bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinematics and Convergent Tectonics of the Northwestern South American Plate During the Cenozoic
Authors: González R. , Oncken O. , Faccenna C. , Le Breton E. , Bezada M. , Mora A.
Published: July 2023

The interaction of the northern Nazca and southwestern Caribbean oceanic plates with northwestern South America (NWSA) and the collision of the Panama‐Choco arc (PCA) have significant implications on the evolution of the northern Andes. Based on a quantitative kinematic reconstruction of the Caribbean and Farallon/Farallon‐derived plates, we reconstructed the subducting geometries beneath NWSA and the PCA accretion to the continent. The persistent northeastward migration of the Caribbean plate relative to NWSA in Cenozoic time caused the continuous northward advance of the Farallon‐Caribbean plate boundary, which in turn resulted in its progressive concave trench bending against NWSA. The increasing complexity during the Paleogene included the onset of Caribbean shallow subduction, the PCA approaching the continent, and the forced shallow Farallon subduction that ended in the fragmentation of the Farallon Plate into the Nazca and Cocos plates and the Coiba and Malpelo microplates by the late Oligocene. The convergence tectonics after late Oligocene comprised the accretional process of the PCA to NWSA, which evolved from subduction erosion of the forearc to collisional tectonics by the middle Miocene, as well as changes of convergence angle and slab dip of the Farallon‐derived plates, and the attachment of the Coiba and Malpelo microplates to the Nazca plate around 9 Ma, resulting in a change of convergence directions. During the Pliocene, the Nazca slab broke at 5.5°N, shaping the modern configuration. Overall, the proposed reconstruction is supported by geophysical data and is well correlated with the magmatic and deformation history of the northern Andes.
Referencing of Continental‐Scale InSAR‐Derived Velocity Fields: Case Study of the Eastern Tibetan Plateau
Authors: Lemrabet Laëtitia , Doin Marie‐Pierre , Lasserre Cécile , Durand Philippe
Published: July 2023

The wealth of Sentinel‐1 data in eastern Tibet allows to discuss whether InSAR‐derived velocity maps measure ground motion in the ITRF reference frame with sufficient accuracy for large‐scale tectonic applications. High elevation, moderate relief and low vegetation cover in eastern Tibet ensure reliable multi‐temporal InSAR results. We automatically process seven 1,200 km long ascending and descending orbits, divided into 2 or 3 overlapping segments along‐track. Linear phase ramps in range and azimuth are removed from interferograms. The ramps and the flattened interferograms are separately inverted into time series and analyzed. The ramps are modeled by their Solid Earth Tides (SET) contribution, seasonal variations, and a trend in time. SET oscillations are clearly visible in the ramp time series. Seasonal tidal amplifications of probable atmospheric origin are also evidenced. Ramp rates are shown to precisely quantify the plate motion of each segment in the ITRF reference frame. They are thus added back to the velocity maps before along‐track merging. Then, a simple referencing procedure implying only a constant and a tilt in azimuth adjusted for each track is constrained by horizontal GNSS data. It allows straightforward vertical and horizontal decomposition. The quality of the merged and referenced data sets can then be quantitatively assessed at 1 mm/yr by the differences between InSAR and GNSS velocities and by the InSAR residuals on track overlaps. The vertical velocity field is dominated at first order by the effect of permafrost degradation, while the horizontal velocity highlights strain accumulation across major strike‐slip faults in eastern Tibet.
Debris‐Flow Process Controls on Steepland Morphology in the San Gabriel Mountains, California
Authors: Struble William T. , McGuire Luke A. , McCoy Scott W. , Barnhart Katherine R. , Marc Odin
Published: July 2023

