bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prompt Appearance of Large‐Amplitude EMIC Waves Induced by Solar Wind Dynamic Pressure Enhancement and the Subsequent Relativistic Electron Precipitation
Authors: Yan Yun , Yue Chao , Ma Qianli , Zhou Xu‐Zhi , Zong Qiu‐Gang , Fu Haobo , Xie Zi‐Kang , Yin Ze‐Fan , Li Yu‐Xuan 
Published: July 2023

AbstractElectromagnetic ion cyclotron (EMIC) waves play an important role in relativistic electron dynamics. In this study, we find a large‐amplitude EMIC wave event induced by the prompt enhancement of solar wind dynamic pressure on 6 November 2015. These large‐amplitude EMIC waves are simultaneously observed by multiple satellites over 13 hr in magnetic local time (MLT) with a peak amplitude of ∼4 nT. Satellites at different locations observed different bands of EMIC waves, implying the importance of background plasma density in EMIC wave generation. Electron pitch angle distributions show obvious responses to EMIC wave activities. During EMIC wave appearance, the fluxes of relativistic electrons with pitch angles around 90° increase, while the fluxes of field‐aligned relativistic electrons decrease, showing distinct “bite‐out” signatures, indicating pitch angle scattering by EMIC waves, and the scattering efficiency depends on the amplitude and polarization of EMIC waves. Combined with phase space density profiles of electrons that are nearly constant at energies below the minimum resonant energy of electrons (Emin) but show dropout at energies above the Emin after EMIC wave activities, we conclude that large‐amplitude EMIC waves can cause rapid electron loss down to several hundred keV. In addition, simultaneous observations of hundreds of keV electron precipitation and tens of keV proton precipitation by Polar Operational Environmental Satellites near the region where EMIC waves are observed, provide direct evidence of relativistic electron precipitation caused by the large‐amplitude EMIC waves, ultimately driven by solar wind structures.
Ion‐Vortex Magnetic Hole With Reversed Field Direction in Earth's Magnetosheath
Authors: Yao S. T. , Li J. H. , Zhou X.‐Z. , Shi Q. Q. , Zong Q.‐G. , Zhang H. , Li W. Y. , Hamrin M. , Volwerk M. , Pitkänen T. , Yang F. 
Published: July 2023

AbstractPlasma vortices are ubiquitous in space and play important roles in the transmission of energy and mass at various scales. For small‐scale plasma vortices on the order of ion gyroradius, however, their properties and characteristics remain unclear. Here, we provide unique findings of an ion‐scale vortex observed in the Earth's magnetosheath. The vortex is generated by the ion diamagnetic drift associated with an isolated magnetic hole (MH). The magnetic field in the axial direction is reversed in the vortex center, which is consistent with ring‐shaped currents carried by the ions. The field strength becomes very weak (<1 nT) at the field reversal region, although the ion distributions vary rather continuously across the entire structure. A kinetic equilibrium model is then applied to reconstruct the above features. These findings can help us understand the plasma vortex and MH from magnetohydrodynamics to kinetic scales.
Drivers of Geomorphic Heterogeneity in Unconfined Non‐Perennial River Corridors
Authors: Scamardo Julianne , Nichols Mary , Rittenour Tammy , Wohl Ellen 
Published: July 2023

AbstractRiver corridors along non‐perennial stream networks provide diverse physical and ecological functions that are thought to be related to the spatial and temporal variability of geomorphic units, also known as geomorphic heterogeneity. While studies on the characteristics and drivers of geomorphic heterogeneity have been developed in perennial streams, similar studies in ephemeral streams are lacking. Given the ubiquity of non‐perennial streams globally, we aim to answer questions regarding the magnitude and drivers of geomorphic heterogeneity in ephemeral river corridors as well as how geomorphic unit assemblages reflect processes related to flood disturbance. Geomorphic units were mapped in 30 unconfined river corridors within six non‐perennial watersheds in Utah and Arizona, USA. Landscape heterogeneity metrics—Shannon's Diversity Index, Shannon's Evenness Index, and patch density—were used to quantify geomorphic heterogeneity within each reach. Additionally, variables that potentially constrain or drive heterogeneity were quantified, including floodplain shape, grain size, large wood abundance, and proxies for flood disturbance. While heterogeneity positively correlated with metrics for morphology and disturbance, statistical models suggest that morphologic context, particularly river corridor width, was a more important predictor for estimating geomorphic heterogeneity. Still, geomorphic units reflected aggradation processes indicative of a range of flood energies, suggesting a strong tie between heterogeneity and disturbance. Results suggest that geomorphic heterogeneity may be resilient to changes in flood disturbance frequency or magnitude, but future studies investigating long‐term temporal heterogeneity are needed.
20 years on – the measurement of blood pressure and detection of hypertension in children and adolescents: a national descriptive survey
Authors: Jones Lily , Park Julie , Blair Joanne , Hawcutt Daniel B. , Lip Gregory Y. H. , Shantsila Alena 
Published: July 2023

