bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coevolution of Extreme Sea Levels and Sea‐Level Rise Under Global Warming
Authors: Boumis Georgios , Moftakhari Hamed R. , Moradkhani Hamid 
Published: July 2023

AbstractDesign of coastal defense structures like seawalls and breakwaters can no longer be based on stationarity assumption. In many parts of the world, an anticipated sea‐level rise (SLR) due to climate change will constitute present‐day extreme sea levels inappropriate for future coastal flood risk assessments since it will significantly increase their probability of occurrence. Here, we first show that global annual maxima sea levels (AMSLs) have been increasing in magnitude over the last decades, primarily due to a positive shift in mean sea level (MSL). Then, we apply non‐stationary extreme value theory to model the extremal behavior of sea levels with MSL as a covariate and quantify the evolution of AMSLs in the following decades using revised probabilistic sea‐level rise projections. Our analysis reveals that non‐stationary distributions exhibit distinct differences compared to simply considering stationary conditions with a change in location parameter equal to the amount of MSL rise. With the use of non‐stationary distributions, we show that by the year 2050 many locations will experience their present‐day 100‐yr return level as an event with return period less than 15 and 9 years under the moderate (RCP4.5) and high (RCP8.5) representative concentration pathways. Also, we find that by the end of this century almost all locations examined will encounter their current 100‐yr return level on an annual basis, even if CO2 concentration is kept at moderate levels (RCP4.5). Our assessment accounts for large uncertainty by incorporating ambiguities in both SLR projections and non‐stationary extreme value distribution parameters via a Monte Carlo simulation.
Xrcc5/Ku80 is required for the repair of DNA damage in fully grown meiotically arrested mammalian oocytes
Authors: Cai Xuebi , Stringer Jessica M. , Zerafa Nadeen , Carroll John , Hutt Karla J. 
Published: July 2023

AbstractMammalian oocytes spend most of their life in a unique state of cell cycle arrest at meiotic prophase I, during which time they are exposed to countless DNA-damaging events. Recent studies have shown that DNA double-strand break repair occurs predominantly via the homologous recombination (HR) pathway in small non-growing meiotically arrested oocytes (primordial follicle stage). However, the DNA repair mechanisms employed by fully grown meiotically arrested oocytes (GV-stage) have not been studied in detail. Here we established a conditional knockout mouse model to explore the role of Ku80, a critical component of the nonhomologous end joining (NHEJ) pathway, in the repair of DNA damage in GV oocytes. GV oocytes lacking Ku80 failed to repair etoposide-induced DNA damage, even when only low levels of damage were sustained. This indicates Ku80 is needed to resolve DSBs and that HR cannot compensate for a compromised NHEJ pathway in fully-grown oocytes. When higher levels of DNA damage were induced, a severe delay in M-phase entry was observed in oocytes lacking XRCC5 compared to wild-type oocytes, suggesting that Ku80-dependent repair of DNA damage is important for the timely release of oocytes from prophase I and resumption of meiosis. Ku80 was also found to be critical for chromosome integrity during meiotic maturation following etoposide exposure. These data demonstrate that Ku80, and NHEJ, are vital for quality control in mammalian GV stage oocytes and reveal that DNA repair pathway choice differs in meiotically arrested oocytes according to growth status.
Beta cell dysfunction induced by bone morphogenetic protein (BMP)-2 is associated with histone modifications and decreased NeuroD1 chromatin binding
Authors: Urizar Adriana Ibarra , Prause Michala , Ingerslev Lars Roed , Wortham Matthew , Sui Yinghui , Sander Maike , Williams Kristine , Barrès Romain , Larsen Martin R. , Christensen Gitte Lund , Billestrup Nils 
Published: July 2023

