoD pathway.
Mechanically resilient, alumina-reinforced carbon nanotube arrays for in-plane shock absorption in micromechanical devices
Authors: Jo Eunhwan , Lee Hojoon , Lee Jae-Ik , Kim Jongbaeg 
Published: June 2023

AbstractMicroelectromechanical systems (MEMS) are of considerable interest due to their compact size and low power consumption when used in modern electronics. MEMS devices intrinsically incorporate three-dimensional (3D) microstructures for their intended operations; however, these microstructures are easily broken by mechanical shocks accompanying high-magnitude transient acceleration, inducing device malfunction. Although various structural designs and materials have been proposed to overcome this limit, developing a shock absorber for easy integration into existing MEMS structures that effectively dissipates impact energy remains challenging. Here, a vertically aligned 3D nanocomposite based on ceramic-reinforced carbon nanotube (CNT) arrays is presented for in-plane shock-absorbing and energy dissipation around MEMS devices. This geometrically aligned composite consists of regionally-selective integrated CNT arrays and a subsequent atomically thick alumina layer coating, which serve as structural and reinforcing materials, respectively. The nanocomposite is integrated with the microstructure through a batch-fabrication process and remarkably improves the in-plane shock reliability of a designed movable structure over a wide acceleration range (0–12,000g). In addition, the enhanced shock reliability through the nanocomposite was experimentally verified through comparison with various control devices.
PPARδ inhibition blocks the induction and function of tumor-induced IL-10+ regulatory B cells and enhances cancer immunotherapy
Authors: Chen Chen , Ma Jianan , Pi Chenchen , Huang Wei , Zhang Tao , Fu Cong , Liu Wentao , Yang Yong-Guang 
Published: June 2023

AbstractIL-10+ regulatory B cells (Bregs) play a significant role in cancer immunotherapy and their presence is an indicator of negative outcome. We found that PPARδ is significantly upregulated in tumor-induced IL-10+ Bregs with a phenotype of CD19+CD24hiIgDlo/−CD38lo or CD19+CD24hiIgDlo/−CD38hi in both mice and humans, and the level of PPARδ expression was correlated with their potential to produce IL-10 and to inhibit T cell activation. Genetic inactivation of PPARδ in B cells impaired the development and function of IL-10+ B cells, and treatment with PPARδ inhibitor diminished the induction of IL-10+ Bregs by tumor and CD40 engagement. Importantly, immunotherapy with anti-CD40 or anti-PD1 antibody achieved a markedly improved outcome in tumor-bearing mice with PPARδ deficiency in B cells or treated with PPARδ inhibitor. This study shows that PPARδ is required for the development and function of IL-10+ Bregs, providing a new and effective target for selectively blocking Bregs and improving antitumor immunotherapy.
Structural insights into dimerization and activation of the mGlu2–mGlu3 and mGlu2–mGlu4 heterodimers
Authors: Wang Xinwei , Wang Mu , Xu Tuo , Feng Ye , Shao Qiang , Han Shuo , Chu Xiaojing , Xu Yechun , Lin Shuling , Zhao Qiang , Wu Beili 
Published: June 2023

AbstractHeterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2–mGlu3 and mGlu2–mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations. These structures provide a full picture of conformational rearrangement of mGlu2–mGlu3 upon activation. The Venus flytrap domains undergo a sequential conformational change, while the transmembrane domains exhibit a substantial rearrangement from an inactive, symmetric dimer with diverse dimerization patterns to an active, asymmetric dimer in a conserved dimerization mode. Combined with functional data, these structures reveal that stability of the inactive conformations of the subunits and the subunit–G protein interaction pattern are determinants of asymmetric signal transduction of the heterodimers. Furthermore, a novel binding site for two mGlu4 positive allosteric modulators was observed in the asymmetric dimer interfaces of the mGlu2–mGlu4 heterodimer and mGlu4 homodimer, and may serve as a drug recognition site. These findings greatly extend our knowledge about signal transduction of the mGlus.
Realistic phase diagram of water from “first principles” data-driven quantum simulations
Authors: Bore Sigbjørn Løland , Paesani Francesco 
Published: June 2023

