bluuebunny/crossref_metadata_2025_split huggingface dataset:
p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer
Authors: Miller Paul , Akama-Garren Elliot H. , Owen Richard P. , Demetriou Constantinos , Carroll Thomas M. , Slee Elizabeth , Al Moussawi Khatoun , Ellis Michael , Goldin Robert , O’Neill Eric , Lu Xin 
Published: June 2023

AbstractOncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRASG12D-driven PC tumorigenesis. iASPP suppresses PC onset driven by KRASG12D alone or KRASG12D in combination with mutant p53R172H. iASPP deletion limits acinar-to-ductal metaplasia (ADM) in vitro but accelerates inflammation and KRASG12D-induced ADM, pancreatitis and PC tumorigenesis in vivo. KRASG12D/iASPPΔ8/Δ8 tumours are well-differentiated classical PCs and their derivative cell lines form subcutaneous tumours in syngeneic and nude mice. Transcriptomically, either iASPP deletion or p53 mutation in the KRASG12D background altered the expression of an extensively overlapping gene set, comprised primarily of NF-κB and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis.
APOBEC3B coordinates R-loop to promote replication stress and sensitize cancer cells to ATR/Chk1 inhibitors
Authors: Zong Chunyan , Zhang Zhe , Gao Li , He Jie , Wang Yiran , Li Qian , Liu Xiaoting , Yang Jie , Chen Di , Huang Rui , Zheng Guopei , Jin Xiaoliang , Wei Wu , Jia Renbing , Shen Jianfeng 
Published: June 2023

AbstractThe cytidine deaminase, Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B, herein termed A3B), is a critical mutation driver that induces genomic instability in cancer by catalyzing cytosine-to-thymine (C-to-T) conversion and promoting replication stress (RS). However, the detailed function of A3B in RS is not fully determined and it is not known whether the mechanism of A3B action can be exploited for cancer therapy. Here, we conducted an immunoprecipitation-mass spectrometry (IP-MS) study and identified A3B to be a novel binding component of R-loops, which are RNA:DNA hybrid structures. Mechanistically, overexpression of A3B exacerbated RS by promoting R-loop formation and altering the distribution of R-loops in the genome. This was rescued by the R-loop gatekeeper, Ribonuclease H1 (RNASEH1, herein termed RNH1). In addition, a high level of A3B conferred sensitivity to ATR/Chk1 inhibitors (ATRi/Chk1i) in melanoma cells, which was dependent on R-loop status. Together, our results provide novel insights into the mechanistic link between A3B and R-loops in the promotion of RS in cancer. This will inform the development of markers to predict the response of patients to ATRi/Chk1i.
Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding
Authors: Faber Erik B. , Sun Luxin , Tang Jian , Roberts Emily , Ganeshkumar Sornakala , Wang Nan , Rasmussen Damien , Majumdar Abir , Hirsch Laura E. , John Kristen , Yang An , Khalid Hira , Hawkinson Jon E. , Levinson Nicholas M. , Chennathukuzhi Vargheese , Harki Daniel A. , Schönbrunn Ernst , Georg Gunda I. 
Published: June 2023

AbstractCompared to most ATP-site kinase inhibitors, small molecules that target an allosteric pocket have the potential for improved selectivity due to the often observed lower structural similarity at these distal sites. Despite their promise, relatively few examples of structurally confirmed, high-affinity allosteric kinase inhibitors exist. Cyclin-dependent kinase 2 (CDK2) is a target for many therapeutic indications, including non-hormonal contraception. However, an inhibitor against this kinase with exquisite selectivity has not reached the market because of the structural similarity between CDKs. In this paper, we describe the development and mechanism of action of type III inhibitors that bind CDK2 with nanomolar affinity. Notably, these anthranilic acid inhibitors exhibit a strong negative cooperative relationship with cyclin binding, which remains an underexplored mechanism for CDK2 inhibition. Furthermore, the binding profile of these compounds in both biophysical and cellular assays demonstrate the promise of this series for further development into a therapeutic selective for CDK2 over highly similar kinases like CDK1. The potential of these inhibitors as contraceptive agents is seen by incubation with spermatocyte chromosome spreads from mouse testicular explants, where they recapitulate Cdk2-/- and Spdya-/- phenotypes.
Discharge domains regulation and dynamic processes of direct-current triboelectric nanogenerator
Authors: Zhang Jiayue , Gao Yikui , Liu Di , Zhao Jing-Shan , Wang Jie 
Published: June 2023