Steep landscapes evolve largely by debris flows, in addition to fluvial and hillslope processes. Abundant field observations document that debris flows incise valley bottoms and transport substantial sediment volumes, yet their contributions to steepland morphology remain uncertain. This has, in turn, limited the development of debris‐flow incision rate formulations that produce morphology consistent with natural landscapes. In many landscapes, including the San Gabriel Mountains (SGM), California, steady‐state fluvial channel longitudinal profiles are concave‐up and exhibit a power‐law relationship between channel slope and drainage area. At low drainage areas, however, valley slopes become nearly constant. These topographic forms result in a characteristically curved slope‐area signature in log‐log space. Here, we use a one‐dimensional landform evolution model that incorporates debris‐flow erosion to reproduce the relationship between this curved slope‐area signature and erosion rate in the SGM. Topographic analysis indicates that the drainage area at which steepland valleys transition to fluvial channels correlates with measured erosion rates in the SGM, and our model results reproduce these relationships. Further, the model only produces realistic valley profiles when parameters that dictate the relationship between debris‐flow erosion, valley‐bottom slope, and debris‐flow depth are within a narrow range. This result helps place constraints on the mathematical form of a debris‐flow incision law. Finally, modeled fluvial incision outpaces debris‐flow erosion at drainage areas less than those at which valleys morphologically transition from near‐invariant slopes to concave profiles. This result emphasizes the critical role of debris‐flow incision for setting steepland form, even as fluvial incision becomes the dominant incisional process.
Hyperspectral Mixture Models in the CHIME Mission Implementation for Topsoil Texture Retrieval
Authors: Valentini Emiliana , Taramelli Andrea , Marinelli Chiara , Martin Laura Piedelobo , Fassari Marco , Troffa Stefano , Mzid Nada , Casa Raffaele , Pignatti Stefano
Published: July 2023

This study is part of the requirements consolidation study for the European Copernicus Hyperspectral Imaging Mission for Environment (CHIME). It explores the value added by existing hyperspectral data of similar characteristics to CHIME, namely AVIRIS‐NG and PRecursore IperSpettrale della Missione Applicativa (PRISMA), for detecting topsoil texture properties. The spatial variability is retrieved using the linear spectral mixture analysis, an image‐based algorithm that breaks down the hyperspectral data set into fractional abundance of spectral classes within each pixel. The fractional abundance of image‐based endmembers is broken into categories to find intervals having a spatial relation with texture components in terms of fine (clay and silt) or coarse (sand) abundance. The fraction maps obtained show similar spatial patterns to the USDA soil texture classification, obtained with a geostatistical approach. Specifically, AVIRIS CHIME‐like FAM1 > 0.45 presented an agreement of 86% with clay and/or silt higher than 45% which, according to the United Stated Agriculture Department (USDA) intervals, correspond to loam‐clay loam classes. Similar results are obtained with PRISMA with FAM2 0.20–0.35, overlapping 63% of the kriging‐based USDA clay‐loam class. The fractional abundance categories showing the highest overlap percentages are correlated with the short‐wave infrared spectral range, showing average coefficients of 0.7 where wavelengths are over 1,500 nm. From 1700 nm, CHIME‐like shows values of 0.8. In conclusion, this exploratory research and results leverage the opportunity of extending the processing chain to a larger number of case studies to better understand the physical relation between the spectral reflectance captured by new spaceborne hyperspectral sensors and the spatial patterns of soil texture classes.
Coral Sr‐U Thermometry Tracks Ocean Temperature and Reconciles Sr/Ca Discrepancies Caused by Rayleigh Fractionation
Authors: Galochkina M. , Cohen A. L. , Oppo D. W. , Mollica N. , Horton F.
Published: July 2023

Understanding climate change at the spatiotemporal scales necessary to improve climate projections requires proxy records that complement sparse and often contradictory observational temperature data sets. Massive long‐lived corals have tremendous potential in this regard, continuously recording information about ocean conditions as they grow. Nevertheless, extracting accurate ocean temperatures from corals is challenging because factors other than temperature influence skeletal chemistry. Here, we tested the ability of the coral Sr‐U thermometer to accurately capture annual sea surface temperatures (SSTs) in the subtropical Atlantic, where year‐to‐year temperatures vary by ∼1°C. Using laser ablation inductively coupled plasma mass spectrometry (LA‐ICP‐MS), we generated sufficient U/Ca – Sr/Ca pairs from a slow‐growing (1−2 mm/yr) Siderastrea siderea coral to calculate annual Sr‐U values. With the fine‐scale spatial resolution attained using the laser, skeleton accreted during both fast and slow growing times of the year was represented in our sampling. The resulting 30‐year‐long Sr‐U record tracked the amplitude and timing of annual SST to within ±0.2°C of observations (r = −0.71), whereas the Sr/Ca record did not (r = 0.23). Furthermore, Sr‐U corrected for Sr/Ca offsets among adjacent skeletal elements approximately 1 mm apart. These offsets are equivalent to differences of 2–3°C if typical Sr/Ca–SST calibrations are applied. Our observations indicate that Sr‐U can accurately constrain decadal‐to‐multidecadal variability and secular SST trends in regions where this information is urgently needed.
In New Zealand, Fish Are Helping Scientists Find Gold
Authors: Morris Bill
Published: July 2023