AbstractSince the experimental characterization of the low-pressure region of water’s phase diagram in the early 1900s, scientists have been on a quest to understand the thermodynamic stability of ice polymorphs on the molecular level. In this study, we demonstrate that combining the MB-pol data-driven many-body potential for water, which was rigorously derived from “first principles” and exhibits chemical accuracy, with advanced enhanced-sampling algorithms, which correctly describe the quantum nature of molecular motion and thermodynamic equilibria, enables computer simulations of water’s phase diagram with an unprecedented level of realism. Besides providing fundamental insights into how enthalpic, entropic, and nuclear quantum effects shape the free-energy landscape of water, we demonstrate that recent progress in “first principles” data-driven simulations, which rigorously encode many-body molecular interactions, has opened the door to realistic computational studies of complex molecular systems, bridging the gap between experiments and simulations.
Identification of BRCA1/2 mutation female carriers using circulating microRNA profiles
Authors: Elias Kevin , Smyczynska Urszula , Stawiski Konrad , Nowicka Zuzanna , Webber James , Kaplan Jakub , Landen Charles , Lubinski Jan , Mukhopadhyay Asima , Chakraborty Dona , Connolly Denise C. , Symecko Heather , Domchek Susan M. , Garber Judy E. , Konstantinopoulos Panagiotis , Fendler Wojciech , Chowdhury Dipanjan 
Published: June 2023

AbstractIdentifying germlineBRCA1/2mutation carriers is vital for reducing their risk of breast and ovarian cancer. To derive a serum miRNA-based diagnostic test we used samples from 653 healthy women from six international cohorts, including 350 (53.6%) withBRCA1/2mutations and 303 (46.4%)BRCA1/2 wild-type. All individuals were cancer-free before and at least 12 months after sampling. RNA-sequencing followed by differential expression analysis identified 19 miRNAs significantly associated withBRCAmutations, 10 of which were ultimately used for classification: hsa-miR-20b-5p, hsa-miR-19b-3p, hsa-let-7b-5p, hsa-miR-320b, hsa-miR-139-3p, hsa-miR-30d-5p, hsa-miR-17-5p, hsa-miR-182-5p, hsa-miR-421, hsa-miR-375-3p. The final logistic regression model achieved area under the receiver operating characteristic curve 0.89 (95% CI: 0.87–0.93), 93.88% sensitivity and 80.72% specificity in an independent validation cohort. Mutated gene, menopausal status or having preemptive oophorectomy did not affect classification performance. Circulating microRNAs may be used to identifyBRCA1/2mutations in patients of high risk of cancer, offering an opportunity to reduce screening costs.
Quantitative constraints on flood variability in the rock record
Authors: McLeod Jonah S. , Wood James , Lyster Sinéad J. , Valenza Jeffery M. , Spencer Alan R. T. , Whittaker Alexander C. 
Published: June 2023

AbstractFloods determine river behaviour in time and space. Yet quantitative measures of discharge variability from geological stratigraphy are sparse, even though they are critical to understand landscape sensitivity to past and future environmental change. Here we show how storm-driven river floods in the geologic past can be quantified, using Carboniferous stratigraphy as an exemplar. The geometries of dune cross-sets demonstrate that discharge-driven disequilibrium dynamics dominated fluvial deposition in the Pennant Formation of South Wales. Based on bedform preservation theory, we quantify dune turnover timescales and hence the magnitude and duration of flow variability, showing that rivers were perennial but prone to flashy floods lasting 4–16 h. This disequilibrium bedform preservation is consistent across 4 Ma of stratigraphy, and coincides with facies-based markers of flooding, such as mass-preservation of woody debris. We suggest that it is now possible to quantify climate-driven sedimentation events in the geologic past, and reconstruct discharge variability from the rock record on a uniquely short (daily) timescale, revealing a formation dominated by flashy floods in perennial rivers.
Enhanced spin Seebeck effect via oxygen manipulation
Authors: Kim Jeong-Mok , Kim Seok-Jong , Kang Min-Gu , Choi Jong-Guk , Lee Soogil , Park Jaehyeon , Van Phuoc Cao , Kim Kyoung-Whan , Kim Kab-Jin , Jeong Jong-Ryul , Lee Kyung-Jin , Park Byong-Guk 
Published: June 2023