AbstractIn 1997 a survey identified a general lack of standardisation of blood pressure (BP) measurement and little consensus on the criteria for diagnosing hypertension amongst paediatricians. We have conducted a new online survey in 2021, to compare clinical practice between the two time periods. A national quality improvement survey was approved by the GAPRUKI committee and then circulated to consultant-grade general paediatricians. 125 analysable replies from 34 different sites were received and compared with the 1997 data. 106 (84.8%) reported clinic nurse involvement in BP measurement, more than twice than reported previously (40.6%). Most paediatricians (53.6%) now rely on oscillometric devices, whereas the mercury sphygmomanometer was favoured previously (82.7%). If assessing BP manually (n = 89), most (79.8%) now use Korotkoff phase V as the auscultatory endpoint for diastolic BP (phase IV was previously used (52.1%)). Diagnostic criteria of hypertension, the criteria (≥95th centile for gender, age and height) were constant, and 100% of paediatricians diagnosed it using systolic BP, but only 43 (34.4%) used diastolic BP, a decrease from 79.4% previously. Ambulatory BP Monitoring was six times more available than in 1997 (81.6% vs 13.6%). Similar to previous findings, only 12 (9.6%) paediatricians would manage hypertensive patients themselves, however 82 (72.6%) would keep general paediatric input. There have been important changes in the assessment of BP in children, including increased nurse involvement and greater use of technology. However, fewer paediatricians are responding to high diastolic pressures than twenty years ago.
Global scale phylogeography of functional traits and microdiversity in Prochlorococcus
Authors: Ustick Lucas J , Larkin Alyse A , Martiny Adam C 
Published: July 2023

Abstract
Prochlorococcus is the most numerically abundant photosynthetic organism in the surface ocean. The Prochlorococcus high-light and warm-water adapted ecotype (HLII) is comprised of extensive microdiversity, but specific functional differences between microdiverse sub-clades remain elusive. Here we characterized both functional and phylogenetic diversity within the HLII ecotype using Bio-GO-SHIP metagenomes. We found widespread variation in gene frequency connected to local environmental conditions. Metagenome-assembled marker genes and genomes revealed a globally distributed novel HLII haplotype defined by adaptation to chronically low P conditions (HLII-P). Environmental correlation analysis revealed different factors were driving gene abundances verses phylogenetic differences. An analysis of cultured HLII genomes and metagenome-assembled genomes revealed a subclade within HLII, which corresponded to the novel HLII-P haplotype. This work represents the first global assessment of the HLII ecotype’s phylogeography and corresponding functional differences. These findings together expand our understanding of how microdiversity structures functional differences and reveals the importance of nutrients as drivers of microdiversity in Prochlorococcus.
LRRK2 phosphorylation status and kinase activity regulate (macro)autophagy in a Rab8a/Rab10-dependent manner
Authors: Kania Elżbieta , Long Jaclyn S. , McEwan David G. , Welkenhuyzen Kirsten , La Rovere Rita , Luyten Tomas , Halpin John , Lobbestael Evy , Baekelandt Veerle , Bultynck Geert , Ryan Kevin M. , Parys Jan B. 
Published: July 2023

AbstractMutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson’s disease (PD), with growing importance also for Crohn’s disease and cancer. LRRK2 is a large and complex protein possessing both GTPase and kinase activity. Moreover, LRRK2 activity and function can be influenced by its phosphorylation status. In this regard, many LRRK2 PD-associated mutants display decreased phosphorylation of the constitutive phosphorylation cluster S910/S935/S955/S973, but the role of these changes in phosphorylation status with respect to LRRK2 physiological functions remains unknown. Here, we propose that the S910/S935/S955/S973 phosphorylation sites act as key regulators of LRRK2-mediated autophagy under both basal and starvation conditions. We show that quadruple LRRK2 phosphomutant cells (4xSA; S910A/S935A/S955A/S973A) have impaired lysosomal functionality and fail to induce and proceed with autophagy during starvation. In contrast, treatment with the specific LRRK2 kinase inhibitors MLi-2 (100 nM) or PF-06447475 (150 nM), which also led to decreased LRRK2 phosphorylation of S910/S935/S955/S973, did not affect autophagy. In explanation, we demonstrate that the autophagy impairment due to the 4xSA LRRK2 phospho-dead mutant is driven by its enhanced LRRK2 kinase activity. We show mechanistically that this involves increased phosphorylation of LRRK2 downstream targets Rab8a and Rab10, as the autophagy impairment in 4xSA LRRK2 cells is counteracted by expression of phosphorylation-deficient mutants T72A Rab8a and T73A Rab10. Similarly, reduced autophagy and decreased LRRK2 phosphorylation at the constitutive sites were observed in cells expressing the pathological R1441C LRRK2 PD mutant, which also displays increased kinase activity. These data underscore the relation between LRRK2 phosphorylation at its constitutive sites and the importance of increased LRRK2 kinase activity in autophagy regulation and PD pathology.
Fatty acid oxidation facilitates DNA double-strand break repair by promoting PARP1 acetylation
Authors: Yang Seungyeon , Hwang Sunsook , Kim Byungjoo , Shin Seungmin , Kim Minjoong , Jeong Seung Min 
Published: July 2023

AbstractDNA repair is a tightly coordinated stress response to DNA damage, which is critical for preserving genome integrity. Accruing evidence suggests that metabolic pathways have been correlated with cellular response to DNA damage. Here, we show that fatty acid oxidation (FAO) is a crucial regulator of DNA double-strand break repair, particularly homologous recombination repair. Mechanistically, FAO contributes to DNA repair by activating poly(ADP-ribose) polymerase 1 (PARP1), an enzyme that detects DNA breaks and promotes DNA repair pathway. Upon DNA damage, FAO facilitates PARP1 acetylation by providing acetyl-CoA, which is required for proper PARP1 activity. Indeed, cells reconstituted with PARP1 acetylation mutants display impaired DNA repair and enhanced sensitivity to DNA damage. Consequently, FAO inhibition reduces PARP1 activity, leading to increased genomic instability and decreased cell viability upon DNA damage. Finally, our data indicate that FAO serves as an important participant of cellular response to DNA damage, supporting DNA repair and genome stability.
PLAGL2 promotes bladder cancer progression via RACGAP1/RhoA GTPase/YAP1 signaling
Authors: Chen Hualin , Yang Wenjie , Li Yingjie , Ji Zhigang 
Published: July 2023

AbstractPLAGL2 is upregulated in various tumors, including bladder cancer (BCa). However, the mechanisms underlying the tumorigenic effects of PLAGL2 in BCa remain unclear. In our study, we proved that PLAGL2 was overexpressed in BCa tissues and correlated with decreased survival. Functionally, PLAGL2 deficiency significantly suppressed the proliferation and metastasis of BCa cells in vitro and in vivo. RNA sequencing, qRT‒PCR, immunoblotting, immunofluorescence staining, luciferase reporter, and ChIP assays revealed that overexpressed PLAGL2 disrupted the Hippo pathway and increased YAP1/TAZ activity by transactivating RACGAP1. Further investigations demonstrated that PLAGL2 activated YAP1/TAZ signaling via RACGAP1-mediated RhoA activation. Importantly, the RhoA inhibitor simvastatin or the YAP1/TAZ inhibitor verteporfin abrogated the proproliferative and prometastatic effects of BCa enhanced by PLAGL2. These findings suggest that PLAGL2 promotes BCa progression via RACGAP1/RhoA GTPase/YAP1 signaling. Hence, the core nodes of signaling may be promising therapeutic targets for BCa.
PTRF-IL33-ZBP1 signaling mediating macrophage necroptosis contributes to HDM-induced airway inflammation
Authors: Du Juan , Liu Yahui , Lan Gelei , Zhou Yao , Ni Yingmeng , Liao Kai , Zheng Fang , Cheng Qijian , Shi Guochao , Su Xiao 
Published: July 2023