Enormous amounts of gold lie buried beneath the rubble of New Zealand’s mountains, and scientists are using freshwater fish genetics to find it.
Newly Discovered Salts May Exist on Icy Moons
Authors: Smith Derek
Published: July 2023

For the first time in more than a century, scientists have identified new sodium chloride crystals. The discovery may reconcile puzzling spectroscopic images of Europa’s surface.
Gardens Are Good for the Neighborhood
Authors: Owen Rebecca
Published: July 2023

A new study highlights the benefits of urban gardens for their human caretakers and local ecosystems.
Deluges of Data Are Changing Astronomical Science
Authors: Kornei Katherine
Published: July 2023

Astronomers today are more likely than ever to access data from an archive rather than travel to a telescope—a shift that’s democratizing science.
Your Databases Need a Reboot
Authors: Micalizio Caryl-Sue
Published: July 2023

Scientists are reassessing dated data in the time of the Cloud.
Urban Water Conservation Success in the Colorado River Basin
Authors: Palmer Jane
Published: July 2023

In the past few decades, cities in Arizona, Colorado, and Nevada have vastly increased their water use efficiency. They’ve also learned lessons that can inform other cities’ efforts.
Tree Ring Width Predicted by Machine Learning
Authors: Rehnberg Morgan
Published: July 2023

When predicting a tree’s annual growth, consider the whole weather system and not just the sum of its parts.
COVID-19 Got You Feeling Under the Weather? Maybe Blame…the Weather
Authors: Sidik Saima
Published: July 2023

High humidity and low temperature altered COVID-19 spread in Brazil, but only slightly.
Decrypting Lunar Craters Quickly and Easily
Authors: Sidik Saima
Published: July 2023

Machine learning can reveal the stories written in the marks on the Moon.
How Big Data is Helping Environmental and Climate Research
Authors: Montillet Jean-Philippe , Caprarelli Graziella , Manighetti Isabelle , Haberreiter Margit , He Xiaoxing
Published: July 2023

A new special collection invites papers focusing on the processing, modeling, and analysis of all types of big datasets in the Earth and space sciences, including the influence of solar forcing on Earth's climate.
Danger in the Dust! The Hazards of Windblown Dust
Authors: Gill Thomas , Tong Daniel , Sprigg William , Van Pelt R. Scott
Published: July 2023

Airborne dust not only causes disease, it also menaces transportation on land, sea, and air; disrupts renewable energy systems; transports pathogens and toxic substances; and poses many other hazards.
Atmospheric Methane: Comparison Between Methane's Record in 2006–2022 and During Glacial Terminations
Authors: Nisbet Euan G. , Manning Martin R. , Dlugokencky Ed J. , Michel Sylvia Englund , Lan Xin , Röckmann Thomas , Denier van der Gon Hugo A. C. , Schmitt Jochen , Palmer Paul I. , Dyonisius Michael N. , Oh Youmi , Fisher Rebecca E. , Lowry David , France James L. , White James W. C. , Brailsford Gordon , Bromley Tony
Published: July 2023

Atmospheric methane's rapid growth from late 2006 is unprecedented in the observational record. Assessment of atmospheric methane data attributes a large fraction of this atmospheric growth to increased natural emissions over the tropics, which appear to be responding to changes in anthropogenic climate forcing. Isotopically lighter measurements of are consistent with the recent atmospheric methane growth being mainly driven by an increase in emissions from microbial sources, particularly wetlands. The global methane budget is currently in disequilibrium and new inputs are as yet poorly quantified. Although microbial emissions from agriculture and waste sources have increased between 2006 and 2022 by perhaps 35 Tg/yr, with wide uncertainty, approximately another 35–45 Tg/yr of the recent net growth in methane emissions may have been driven by natural biogenic processes, especially wetland feedbacks to climate change. A model comparison shows that recent changes may be comparable or greater in scale and speed than methane's growth and isotopic shift during past glacial/interglacial termination events. It remains possible that methane's current growth is within the range of Holocene variability, but it is also possible that methane's recent growth and isotopic shift may indicate a large‐scale reorganization of the natural climate and biosphere is under way.
Tug‐Of‐War on Idealized Midlatitude Cyclones Between Radiative Heating From Low‐Level and High‐Level Clouds
Authors: Voigt Aiko , Keshtgar Behrooz , Butz Klara
Published: July 2023