AbstractSpin Seebeck effect (SSE) refers to the generation of an electric voltage transverse to a temperature gradient via a magnon current. SSE offers the potential for efficient thermoelectric devices because the transverse geometry of SSE enables to utilize waste heat from a large-area source by greatly simplifying the device structure. However, SSE suffers from a low thermoelectric conversion efficiency that must be improved for widespread application. Here we show that the SSE substantially enhances by oxidizing a ferromagnet in normal metal/ferromagnet/oxide structures. In W/CoFeB/AlOx structures, voltage-induced interfacial oxidation of CoFeB modifies the SSE, resulting in the enhancement of thermoelectric signal by an order of magnitude. We describe a mechanism for the enhancement that results from a reduced exchange interaction of the oxidized region of ferromagnet, which in turn increases a temperature difference between magnons in the ferromagnet and electrons in the normal metal and/or a gradient of magnon chemical potential in the ferromagnet. Our result will invigorate research for thermoelectric conversion by suggesting a promising way of improving the SSE efficiency.
Uncovering the chiral bias of meteoritic isovaline through asymmetric photochemistry
Authors: Bocková Jana , Jones Nykola C. , Topin Jérémie , Hoffmann Søren V. , Meinert Cornelia 
Published: June 2023

AbstractSystematic enrichments of l-amino acids in meteorites is a strong indication that biological homochirality originated beyond Earth. Although still unresolved, stellar UV circularly polarized light (CPL) is the leading hypothesis to have caused the symmetry breaking in space. This involves the differential absorption of left- and right-CPL, a phenomenon called circular dichroism, which enables chiral discrimination. Here we unveil coherent chiroptical spectra of thin films of isovaline enantiomers, the first step towards asymmetric photolysis experiments using a tunable laser set-up. As analogues to amino acids adsorbed on interstellar dust grains, CPL-helicity dependent enantiomeric excesses of up to 2% were generated in isotropic racemic films of isovaline. The low efficiency of chirality transfer from broadband CPL to isovaline could explain why its enantiomeric excess is not detected in the most pristine chondrites. Notwithstanding, small, yet consistent l-biases induced by stellar CPL would have been crucial for its amplification during aqueous alteration of meteorite parent bodies.
Bioinspired engineering of fusogen and targeting moiety equipped nanovesicles
Authors: Wang Lixue , Wang Guosheng , Mao Wenjun , Chen Yundi , Rahman Md. Mofizur , Zhu Chuandong , Prisinzano Peter M. , Kong Bo , Wang Jing , Lee Luke P. , Wan Yuan 
Published: June 2023

AbstractCell-derived small extracellular vesicles have been exploited as potent drug vehicles. However, significant challenges hamper their clinical translation, including inefficient cytosolic delivery, poor target-specificity, low yield, and inconsistency in production. Here, we report a bioinspired material, engineered fusogen and targeting moiety co-functionalized cell-derived nanovesicle (CNV) called eFT-CNV, as a drug vehicle. We show that universal eFT-CNVs can be produced by extrusion of genetically modified donor cells with high yield and consistency. We demonstrate that bioinspired eFT-CNVs can efficiently and selectively bind to targets and trigger membrane fusion, fulfilling endo-lysosomal escape and cytosolic drug delivery. We find that, compared to counterparts, eFT-CNVs significantly improve the treatment efficacy of drugs acting on cytosolic targets. We believe that our bioinspired eFT-CNVs will be promising and powerful tools for nanomedicine and precision medicine.
DNA methyltransferase 1 deficiency improves macrophage motility and wound healing by ameliorating cholesterol accumulation
Authors: Zhao Chuanrong , Yang Qianru , Tang Runze , Li Wang , Wang Jin , Yang Fangfang , Zhao Jianan , Zhu Juanjuan , Pang Wei , Li Ning , Zhang Xu , Tian Xiao Yu , Yao Weijuan , Zhou Jing 
Published: June 2023

