bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Window Into Eastern Mediterranean Productivity Conditions Over Three Pliocene Precession‐Forced Climate Cycles
Authors: Cutmore A. , Bale N. , De Lange G. J. , Nijenhuis I. A. , Lourens L. J. 
Published: April 2023

AbstractHere, we explore the importance of export productivity versus anoxia in the formation of sedimentary layers with enhanced total organic carbon (TOC) content. We use geochemical, sedimentological and micropaleontological records from two SW Sicily outcropping successions, Lido Rossello (LR) and Punta di Maiata (PM), over three Early Pliocene precession‐forced climate cycles (4.7–4.6 million years ago [Ma]). Gray marls, deposited during precession minima, show enhanced TOC in both records. We suggest that basin‐wide, low‐oxygenated bottom‐waters, resulting from freshwater‐induced stratification during precession minimum, was integral to preserving gray marl TOC. Furthermore, prolonged eastern Mediterranean stratification may have produced a deep chlorophyll maximum (DCM), leading to “shade‐flora” dominated productivity. The LR succession displays two unique laminated layers containing enhanced TOC. These laminations do not occur at specific times in the precession cycle or in time‐equivalent PM samples. They are likely to have been produced by an intermittent dysoxic/anoxic pool at LR, caused by a local depression, which enhanced TOC preservation. Consequently, the laminations provide a rare window into “true” eastern Mediterranean productivity conditions during precession maxima, as organic matter is typically poorly preserved during these period due to enhanced ventilation. The laminated “windows” indicate that eastern Mediterranean export productivity may not have been significantly lower during precession maxima compared to precession minima, as previously thought. During these periods, productivity conditions are likely to have been comparable to the modern eastern Mediterranean, with a spring‐bloom caused by enhanced winter/spring deep‐water mixing preceding a summer “shade‐flora” bloom caused by a summer‐stratification induced DCM.
Influence of Bed Roughness on Flow and Turbulence Structure Around a Partially‐Buried, Isolated Freshwater Mussel
Authors: Lazzarin T. , Constantinescu G. , Di Micco L. , Wu H. , Lavignani F. , Lo Brutto M. , Termini D. , Viero D. P. 
Published: April 2023

AbstractThe present study uses eddy‐resolving numerical simulations to investigate how bed roughness affects flow and turbulence structure around an isolated, partially‐buried mussel (Unio elongatulus) aligned with the incoming flow. The rough‐bed simulations resolve the flow past the exposed part of a gravel bed, whose surface is obtained from a laboratory experiment that also provides some additional data for validation of the numerical model. Results are also discussed for the limiting case of a horizontal smooth bed. Additionally, the effects of varying the level of burial of the mussel inside the substrate and the discharge through the two mussel siphons are investigated via a set of simulations in which the ratio between the median diameter of the (gravel) particles forming the rough bed, d50, and the height of the exposed part of the mussel, h, varies between 0.10 and 0.22. The increase of the bed roughness is associated with a strong amplification of the turbulence kinetic energy in the near‐wake region. Increasing the bed roughness and/or reducing h intensifies the interactions of the eddies generated by the bed particles with the base and tip vortices induced by the active filtering and by the mussel shell, respectively, which, in turn, induces a more rapid dissipation of these vortices. Increasing the bed roughness also reduces the strength of the main downwelling flow region forming in the wake. The strong downwelling near the symmetry plane is the main reason why the symmetric wake shedding mode dominates in the smooth bed simulations with negligible active filtering. By contrast, the anti‐symmetric wake shedding mode dominates in the simulations conduced with a high value of the bed roughness. The mean streamwise drag force coefficient for the emerged part of the shell and the dilution of the excurrent siphon jet increase with increasing bed roughness.
Hot Rocks: Interpreting Extremes of Earth Surface Temperatures From the Geologic Record
Authors: Suarez Marina B. 
Published: April 2023

AbstractHow hot can we expect Greenhouse Earth to have been in the past and the future? This is a question that deep‐time paleoclimatologists have long investigated. In a new paper by Fetrow et al. (2022), https://doi.org/10.1029/2022PA004517, deconvolving the depositional environments and burial history of continental carbonates deposited during known greenhouse climates, such as the Cretaceous, highlight the way Earth scientists can embark on understanding the clumped isotope derived temperatures and properly interpreting such temperatures.
Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids
Authors: Stiernman Louise , Dubol Manon , Comasco Erika , Sundström-Poromaa Inger , Boraxbekk Carl-Johan , Johansson Maja , Bixo Marie 
Published: April 2023