AbstractDirect-current triboelectric nanogenerators arising from electrostatic breakdown can eliminate the bottleneck problem of air breakdown in conventional triboelectric nanogenerators, offering critical benefits of constant-current output, resistance to electromagnetic interference, and high output power density. Previous understanding is that its output characteristics are described by a capacitor-breakdown model or dictated by one or two discharge domains in direct-current triboelectric nanogenerators. Here, we demonstrate that the former holds only for ideal conditions and the latter cannot fully explain the dynamic process and output performance. We systematically image, define, and regulate three discharge domains in direct-current triboelectric nanogenerators, then a “cask model” is developed to bridge the cascaded-capacitor-breakdown dynamic model in ideal conditions and real outputs. Under its guidance, the output power is increased by an order of magnitude within a wide range of resistive loads. These unexplored discharge domains and optimization methods revolutionize the output performance and potential applications of direct-current triboelectric nanogenerators.
CasTuner is a degron and CRISPR/Cas-based toolkit for analog tuning of endogenous gene expression
Authors: Noviello Gemma , Gjaltema Rutger A. F. , Schulz Edda G. 
Published: June 2023

AbstractCertain cellular processes are dose-dependent, requiring specific quantities or stoichiometries of gene products, as exemplified by haploinsufficiency and sex-chromosome dosage compensation. Understanding dosage-sensitive processes requires tools to quantitatively modulate protein abundance. Here we present CasTuner, a CRISPR-based toolkit for analog tuning of endogenous gene expression. The system exploits Cas-derived repressors that are quantitatively tuned by ligand titration through a FKBP12F36V degron domain. CasTuner can be applied at the transcriptional or post-transcriptional level using a histone deacetylase (hHDAC4) fused to dCas9, or the RNA-targeting CasRx, respectively. We demonstrate analog tuning of gene expression homogeneously across cells in mouse and human cells, as opposed to KRAB-dependent CRISPR-interference systems, which exhibit digital repression. Finally, we quantify the system’s dynamics and use it to measure dose-response relationships of NANOG and OCT4 with their target genes and with the cellular phenotype. CasTuner thus provides an easy-to-implement tool to study dose-responsive processes in their physiological context.
Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity
Authors: Turner Jacqueline A. , Fredrickson Malia A. , D’Antonio Marc , Katsnelson Elizabeth , MacBeth Morgan , Van Gulick Robert , Chimed Tugs-Saikhan , McCarter Martin , D’Alessandro Angelo , Robinson William A. , Couts Kasey L. , Pelanda Roberta , Klarquist Jared , Tobin Richard P. , Torres Raul M. 
Published: June 2023

AbstractLysophosphatidic acid (LPA) is a bioactive lipid which increases in concentration locally and systemically across different cancer types. Yet, the exact mechanism(s) of how LPA affects CD8 T cell immunosurveillance during tumor progression remain unknown. We show LPA receptor (LPAR) signaling by CD8 T cells promotes tolerogenic states via metabolic reprogramming and potentiating exhaustive-like differentiation to modulate anti-tumor immunity. We found LPA levels predict response to immunotherapy and Lpar5 signaling promotes cellular states associated with exhausted phenotypes on CD8 T cells. Importantly, we show that Lpar5 regulates CD8 T cell respiration, proton leak, and reactive oxygen species. Together, our findings reveal that LPA serves as a lipid-regulated immune checkpoint by modulating metabolic efficiency through LPAR5 signaling on CD8 T cells. Our study offers key insights into the mechanisms governing adaptive anti-tumor immunity and demonstrates LPA could be exploited as a T cell directed therapy to improve dysfunctional anti-tumor immunity.
Flavodiiron-mediated O2 photoreduction at photosystem I acceptor-side provides photoprotection to conifer thylakoids in early spring
Authors: Bag Pushan , Shutova Tatyana , Shevela Dmitry , Lihavainen Jenna , Nanda Sanchali , Ivanov Alexander G. , Messinger Johannes , Jansson Stefan 
Published: June 2023