AbstractPolymerase 1 and transcript release factor (PTRF, encoding by Cavin-1) regulates interleukin 33 (IL-33) release, which is implicated in asthma development. Z-DNA binding protein 1 (ZBP1)-sensing Z-RNAs induces necroptosis which causes inflammatory diseases. House dust mite (HDM) is the major source of allergen in house dust and is strongly associated with the development of asthma. Whether PTRF via IL-33 and ZBP1 mediates HDM-induced macrophage necroptosis and airway inflammation remains unclear. Here, we found that deficiency of PTRF could reduce lung IL-33, ZBP1, phosphor-receptor-interacting protein kinase 3 (p-RIPK3), and phosphor-mixed lineage kinase domain-like (p-MLKL) (necroptosis executioner), and airway inflammation in an HDM-induced asthma mouse model. In HDM-treated macrophages, ZBP1, p-RIPK3, and p-MLKL levels were markedly increased, and these changes were reversed by deletion of Cavin-1. Deletion of Il33 also reduced expression of ZBP1, p-RIPK3, and p-MLKL in HDM-challenged lungs. Moreover, IL-33 synergizing with HDM boosted expression of ZBP1, p-RIPK3, and p-MLKL in macrophages. In bronchial epithelial cells rather than macrophages and vascular endothelial cells, PTRF positively regulates IL-33 expression. Therefore, we conclude that PTRF mediates HDM-induced macrophage ZBP1/necroptosis and airway inflammation, and this effect could be boosted by bronchial epithelial cell-derived IL-33. Our findings suggest that PTRF-IL33-ZBP1 signaling pathway might be a promising target for dampening airway inflammation.
FGF19 induces the cell cycle arrest at G2-phase in chondrocytes
Authors: Chen Hao , Li Jiazhou , Pi Caixia , Guo Daimo , Zhang Demao , Zhou Xuedong , Xie Jing 
Published: July 2023

AbstractFibroblast growth factor 19 (FGF19) has appeared as a new possible avenue in the treatment of skeletal metabolic disorders. However, the role of FGF19 on cell cycle progression in skeletal system is poorly understood. Here we demonstrated that FGF19 had the ability to reduce the proliferation of chondrocytes and cause cell cycle G2 phase arrest through its interaction with β-Klotho (KLB), an important accessory protein that helps FGF19 link to its receptor. FGF19-mediated cell cycle arrest by regulating the expressions of cdk1/cylinb1, chk1 and gadd45a. We then confirmed that the binding of FGF19 to the membrane receptor FGFR4 was necessary for FGF19-mediated cell cycle arrest, and further proved that FGF19-mediated cell cycle arrest was via activation of p38/MAPK signaling. Through inhibitor experiments, we discovered that inhibition of FGFR4 led to down-regulation of p38 signaling even in the presence of FGF19. Meanwhile, inhibiting p38 signaling reduced the cell cycle arrest of chondrocytes induced by FGF19. Furthermore, blocking p38 signaling facilitated to retain the expression of cdk1 and cyclinb1 that had been reduced in chondrocytes by FGF19 and decreased the expression of chk1 and gadd45a that had been enhanced by FGF19 in chondrocytes. Taking together, this study is the first to demonstrate that FGF19 induces cell cycle arrest at G2 phase via FGFR4-p38/MAPK axis and enlarges our understanding about the role of FGF19 on cell cycle progression in chondrocytes.
Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification
Authors: Lin Zhipeng , Dhawa Uttam , Hou Xiaoyan , Surke Max , Yuan Binbin , Li Shu-Wen , Liou Yan-Cheng , Johansson Magnus J. , Xu Li-Cheng , Chao Chen-Hang , Hong Xin , Ackermann Lutz 
Published: July 2023

AbstractElectrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C−H activations, these arene functionalizations generally require directing groups to enable the C−H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C−H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C−H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C−H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C−H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations.
Impact of TMB/PD-L1 expression and pneumonitis on chemoradiation and durvalumab response in stage III NSCLC
Authors: Alessi Joao V. , Ricciuti Biagio , Wang Xinan , Pecci Federica , Di Federico Alessandro , Lamberti Giuseppe , Elkrief Arielle , Rodig Scott J. , Lebow Emily S. , Eicholz Jordan E. , Thor Maria , Rimner Andreas , Schoenfeld Adam J. , Chaft Jamie E. , Johnson Bruce E. , Gomez Daniel R. , Awad Mark M. , Shaverdian Narek 
Published: July 2023