AbstractHealing of the cutaneous wound requires macrophage recruitment at the sites of injury, where chemotactic migration of macrophages toward the wound is regulated by local inflammation. Recent studies suggest a positive contribution of DNA methyltransferase 1 (Dnmt1) to macrophage pro-informatory responses; however, its role in regulating macrophage motility remains unknown. In this study, myeloid-specific depletion of Dnmt1 in mice promoted cutaneous wound healing and de-suppressed the lipopolysaccharides (LPS)-inhibited macrophage motility. Dnmt1 inhibition in macrophages eliminated the LPS-stimulated changes in cellular mechanical properties in terms of elasticity and viscoelasticity. LPS increased the cellular accumulation of cholesterol in a Dnmt1-depedent manner; cholesterol content determined cellular stiffness and motility. Lipidomic analysis indicated that Dnmt1 inhibition altered the cellular lipid homeostasis, probably through down-regulating the expression of cluster of differentiation 36 CD36 (facilitating lipid influx) and up-regulating the expression of ATP-binding cassette transporter ABCA1 (mediating lipid efflux) and sterol O-acyltransferase 1 SOAT1 (also named ACAT1, catalyzing the esterification of cholesterol). Our study revealed a Dnmt1-dependent epigenetic mechanism in the control of macrophage mechanical properties and the related chemotactic motility, indicating Dnmt1 as both a marker of diseases and a potential target of therapeutic intervention for wound healing.
Multiple timescales of learning indicated by changes in evidence-accumulation processes during perceptual decision-making
Authors: Cochrane Aaron , Sims Chris R. , Bejjanki Vikranth R. , Green C. Shawn , Bavelier Daphne 
Published: June 2023

AbstractEvidence accumulation models have enabled strong advances in our understanding of decision-making, yet their application to examining learning has not been common. Using data from participants completing a dynamic random dot-motion direction discrimination task across four days, we characterized alterations in two components of perceptual decision-making (Drift Diffusion Model drift rate and response boundary). Continuous-time learning models were applied to characterize trajectories of performance change, with different models allowing for varying dynamics. The best-fitting model included drift rate changing as a continuous, exponential function of cumulative trial number. In contrast, response boundary changed within each daily session, but in an independent manner across daily sessions. Our results highlight two different processes underlying the pattern of behavior observed across the entire learning trajectory, one involving a continuous tuning of perceptual sensitivity, and another more variable process describing participants’ threshold of when enough evidence is present to act.
A general method for the development of multicolor biosensors with large dynamic ranges
Authors: Hellweg Lars , Edenhofer Anna , Barck Lucas , Huppertz Magnus-Carsten , Frei Michelle. S. , Tarnawski Miroslaw , Bergner Andrea , Koch Birgit , Johnsson Kai , Hiblot Julien 
Published: June 2023

AbstractFluorescent biosensors enable the study of cell physiology with spatiotemporal resolution; yet, most biosensors suffer from relatively low dynamic ranges. Here, we introduce a family of designed Förster resonance energy transfer (FRET) pairs with near-quantitative FRET efficiencies based on the reversible interaction of fluorescent proteins with a fluorescently labeled HaloTag. These FRET pairs enabled the straightforward design of biosensors for calcium, ATP and NAD+ with unprecedented dynamic ranges. The color of each of these biosensors can be readily tuned by changing either the fluorescent protein or the synthetic fluorophore, which enables simultaneous monitoring of free NAD+ in different subcellular compartments following genotoxic stress. Minimal modifications of these biosensors furthermore allow their readout to be switched to fluorescence intensity, fluorescence lifetime or bioluminescence. These FRET pairs thus establish a new concept for the development of highly sensitive and tunable biosensors.
Defining blood-induced microglia functions in neurodegeneration through multiomic profiling
Authors: Mendiola Andrew S. , Yan Zhaoqi , Dixit Karuna , Johnson Jeffrey R. , Bouhaddou Mehdi , Meyer-Franke Anke , Shin Min-Gyoung , Yong Yu , Agrawal Ayushi , MacDonald Eilidh , Muthukumar Gayathri , Pearce Clairice , Arun Nikhita , Cabriga Belinda , Meza-Acevedo Rosa , Alzamora Maria del Pilar S. , Zamvil Scott S. , Pico Alexander R. , Ryu Jae Kyu , Krogan Nevan J. , Akassoglou Katerina 
Published: June 2023

AbstractBlood protein extravasation through a disrupted blood–brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer’s disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.