AbstractGreen organisms evolve oxygen (O2) via photosynthesis and consume it by respiration. Generally, net O2 consumption only becomes dominant when photosynthesis is suppressed at night. Here, we show that green thylakoid membranes of Scots pine (Pinus sylvestris L) and Norway spruce (Picea abies) needles display strong O2 consumption even in the presence of light when extremely low temperatures coincide with high solar irradiation during early spring (ES). By employing different electron transport chain inhibitors, we show that this unusual light-induced O2 consumption occurs around photosystem (PS) I and correlates with higher abundance of flavodiiron (Flv) A protein in ES thylakoids. With P700 absorption changes, we demonstrate that electron scavenging from the acceptor-side of PSI via O2 photoreduction is a major alternative pathway in ES. This photoprotection mechanism in vascular plants indicates that conifers have developed an adaptative evolution trajectory for growing in harsh environments.
Dynamic pathogen detection and social feedback shape collective hygiene in ants
Authors: Casillas-Pérez Barbara , Boďová Katarína , Grasse Anna V. , Tkačik Gašper , Cremer Sylvia 
Published: June 2023

AbstractCooperative disease defense emerges as group-level collective behavior, yet how group members make the underlying individual decisions is poorly understood. Using garden ants and fungal pathogens as an experimental model, we derive the rules governing individual ant grooming choices and show how they produce colony-level hygiene. Time-resolved behavioral analysis, pathogen quantification, and probabilistic modeling reveal that ants increase grooming and preferentially target highly-infectious individuals when perceiving high pathogen load, but transiently suppress grooming after having been groomed by nestmates. Ants thus react to both, the infectivity of others and the social feedback they receive on their own contagiousness. While inferred solely from momentary ant decisions, these behavioral rules quantitatively predict hour-long experimental dynamics, and synergistically combine into efficient colony-wide pathogen removal. Our analyses show that noisy individual decisions based on only local, incomplete, yet dynamically-updated information on pathogen threat and social feedback can lead to potent collective disease defense.
Importance of broken geometric symmetry of single-atom Pt sites for efficient electrocatalysis
Authors: Cho Junsic , Lim Taejung , Kim Haesol , Meng Ling , Kim Jinjong , Lee Seunghoon , Lee Jong Hoon , Jung Gwan Yeong , Lee Kug-Seung , Viñes Francesc , Illas Francesc , Exner Kai S. , Joo Sang Hoon , Choi Chang Hyuck 
Published: June 2023

AbstractPlatinum single-atom catalysts hold promise as a new frontier in heterogeneous electrocatalysis. However, the exact chemical nature of active Pt sites is highly elusive, arousing many hypotheses to compensate for the significant discrepancies between experiments and theories. Here, we identify the stabilization of low-coordinated PtIIspecies on carbon-based Pt single-atom catalysts, which have rarely been found as reaction intermediates of homogeneous PtIIcatalysts but have often been proposed as catalytic sites for Pt single-atom catalysts from theory. Advanced online spectroscopic studies reveal multiple identities of PtIImoieties on the single-atom catalysts beyond ideally four-coordinated PtII–N4. Notably, decreasing Pt content to 0.15 wt.% enables the differentiation of low-coordinated PtIIspecies from the four-coordinated ones, demonstrating their critical role in the chlorine evolution reaction. This study may afford general guidelines for achieving a high electrocatalytic performance of carbon-based single-atom catalysts based on otherd8metal ions.
Extreme atmospheric rivers in a warming climate
Authors: Wang Shuyu , Ma Xiaohui , Zhou Shenghui , Wu Lixin , Wang Hong , Tang Zhili , Xu Guangzhi , Jing Zhao , Chen Zhaohui , Gan Bolan 
Published: June 2023