AbstractPremenstrual dysphoric disorder (PMDD) is a debilitating disorder characterized by severe mood symptoms in the luteal phase of the menstrual cycle. PMDD symptoms are hypothesized to be linked to an altered sensitivity to normal luteal phase levels of allopregnanolone (ALLO), a GABAA-modulating progesterone metabolite. Moreover, the endogenous 3β-epimer of ALLO, isoallopregnanolone (ISO), has been shown to alleviate PMDD symptoms through its selective and dose-dependent antagonism of the ALLO effect. There is preliminary evidence showing altered recruitment of brain regions during emotion processing in PMDD, but whether this is associated to serum levels of ALLO, ISO or their relative concentration is unknown. In the present study, subjects with PMDD and asymptomatic controls underwent functional magnetic resonance imaging (fMRI) in the mid-follicular and the late-luteal phase of the menstrual cycle. Brain responses to emotional stimuli were investigated and related to serum levels of ovarian steroids, the neurosteroids ALLO, ISO, and their ratio ISO/ALLO. Participants with PMDD exhibited greater activity in brain regions which are part of emotion-processing networks during the late-luteal phase of the menstrual cycle. Furthermore, activity in key regions of emotion processing networks - the parahippocampal gyrus and amygdala - was differentially associated to the ratio of ISO/ALLO levels in PMDD subjects and controls. Specifically, a positive relationship between ISO/ALLO levels and brain activity was found in PMDD subjects, while the opposite was observed in controls. In conclusion, individuals with PMDD show altered emotion-induced brain responses in the late-luteal phase of the menstrual cycle which may be related to an abnormal response to physiological levels of GABAA-active neurosteroids.
Upregulation of β-catenin signaling represents a single common pathway leading to the various phenotypes of spinal degeneration and pain
Authors: Lu Ke , Wang Qingyun , Jiang Hua , Li Jun , Yao Zhou , Huang Yongcan , Chen Jianquan , Zhang Yejia , Xiao Guozhi , Hu Xueyu , Luo Zhuojing , Yang Liu , Tong Liping , Chen Di 
Published: April 2023

AbstractSpine degeneration is an aging-related disease, but its molecular mechanisms remain unknown, although elevated β-catenin signaling has been reported to be involved in intervertebral disc degeneration. Here, we determined the role of β-catenin signaling in spinal degeneration and in the homeostasis of the functional spinal unit (FSU), which includes the intervertebral disc, vertebra and facet joint and is the smallest physiological motion unit of the spine. We showed that pain sensitivity in patients with spinal degeneration is highly correlated with β-catenin protein levels. We then generated a mouse model of spinal degeneration by transgenic expression of constitutively active β-catenin in Col2+ cells. We found that β-catenin-TCF7 activated the transcription of CCL2, a known critical factor in osteoarthritic pain. Using a lumbar spine instability model, we showed that a β-catenin inhibitor relieved low back pain. Our study indicates that β-catenin plays a critical role in maintaining spine tissue homeostasis, its abnormal upregulation leads to severe spinal degeneration, and its targeting could be an avenue to treat this condition.
CYP1B1 inhibits ferroptosis and induces anti-PD-1 resistance by degrading ACSL4 in colorectal cancer
Authors: Chen Congcong , Yang Yabing , Guo Yanguan , He Jiashuai , Chen Zuyang , Qiu Shenghui , Zhang Yiran , Ding Hui , Pan Jinghua , Pan Yunlong 
Published: April 2023

AbstractImmune checkpoint blockade (ICB) is a promising treatment strategy for colorectal cancer (CRC) patients. However, most CRC patients do not response well to ICB therapy. Increasing evidence indicates that ferroptosis plays a critical role in immunotherapy. ICB efficacy may be enhanced by inducing tumor ferroptosis. Cytochrome P450 1B1 (CYP1B1) is a metabolic enzyme that participates in arachidonic acid metabolism. However, the role of CYP1B1 in ferroptosis remains unclear. In this study, we demonstrated that CYP1B1 derived 20-HETE activated the protein kinase C pathway to increase FBXO10 expression, which in turn promoted the ubiquitination and degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4), ultimately inducing tumor cells resistance to ferroptosis. Furthermore, inhibiting CYP1B1 sensitized tumor cells to anti-PD-1 antibody in a mouce model. In addition, CYP1B1 expression was negatively correlated with ACSL4 expression, and high expression indicates poor prognosis in CRC. Taken together, our work identified CYP1B1 as a potential biomarker for enhancing anti-PD-1 therapy in CRC.
Sestrin2-mediated disassembly of stress granules dampens aerobic glycolysis to overcome glucose starvation
Authors: Li Mingyue , Thorne Rick Francis , Wang Ruijie , Cao Leixi , Cheng Fangyuan , Sun Xuedan , Wu Mian , Ma Jianli , Liu Lianxin 
Published: April 2023