We present baroclinic life‐cycle simulations with two versions of the atmosphere model ICON to understand how cloud‐radiative heating and cooling affect an idealized midlatitude cyclone. Both versions simulate the same cyclone when run without radiation, but disagree when cloud‐radiation‐interaction is taken into account. The radiative effects of clouds weaken the cyclone in ICON2.1 but strengthen it in ICON2.6. We attribute the disagreement to low‐level clouds, which in ICON2.1 are more abundant and show stronger radiative cooling of the boundary layer. We argue that radiative cooling from low‐level cloud tops weakens the cyclone by increasing boundary‐layer static stability, and that radiative cooling from high‐level cloud tops strengthens the cyclone by decreasing static stability in the upper troposphere and sharpening the tropopause. Our results indicate that clouds and the vertical distribution of their radiative heating and cooling can influence the dynamics of midlatitude cyclones.
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

Electromagnetic 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

Plasma 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

River 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

In 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

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

Mutations 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

DNA 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

PLAGL2 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

Polymerase 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

Fibroblast 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

Electrooxidation 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

Although 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

Synergistically 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

Immunotherapy 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.
Finding defects in glasses through machine learning
Authors: Ciarella Simone , Khomenko Dmytro , Berthier Ludovic , Mocanu Felix C. , Reichman David R. , Scalliet Camille , Zamponi Francesco
Published: July 2023

Structural defects control the kinetic, thermodynamic and mechanical properties of glasses. For instance, rare quantum tunneling two-level systems (TLS) govern the physics of glasses at very low temperature. Due to their extremely low density, it is very hard to directly identify them in computer simulations. We introduce a machine learning approach to efficiently explore the potential energy landscape of glass models and identify desired classes of defects. We focus in particular on TLS and we design an algorithm that is able to rapidly predict the quantum splitting between any two amorphous configurations produced by classical simulations. This in turn allows us to shift the computational effort towards the collection and identification of a larger number of TLS, rather than the useless characterization of non-tunneling defects which are much more abundant. Finally, we interpret our machine learning model to understand how TLS are identified and characterized, thus giving direct physical insight into their microscopic nature.
Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma
Authors: Abbas Sujath , Pich Oriol , Devonshire Ginny , Zamani Shahriar A. , Katz-Summercorn Annalise , Killcoyne Sarah , Cheah Calvin , Nutzinger Barbara , Grehan Nicola , Lopez-Bigas Nuria ,   OCCAMS Consortium, Edwards Paul A. W. , Fidziukiewicz Elwira , Redmond Aisling M. , Freeman Adam , Smyth Elizabeth C. , O’Donovan Maria , Miremadi Ahmad , Malhotra Shalini , Tripathi Monika , Coles Hannah , Flint Conor , Eldridge Matthew , Jammula Sriganesh , Davies Jim , Crichton Charles , Carroll Nick , Hardwick Richard H. , Safranek Peter , Hindmarsh Andrew , Sujendran Vijayendran , Hayes Stephen J. , Ang Yeng , Sharrocks Andrew , Preston Shaun R. , Bagwan Izhar , Save Vicki , Skipworth Richard J. E. , Hupp Ted R. , O’Neill J. Robert , Tucker Olga , Beggs Andrew , Taniere Philippe , Puig Sonia , Contino Gianmarco , Underwood Timothy J. , Walker Robert C. , Grace Ben L. , Lagergren Jesper , Gossage James , Davies Andrew , Chang Fuju , Mahadeva Ula , Goh Vicky , Ciccarelli Francesca D. , Sanders Grant , Berrisford Richard , Chan David , Cheong Ed , Kumar Bhaskar , Sreedharan L. , Parsons Simon L. , Soomro Irshad , Kaye Philip , Saunders John , Lovat Laurence , Haidry Rehan , Scott Michael , Sothi Sharmila , Lishman Suzy , Hanna George B. , Peters Christopher J. , Moorthy Krishna , Grabowska Anna , Turkington Richard , McManus Damian , Coleman Helen , Petty Russell D. , Bartlett Freddie , Fitzgerald Rebecca C. , Secrier Maria
Published: July 2023