SummaryInsufficient insulin secretion is a hallmark of type 2 diabetes and has been attributed to beta cell identity loss characterized by decreased expression of several key beta cell genes. The pro-inflammatory factor BMP-2 is upregulated in islets of Langerhans from individuals with diabetes and acts as an inhibitor of beta cell function and proliferation. Exposure to BMP-2 induces expression of Id1-4, Hes-1, and Hey-1 which are transcriptional regulators associated with loss of differentiation. The aim of this study was to investigate the mechanism by which BMP-2 induces beta cell dysfunction and loss of cell maturity. Mouse islets exposed to BMP-2 for 10 days showed impaired glucose-stimulated insulin secretion and beta cell proliferation. BMP-2-induced beta cell dysfunction was associated with decreased expression of cell maturity and proliferation markers specific to the beta cell such as Ins1, Ucn3, and Ki67 and increased expression of Id1-4, Hes-1, and Hey-1. The top 30 most regulated proteins significantly correlated with corresponding mRNA expression. BMP-2-induced gene expression changes were associated with a predominant reduction in acetylation of H3K27 and a decrease in NeuroD1 chromatin binding activity. These results show that BMP-2 induces loss of beta cell maturity and suggest that remodeling of H3K27ac and decreased NeuroD1 DNA binding activity participate in the effect of BMP-2 on beta cell dysfunction.
Profiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform
Authors: Zeghal Manel , Laroche Geneviève , Freitas Julia Douglas , Wang Rebecca , Giguère Patrick M. 
Published: July 2023

AbstractRepresenting the most attractive and successful druggable receptors of the proteome, GPCRs regulate a myriad of physiological and pathophysiological functions. Although over half of present pharmaceuticals target GPCRs, the advancement of drug discovery is hampered by a lack of adequate screening tools, the majority of which are limited to probing agonist-induced G-protein and β-arrestin-2-mediated events as a measure of receptor activation. Here, we develop Tango-Trio, a comprehensive cell-based high-throughput platform comprising cumate-inducible expression of transducers, capable of the parallelized profiling of both basal and agonist-dependent GPCR activities. We capture the functional diversity of GPCRs, reporting β-arrestin-1/2 couplings, selectivities, and receptor internalization signatures across the GPCRome. Moreover, we present the construction of cumate-induced basal activation curves at approximately 200 receptors, including over 50 orphans. Overall, Tango-Trio’s robustness is well-suited for the functional characterization and screening of GPCRs, especially for parallel interrogation, and is a valuable addition to the pharmacological toolbox.
Closed-loop brain stimulation augments fear extinction in male rats
Authors: Sierra Rodrigo Ordoñez , Pedraza Lizeth Katherine , Barcsai Lívia , Pejin Andrea , Li Qun , Kozák Gábor , Takeuchi Yuichi , Nagy Anett J. , Lőrincz Magor L. , Devinsky Orrin , Buzsáki György , Berényi Antal 
Published: July 2023

AbstractDysregulated fear reactions can result from maladaptive processing of trauma-related memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., ‘renewal’ and ‘reinstatement’) and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWR-triggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders.
Fano resonant optical coatings platform for full gamut and high purity structural colors
Authors: ElKabbash Mohamed , Hoffman Nathaniel , Lininger Andrew R. , Jalil Sohail A. , Letsou Theodore , Hinczewski Michael , Strangi Giuseppe , Guo Chunlei 
Published: July 2023

AbstractStructural coloring is a photostable and environmentally friendly coloring approach that harnesses optical interference and nanophotonic resonances to obtain colors with a range of applications including display technologies, colorful solar panels, steganography, décor, data storage, and anticounterfeiting measures. We show that optical coatings exhibiting the photonic Fano Resonance present an ideal platform for structural coloring; they provide full color access, high color purity, high brightness, controlled iridescence, and scalable manufacturing. We show that an additional oxide film deposited on Fano resonant optical coatings (FROCs) increases the color purity (up to 99%) and color gamut coverage range of FROCs to 61% of the CIE color space. For wide-area structural coloring applications, FROCs have a significant advantage over existing structural coloring schemes.
RAS-independent ERK activation by constitutively active KSR3 in non-chordate metazoa
Authors: Chessel Aline , De Crozé Noémie , Molina Maria Dolores , Taberner Laura , Dru Philippe , Martin Luc , Lepage Thierry 
Published: July 2023