AbstractExtreme atmospheric rivers (EARs) are responsible for most of the severe precipitation and disastrous flooding along the coastal regions in midlatitudes. However, the current non-eddy-resolving climate models severely underestimate (~50%) EARs, casting significant uncertainties on their future projections. Here, using an unprecedented set of eddy-resolving high-resolution simulations from the Community Earth System Model simulations, we show that the models’ ability of simulating EARs is significantly improved (despite a slight overestimate of ~10%) and the EARs are projected to increase almost linearly with temperature warming. Under the Representative Concentration Pathway 8.5 warming scenario, there will be a global doubling or more of the occurrence, integrated water vapor transport and precipitation associated with EARs, and a more concentrated tripling for the landfalling EARs, by the end of the 21st century. We further demonstrate that the coupling relationship between EARs and storms will be reduced in a warming climate, potentially influencing the predictability of future EARs.
Strain-tunable Berry curvature in quasi-two-dimensional chromium telluride
Authors: Chi Hang , Ou Yunbo , Eldred Tim B. , Gao Wenpei , Kwon Sohee , Murray Joseph , Dreyer Michael , Butera Robert E. , Foucher Alexandre C. , Ambaye Haile , Keum Jong , Greenberg Alice T. , Liu Yuhang , Neupane Mahesh R. , de Coster George J. , Vail Owen A. , Taylor Patrick J. , Folkes Patrick A. , Rong Charles , Yin Gen , Lake Roger K. , Ross Frances M. , Lauter Valeria , Heiman Don , Moodera Jagadeesh S. 
Published: June 2023

AbstractMagnetic transition metal chalcogenides form an emerging platform for exploring spin-orbit driven Berry phase phenomena owing to the nontrivial interplay between topology and magnetism. Here we show that the anomalous Hall effect in pristine Cr2Te3 thin films manifests a unique temperature-dependent sign reversal at nonzero magnetization, resulting from the momentum-space Berry curvature as established by first-principles simulations. The sign change is strain tunable, enabled by the sharp and well-defined substrate/film interface in the quasi-two-dimensional Cr2Te3 epitaxial films, revealed by scanning transmission electron microscopy and depth-sensitive polarized neutron reflectometry. This Berry phase effect further introduces hump-shaped Hall peaks in pristine Cr2Te3 near the coercive field during the magnetization switching process, owing to the presence of strain-modulated magnetic layers/domains. The versatile interface tunability of Berry curvature in Cr2Te3 thin films offers new opportunities for topological electronics.
CFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis
Authors: Yang Seung Chel , Park Mira , Hong Kwon-Ho , La Hyeonwoo , Park Chanhyeok , Wang Peike , Li Gaizhen , Chen Qionghua , Choi Youngsok , DeMayo Francesco J. , Lydon John P. , Skalnik David G. , Lim Hyunjung J. , Hong Seok-Ho , Park So Hee , Kim Yeon Sun , Kim Hye-Ryun , Song Haengseok 
Published: June 2023

AbstractProgesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus.Cfp1f/f;Pgr-Cre (Cfp1d/d) mice showed impaired P4responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent but also in H3K4me3-independent manners. CFP1 directly regulates important P4response genes, includingGata2,Sox17, andIhh, which activate smoothened signaling pathway in the uterus. In a mouse model of endometriosis,Cfp1d/dectopic lesions showed P4resistance, which was rescued by a smoothened agonist. In human endometriosis, CFP1 was significantly downregulated, and expression levels between CFP1 and these P4targets are positively related regardless of PGR levels. In brief, our study provides that CFP1 intervenes in the P4-epigenome-transcriptome networks for uterine receptivity for embryo implantation and the pathogenesis of endometriosis.
Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition
Authors: Zaghi Mattia , Banfi Federica , Massimino Luca , Volpin Monica , Bellini Edoardo , Brusco Simone , Merelli Ivan , Barone Cristiana , Bruni Michela , Bossini Linda , Lamparelli Luigi Antonio , Pintado Laura , D’Aliberti Deborah , Spinelli Silvia , Mologni Luca , Colasante Gaia , Ungaro Federica , Cioni Jean-Michel , Azzoni Emanuele , Piazza Rocco , Montini Eugenio , Broccoli Vania , Sessa Alessandro 
Published: June 2023