A variety of mutational processes drive cancer development, but their dynamics across the entire disease spectrum from pre-cancerous to advanced neoplasia are poorly understood. We explore the mutagenic processes shaping oesophageal adenocarcinoma tumorigenesis in 997 instances comprising distinct stages of this malignancy, from Barrett Oesophagus to primary tumours and advanced metastatic disease. The mutational landscape is dominated by the C[T > C/G]T substitution enriched signatures SBS17a/b, which are linked withTP53mutations, increased proliferation, genomic instability and disease progression. The APOBEC mutagenesis signature is a weak but persistent signal amplified in primary tumours. We also identify prevalent alterations in DNA damage repair pathways, with homologous recombination, base and nucleotide excision repair and translesion synthesis mutated in up to 50% of the cohort, and surprisingly uncoupled from transcriptional activity. Among these, the presence of base excision repair deficiencies show remarkably poor prognosis in the cohort. In this work, we provide insights on the mutational aetiology and changes enabling the transition from pre-neoplastic to advanced oesophageal adenocarcinoma.
Structural basis for specific RNA recognition by the alternative splicing factor RBM5
Authors: Soni Komal , Jagtap Pravin Kumar Ankush , Martínez-Lumbreras Santiago , Bonnal Sophie , Geerlof Arie , Stehle Ralf , Simon Bernd , Valcárcel Juan , Sattler Michael
Published: July 2023

The RNA-binding motif protein RBM5 belongs to a family of multi-domain RNA binding proteins that regulate alternative splicing of genes important for apoptosis and cell proliferation and have been implicated in cancer. RBM5 harbors structural modules for RNA recognition, such as RRM domains and a Zn finger, and protein-protein interactions such as an OCRE domain. Here, we characterize binding of the RBM5 RRM1-ZnF1-RRM2 domains to cis-regulatory RNA elements. A structure of the RRM1-ZnF1 region in complex with RNA shows how the tandem domains cooperate to sandwich target RNA and specifically recognize a GG dinucleotide in a non-canonical fashion. While the RRM1-ZnF1 domains act as a single structural module, RRM2 is connected by a flexible linker and tumbles independently. However, all three domains participate in RNA binding and adopt a closed architecture upon RNA binding. Our data highlight how cooperativity and conformational modularity of multiple RNA binding domains enable the recognition of distinct RNA motifs, thereby contributing to the regulation of alternative splicing. Remarkably, we observe surprising differences in coupling of the RNA binding domains between the closely related homologs RBM5 and RBM10.
pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle
Authors: Berger Fiona , Gomez Guillermo M. , Sanchez Cecilia P. , Posch Britta , Planelles Gabrielle , Sohraby Farzin , Nunes-Alves Ariane , Lanzer Michael
Published: July 2023

The chloroquine resistance transporter, PfCRT, of the human malaria parasitePlasmodium falciparumis sensitive to acidic pH. Consequently, PfCRT operates at 60% of its maximal drug transport activity at the pH of 5.2 of the digestive vacuole, a proteolytic organelle from which PfCRT expels drugs interfering with heme detoxification. Here we show by alanine-scanning mutagenesis that E207 is critical for pH sensing. The E207A mutation abrogates pH-sensitivity, while preserving drug substrate specificity. Substituting E207 with Asp or His, but not other amino acids, restores pH-sensitivity. Molecular dynamics simulations and kinetics analyses suggest an allosteric binding model in which PfCRT can accept both protons and chloroquine in a partial noncompetitive manner, with increased proton concentrations decreasing drug transport. Further simulations reveal that E207 relocates from a peripheral to an engaged location during the transport cycle, forming a salt bridge with residue K80. We propose that the ionized carboxyl group of E207 acts as a hydrogen acceptor, facilitating transport cycle progression, with pH sensing as a by-product.
Long-term neurological outcome after COVID-19 using all SARS-CoV-2 test results and hospitalisations in Denmark with 22-month follow-up
Authors: Grønkjær Clara S. , Christensen Rune H. B. , Kondziella Daniel , Benros Michael E.
Published: July 2023

Hospitalisation with COVID-19 is associated with an increased risk of neurological sequelae; however, representative nationwide studies comparing to other infections with similar severity and also including milder SARS-CoV-2 infections have been lacking. Using the nationwide Danish registers including all SARS-CoV-2 PCR test results and hospitalisations between March 1, 2020, and December 31, 2021, we estimate the risk of any first neurological disorder diagnosed in inpatient, outpatient, or emergency room settings. We show that positive tests increase the rate of neurological disorders by a hazard ratio of 1.96 (95% confidence interval: 1.88–2.05) compared to individuals not tested and by a hazard ratio of 1.11 (95% confidence interval: 1.07-1.16) compared to individuals with negative tests only. However, there is no evidence that the risk of neurological disorders is higher for individuals who test positive compared to non-COVID-19 infections treated with anti-infective medication. The risk of neurological disorders is increased after COVID-19-hospitalisation compared to no COVID-19 hospital admission; however, these risks are comparable to hospitalisation with other respiratory infections (Pvalue 0.328). In conclusion, COVID-19 is associated with an increased risk of neurological disorders, but no more than that observed after other infections of similar severity.