AbstractDuring early development of the sea urchin embryo, activation of ERK signalling in mesodermal precursors is not triggered by extracellular RTK ligands but by a cell-autonomous, RAS-independent mechanism that was not understood. We discovered that in these cells, ERK signalling is activated through the transcriptional activation of a gene encoding a protein related to Kinase Suppressor of Ras, that we named KSR3. KSR3 belongs to a family of catalytically inactive allosteric activators of RAF. Phylogenetic analysis revealed that genes encoding kinase defective KSR3 proteins are present in most non-chordate metazoa but have been lost in flies and nematodes. We show that the structure of KSR3 factors resembles that of several oncogenic human RAF mutants and that KSR3 from echinoderms, cnidarians and hemichordates activate ERK signalling independently of RAS when overexpressed in cultured cells. Finally, we used the sequence of KSR3 factors to identify activating mutations of human B-RAF. These findings reveal key functions for this family of factors as activators of RAF in RAS-independent ERK signalling in invertebrates. They have implications on the evolution of the ERK signalling pathway and suggest a mechanism for its co-option in the course of evolution.
Structure of engineered hepatitis C virus E1E2 ectodomain in complex with neutralizing antibodies
Authors: Metcalf Matthew C. , Janus Benjamin M. , Yin Rui , Wang Ruixue , Guest Johnathan D. , Pozharski Edwin , Law Mansun , Mariuzza Roy A. , Toth Eric A. , Pierce Brian G. , Fuerst Thomas R. , Ofek Gilad 
Published: July 2023

AbstractHepatitis C virus (HCV) is a major global health burden as the leading causative agent of chronic liver disease and hepatocellular carcinoma. While the main antigenic target for HCV-neutralizing antibodies is the membrane-associated E1E2 surface glycoprotein, the development of effective vaccines has been hindered by complications in the biochemical preparation of soluble E1E2 ectodomains. Here, we present a cryo-EM structure of an engineered, secreted E1E2 ectodomain of genotype 1b in complex with neutralizing antibodies AR4A, HEPC74, and IGH520. Structural characterization of the E1 subunit and C-terminal regions of E2 reveal an overall architecture of E1E2 that concurs with that observed for non-engineered full-length E1E2. Analysis of the AR4A epitope within a region of E2 that bridges between the E2 core and E1 defines the structural basis for its broad neutralization. Our study presents the structure of an E1E2 complex liberated from membrane via a designed scaffold, one that maintains all essential structural features of native E1E2. The study advances the understanding of the E1E2 heterodimer structure, crucial for the rational design of secreted E1E2 antigens in vaccine development.
Cryo-EM and femtosecond spectroscopic studies provide mechanistic insight into the energy transfer in CpcL-phycobilisomes
Authors: Zheng Lvqin , Zhang Zhengdong , Wang Hongrui , Zheng Zhenggao , Wang Jiayu , Liu Heyuan , Chen Hailong , Dong Chunxia , Wang Guopeng , Weng Yuxiang , Gao Ning , Zhao Jindong 
Published: July 2023

AbstractPhycobilisomes (PBS) are the major light harvesting complexes of photosynthesis in the cyanobacteria and red algae. CpcL-PBS is a type of small PBS in cyanobacteria that transfers energy directly to photosystem I without the core structure. Here we report the cryo-EM structure of the CpcL-PBS from the cyanobacterium Synechocystis sp. PCC 6803 at 2.6-Å resolution. The structure shows the CpcD domain of ferredoxin: NADP+ oxidoreductase is located at the distal end of CpcL-PBS, responsible for its attachment to PBS. With the evidence of ultrafast transient absorption and fluorescence spectroscopy, the roles of individual bilins in energy transfer are revealed. The bilin 1Iβ822 located near photosystem I has an enhanced planarity and is the red-bilin responsible for the direct energy transfer to photosystem I.
Direct mapping of kidney function by DCE-MRI urography using a tetrazinanone organic radical contrast agent
Authors: Calvert Nicholas D. , Kirby Alexia , Suchý Mojmír , Pallister Peter , Torrens Aidan A. , Burger Dylan , Melkus Gerd , Schieda Nicola , Shuhendler Adam J. 
Published: July 2023