AbstractWithin the chromatin, distal elements interact with promoters to regulate specific transcriptional programs. Histone acetylation, interfering with the net charges of the nucleosomes, is a key player in this regulation. Here, we report that the oncoprotein SET is a critical determinant for the levels of histone acetylation within enhancers. We disclose that a condition in which SET is accumulated, the severe Schinzel-Giedion Syndrome (SGS), is characterized by a failure in the usage of the distal regulatory regions typically employed during fate commitment. This is accompanied by the usage of alternative enhancers leading to a massive rewiring of the distal control of the gene transcription. This represents a (mal)adaptive mechanism that, on one side, allows to achieve a certain degree of differentiation, while on the other affects the fine and corrected maturation of the cells. Thus, we propose the differential in cis-regulation as a contributing factor to the pathological basis of SGS and possibly other the SET-related disorders in humans.
Tough, rapid self-recovery and responsive organogel-based ionotronic for intelligent continuous passive motion system
Authors: Tang Jie , He Yuan , Xu Dan , Zhang Weijie , Hu Yang , Song Heming , Zhang Yunxia , Chen Yong Mei , Yang Yang , Zhang Kai 
Published: June 2023

AbstractContinuous passive motion (CPM) is an adjunct therapy to the standard postoperative rehabilitation regimen of joint injuries. The capability of real-time monitoring actual bending angle of knee joints is highly desired for treatment strategies of personalized postoperative rehabilitation and telemedicine. Here we report an intelligent CPM system for personalized rehabilitation and telemedicine based on the flexible and versatile ionotronic that possesses impressive mechanical properties (2.56 MPa tensile strength; 11.63 MJ m−3 toughness), fast self-recovery ability (60 s) and broaden environmental tolerance (−60–45 °C). Especially, the ionotronic responds fast and shows stability for cyclic strain sensing, ensuring the detection of actual joint bending angle with high sensitivity and reliability. The intelligent CPM system assembled with this ionotronic and a wireless transmitter was constructed, opening up a horizon for developing digital intelligent medical that can remotely monitor the movement of hospitalized/at-home patients who use CPM for personalized postoperative rehabilitation.
Ultra-flexible semitransparent organic photovoltaics
Authors: Lee Hanbee , Jeong Soyeong , Kim Jae-Hyun , Jo Yong-Ryun , Eun Hyeong Ju , Park Byoungwook , Yoon Sung Cheol , Kim Jong H. , Lee Seung-Hoon , Park Sungjun 
Published: June 2023

AbstractUltra-flexible organic photovoltaics (OPVs) are promising candidates for next-generation power sources owing to their low weight, transparency, and flexibility. However, obtaining ultra-flexibility under extreme repetitive mechanical stress while maintaining optical transparency remains challenging because of the intrinsic brittleness of transparent electrodes. Here, we introduce strain-durable ultra-flexible semitransparent OPVs with a thickness below 2 μm. The conformal surface coverage of nanoscale thin metal electrodes (< 10 nm) is achieved, resulting in extremely low flexural rigidity and high strain durability. In-depth optical and electrical analyses on ultrathin metal electrodes showed that the devices maintain over 73% of their initial efficiency after 1000 cycles of repetitive compression and release at 66% compressive strain, and the average visible light transmittances remain higher than 30%. To our knowledge, this is the first systematical study on mechanical behaviors of strain-durable ultra-flexible ST-OPVs through precise adjustment of each ultrathin electrode thickness toward the emergence of next-generation flexible power sources.
Targeted metabolomic analysis in Parkinson’s disease brain frontal cortex and putamen with relation to cognitive impairment
Authors: Kalecký Karel , Bottiglieri Teodoro 
Published: June 2023

AbstractWe performed liquid chromatography tandem mass spectrometry analysis with the targeted metabolomic kit Biocrates MxP Quant 500, in human brain cortex (Brodmann area 9) and putamen, to reveal metabolic changes characteristic of Parkinson’s disease (PD) and PD-related cognitive decline. This case-control study involved 101 subjects (33 PD without dementia, 32 PD with dementia (cortex only), 36 controls). We found changes associated with PD, cognitive status, levodopa levels, and disease progression. The affected pathways include neurotransmitters, bile acids, homocysteine metabolism, amino acids, TCA cycle, polyamines, β-alanine metabolism, fatty acids, acylcarnitines, ceramides, phosphatidylcholines, and several microbiome-derived metabolites. Previously reported levodopa-related homocysteine accumulation in cortex still best explains the dementia status in PD, which can be modified by dietary supplementation. Further investigation is needed to reveal the exact mechanisms behind this pathological change.