AbstractAlthough concurrent chemoradiation (CRT) and durvalumab consolidation has become a standard treatment for stage III non-small cell lung cancer (NSCLC), clinicopathologic and genomic factors associated with its efficacy remain poorly characterized. Here, in a multi-institutional retrospective cohort study of 328 patients treated with CRT and durvalumab, we identify that very high PD-L1 tumor proportion score (TPS) expression ( ≥ 90%) and increased tumor mutational burden (TMB) are independently associated with prolonged disease control. Additionally, we identify the impact of pneumonitis and its timing on disease outcomes among patients who discontinue durvalumab: compared to patients who experienced early-onset pneumonitis ( < 3 months) leading to durvalumab discontinuation, patients with late-onset pneumonitis had a significantly longer PFS (12.7 months vs not reached; HR 0.24 [95% CI, 0.10 to 0.58]; P = 0.001) and overall survival (37.2 months vs not reached; HR 0.26 [95% CI, 0.09 to 0.79]; P = 0.017). These findings suggest that opportunities exist to improve outcomes in patients with lower PD-L1 and TMB levels, and those at highest risk for pneumonitis.
mRNA lipid nanoparticle-mediated pyroptosis sensitizes immunologically cold tumors to checkpoint immunotherapy
Authors: Li Fengqiao , Zhang Xue-Qing , Ho William , Tang Maoping , Li Zhongyu , Bu Lei , Xu Xiaoyang 
Published: July 2023

AbstractSynergistically improving T-cell responsiveness is promising for favorable therapeutic outcomes in immunologically cold tumors, yet current treatments often fail to induce a cascade of cancer-immunity cycle for effective antitumor immunity. Gasdermin-mediated pyroptosis is a newly discovered mechanism in cancer immunotherapy; however, cleavage in the N terminus is required to activate pyroptosis. Here, we report a single-agent mRNA nanomedicine-based strategy that utilizes mRNA lipid nanoparticles (LNPs) encoding only the N-terminus of gasdermin to trigger pyroptosis, eliciting robust antitumor immunity. In multiple female mouse models, we show that pyroptosis-triggering mRNA/LNPs turn cold tumors into hot ones and create a positive feedback loop to promote antitumor immunity. Additionally, mRNA/LNP-induced pyroptosis sensitizes tumors to anti-PD-1 immunotherapy, facilitating tumor growth inhibition. Antitumor activity extends beyond the treated lesions and suppresses the growth of distant tumors. We implement a strategy for inducing potent antitumor immunity, enhancing immunotherapy responses in immunologically cold tumors.
Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons
Authors: Liu Yanan , Hu Longmiao , Wu Zhengzhen , Yuan Kun , Hong Guangliang , Lian Zhengke , Feng Juanjuan , Li Na , Li Dali , Wong Jiemin , Chen Jiekai , Liu Mingyao , He Jiangping , Pang Xiufeng 
Published: July 2023

AbstractImmunotherapy has become established as major treatment modality for multiple types of solid tumors, including colorectal cancer. Identifying novel immunotherapeutic targets to enhance anti-tumor immunity and sensitize current immune checkpoint blockade (ICB) in colorectal cancer is needed. Here we report the histone demethylase PHD finger protein 8 (PHF8, KDM7B), a Jumonji C domain-containing protein that erases repressive histone methyl marks, as an essential mediator of immune escape. Ablation the function of PHF8 abrogates tumor growth, activates anti-tumor immune memory, and augments sensitivity to ICB therapy in mouse models of colorectal cancer. Strikingly, tumor PHF8 deletion stimulates a viral mimicry response in colorectal cancer cells, where the depletion of key components of endogenous nucleic acid sensing diminishes PHF8 loss-meditated antiviral immune responses and anti-tumor effects in vivo. Mechanistically, PHF8 inhibition elicits H3K9me3-dependent retrotransposon activation by promoting proteasomal degradation of the H3K9 methyltransferase SETDB1 in a demethylase-independent manner. Moreover, PHF8 expression is anti-correlated with canonical immune signatures and antiviral immune responses in human colorectal adenocarcinoma. Overall, our study establishes PHF8 as an epigenetic checkpoint, and targeting PHF8 is a promising viral mimicry-inducing approach to enhance intrinsic anti-tumor immunity or to conquer immune resistance.