AbstractChronic kidney disease (CKD) and acute kidney injury (AKI) are ongoing global health burdens. Glomerular filtration rate (GFR) is the gold standard measure of kidney function, with clinical estimates providing a global assessment of kidney health without spatial information of kidney- or region-specific dysfunction. The addition of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to the anatomical imaging already performed would yield a ‘one-stop-shop’ for renal assessment in cases of suspected AKI and CKD. Towards urography by DCE-MRI, we evaluated a class of nitrogen-centered organic radicals known as verdazyls, which are extremely stable even in highly reducing environments. A glucose-modified verdazyl, glucoverdazyl, provided contrast limited to kidney and bladder, affording functional kidney evaluation in mouse models of unilateral ureteral obstruction (UUO) and folic acid-induced nephropathy (FAN). Imaging outcomes correlated with histology and hematology assessing kidney dysfunction, and glucoverdazyl clearance rates were found to be a reliable surrogate measure of GFR.
The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells
Authors: Kunkel Thaddeus J. , Townsend Alice , Sullivan Kyle A. , Merlet Jean , Schuchman Edward H. , Jacobson Daniel A. , Lieberman Andrew P. 
Published: July 2023

AbstractThe intracellular cholesterol transporter NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann–Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. Here, we use single-nucleus RNA-seq on the forebrain of Npc1−/− mice at P16 to identify cell types and pathways affected early in pathogenesis. Our analysis uncovers significant transcriptional changes in the oligodendrocyte lineage during developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. We identify upregulation of genes associated with neurogenesis and synapse formation in Npc1−/− oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3. Npc1−/− oligodendrocyte progenitor cells reproduce impaired maturation in vitro, and this phenotype is rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. Moreover, mobilizing stored cholesterol in Npc1−/− mice by a single administration of 2-hydroxypropyl-β-cyclodextrin at P7 rescues myelination, epigenetic marks, and oligodendrocyte gene expression. Our findings highlight an important role for NPC1 in oligodendrocyte lineage maturation and epigenetic regulation, and identify potential targets for therapeutic intervention.
Toll-like receptor mediated inflammation directs B cells towards protective antiviral extrafollicular responses
Authors: Lam Jonathan H. , Baumgarth Nicole 
Published: July 2023

AbstractExtrafollicular plasmablast responses (EFRs) are considered to generate antibodies of low affinity that offer little protection from infections. Paradoxically, high avidity antigen-B cell receptor engagement is thought to be the main driver of B cell differentiation, whether in EFRs or slower-developing germinal centers (GCs). Here we show that influenza infection rapidly induces EFRs, generating protective antibodies via Toll-like receptor (TLR)-mediated mechanisms that are both B cell intrinsic and extrinsic. B cell-intrinsic TLR signals support antigen-stimulated B cell survival, clonal expansion, and the differentiation of B cells via induction of IRF4, the master regulator of B cell differentiation, through activation of NF-kB c-Rel. Provision of sustained TLR4 stimulation after immunization shifts the fate of virus-specific B cells towards EFRs instead of GCs, prompting rapid antibody production and improving their protective capacity over antigen/alum administration alone. Thus, inflammatory signals act as B cell fate-determinants for the rapid generation of protective antiviral extrafollicular responses.
Laser maskless fast patterning for multitype microsupercapacitors
Authors: Yuan Yongjiu , Li Xin , Jiang Lan , Liang Misheng , Zhang Xueqiang , Wu Shouyu , Wu Junrui , Tian Mengyao , Zhao Yang , Qu Liangti 
Published: July 2023

AbstractDownsizing electrode architectures have significant potential for microscale energy storage devices. Asymmetric micro-supercapacitors play an essential role in various applications due to their high voltage window and energy density. However, efficient production and sophisticated miniaturization of asymmetric micro-supercapacitors remains challenging. Here, we develop a maskless ultrafast fabrication of multitype micron-sized (10 × 10 μm2) micro-supercapacitors via temporally and spatially shaped femtosecond laser. MXene/1T-MoS2 can be integrated with laser-induced MXene-derived TiO2 and 1T-MoS2-derived MoO3 to generate over 6,000 symmetric micro-supercapacitors or 3,000 asymmetric micro-supercapacitors with high-resolution (200 nm) per minute. The asymmetric micro-supercapacitors can be integrated with other micro devices, thanks to the ultrahigh specific capacitance (220 mF cm−2 and 1101 F cm−3), voltage windows in series (52 V), energy density (0.495 Wh cm−3) and power density (28 kW cm−3). Our approach enables the industrial manufacturing of multitype micro-supercapacitors and improves the feasibility and flexibility of micro-supercapacitors in practical applications.
Variation in bridgmanite grain size accounts for the mid-mantle viscosity jump
Authors: Fei Hongzhan , Ballmer Maxim D. , Faul Ulrich , Walte Nicolas , Cao Weiwei , Katsura Tomoo 
Published: July 2023

AbstractA viscosity jump of one to two orders of magnitude in the lower mantle of Earth at 800–1,200-km depth is inferred from geoid inversions and slab-subducting speeds. This jump is known as the mid-mantle viscosity jump1,2. The mid-mantle viscosity jump is a key component of lower-mantle dynamics and evolution because it decelerates slab subduction3, accelerates plume ascent4and inhibits chemical mixing5. However, because phase transitions of the main lower-mantle minerals do not occur at this depth, the origin of the viscosity jump remains unknown. Here we show that bridgmanite-enriched rocks in the deep lower mantle have a grain size that is more than one order of magnitude larger and a viscosity that is at least one order of magnitude higher than those of the overlying pyrolitic rocks. This contrast is sufficient to explain the mid-mantle viscosity jump1,2. The rapid growth in bridgmanite-enriched rocks at the early stage of the history of Earth and the resulting high viscosity account for their preservation against mantle convection5–7. The high Mg:Si ratio of the upper mantle relative to chondrites8, the anomalous142Nd:144Nd,182W:184W and3He:4He isotopic ratios in hot-spot magmas9,10, the plume deflection4and slab stagnation in the mid-mantle3as well as the sparse observations of seismic anisotropy11,12can be explained by the long-term preservation of bridgmanite-enriched rocks in the deep lower mantle as promoted by their fast grain growth.
A rise-to-threshold process for a relative-value decision
Authors: Vijayan Vikram , Wang Fei , Wang Kaiyu , Chakravorty Arun , Adachi Atsuko , Akhlaghpour Hessameddin , Dickson Barry J. , Maimon Gaby 
Published: July 2023

AbstractWhereas progress has been made in the identification of neural signals related to rapid, cued decisions1–3, less is known about how brains guide and terminate more ethologically relevant decisions in which an animal’s own behaviour governs the options experienced over minutes4–6. Drosophila search for many seconds to minutes for egg-laying sites with high relative value7,8 and have neurons, called oviDNs, whose activity fulfills necessity and sufficiency criteria for initiating the egg-deposition motor programme9. Here we show that oviDNs express a calcium signal that (1) dips when an egg is internally prepared (ovulated), (2) drifts up and down over seconds to minutes—in a manner influenced by the relative value of substrates—as a fly determines whether to lay an egg and (3) reaches a consistent peak level just before the abdomen bend for egg deposition. This signal is apparent in the cell bodies of oviDNs in the brain and it probably reflects a behaviourally relevant rise-to-threshold process in the ventral nerve cord, where the synaptic terminals of oviDNs are located and where their output can influence behaviour. We provide perturbational evidence that the egg-deposition motor programme is initiated once this process hits a threshold and that subthreshold variation in this process regulates the time spent considering options and, ultimately, the choice taken. Finally, we identify a small recurrent circuit that feeds into oviDNs and show that activity in each of its constituent cell types is required for laying an egg. These results argue that a rise-to-threshold process regulates a relative-value, self-paced decision and provide initial insight into the underlying circuit mechanism for building this process.