AbstractSestrins are a small gene family of pleiotropic factors whose actions promote cell adaptation to a range of stress conditions. In this report we disclose the selective role of Sestrin2 (SESN2) in dampening aerobic glycolysis to adapt to limiting glucose conditions. Removal of glucose from hepatocellular carcinoma (HCC) cells inhibits glycolysis associated with the downregulation of the rate-limiting glycolytic enzyme hexokinase 2 (HK2). Moreover, the accompanying upregulation of SESN2 through an NRF2/ATF4-dependent mechanism plays a direct role in HK2 regulation by destabilizing HK2 mRNA. We show SESN2 competes with insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) for binding with the 3′-UTR region of HK2 mRNA. Interactions between IGF2BP3 and HK2 mRNA result in their coalescence into stress granules via liquid-liquid phase separation (LLPS), a process which serves to stabilize HK2 mRNA. Conversely, the enhanced expression and cytoplasmic localization of SESN2 under glucose deprivation conditions favors the downregulation of HK2 levels via decreases in the half-life of HK2 mRNA. The resulting dampening of glucose uptake and glycolytic flux inhibits cell proliferation and protect cells from glucose starvation-induced apoptotic cell death. Collectively, our findings reveal an intrinsic survival mechanism allowing cancer cells to overcome chronic glucose shortages, also providing new mechanistic insights into SESN2 as an RNA-binding protein with a role in reprogramming of cancer cell metabolism.
The expanding genetic and clinical landscape associated with Meier-Gorlin syndrome
Authors: Nielsen-Dandoroff Emily , Ruegg Mischa S. G. , Bicknell Louise S. 
Published: April 2023

AbstractHigh-throughput sequencing has become a standard first-tier approach for both diagnostics and research-based genetic testing. Consequently, this hypothesis-free testing manner has revealed the true breadth of clinical features for many established genetic disorders, including Meier-Gorlin syndrome (MGORS). Previously known as ear-patella short stature syndrome, MGORS is characterized by growth delay, microtia, and patella hypo/aplasia, as well as genital abnormalities, and breast agenesis in females. Following the initial identification of genetic causes in 2011, a total of 13 genes have been identified to date associated with MGORS. In this review, we summarise the genetic and clinical findings of each gene associated with MGORS and highlight molecular insights that have been made through studying patient variants. We note interesting observations arising across this group of genes as the number of patients has increased, such as the unusually high number of synonymous variants affecting splicing in CDC45 and a subgroup of genes that also cause craniosynostosis. We focus on the complicated molecular genetics for DONSON, where we examine potential genotype-phenotype patterns using the first 3D structural model of DONSON. The canonical role of all proteins associated with MGORS are involved in different stages of DNA replication and in addition to summarising how patient variants impact on this process, we discuss the potential contribution of non-canonical roles of these proteins to the pathophysiology of MGORS.
Oncogenic drivers dictate immune control of acute myeloid leukemia
Authors: Austin Rebecca J. , Straube Jasmin , Halder Rohit , Janardhanan Yashaswini , Bruedigam Claudia , Witkowski Matthew , Cooper Leanne , Porter Amy , Braun Matthias , Souza-Fonseca-Guimaraes Fernando , Minnie Simone A. , Cooper Emily , Jacquelin Sebastien , Song Axia , Bald Tobias , Nakamura Kyohei , Hill Geoffrey R. , Aifantis Iannis , Lane Steven W. , Bywater Megan J. 
Published: April 2023

AbstractAcute myeloid leukemia (AML) is a genetically heterogeneous, aggressive hematological malignancy induced by distinct oncogenic driver mutations. The effect of specific AML oncogenes on immune activation or suppression is unclear. Here, we examine immune responses in genetically distinct models of AML and demonstrate that specific AML oncogenes dictate immunogenicity, the quality of immune response and immune escape through immunoediting. Specifically, expression of NrasG12D alone is sufficient to drive a potent anti-leukemia response through increased MHC Class II expression that can be overcome with increased expression of Myc. These data have important implications for the design and implementation of personalized immunotherapies for patients with AML.
Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii
Authors: Jonkergouw Christopher , Beyeh Ngong Kodiah , Osmekhina Ekaterina , Leskinen Katarzyna , Taimoory S. Maryamdokht , Fedorov Dmitrii , Anaya-Plaza Eduardo , Kostiainen Mauri A. , Trant John F. , Ras Robin H. A. , Saavalainen Päivi , Linder Markus B. 
Published: April 2023

AbstractThe limited diversity in targets of available antibiotic therapies has put tremendous pressure on the treatment of bacterial pathogens, where numerous resistance mechanisms that counteract their function are becoming increasingly prevalent. Here, we utilize an unconventional anti-virulence screen of host-guest interacting macrocycles, and identify a water-soluble synthetic macrocycle, Pillar[5]arene, that is non-bactericidal/bacteriostatic and has a mechanism of action that involves binding to both homoserine lactones and lipopolysaccharides, key virulence factors in Gram-negative pathogens. Pillar[5]arene is active against Top Priority carbapenem- and third/fourth-generation cephalosporin-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, suppressing toxins and biofilms and increasing the penetration and efficacy of standard-of-care antibiotics in combined administrations. The binding of homoserine lactones and lipopolysaccharides also sequesters their direct effects as toxins on eukaryotic membranes, neutralizing key tools that promote bacterial colonization and impede immune defenses, both in vitro and in vivo. Pillar[5]arene evades both existing antibiotic resistance mechanisms, as well as the build-up of rapid tolerance/resistance. The versatility of macrocyclic host-guest chemistry provides ample strategies for tailored targeting of virulence in a wide range of Gram-negative infectious diseases.
In mitosis integrins reduce adhesion to extracellular matrix and strengthen adhesion to adjacent cells
Authors: Huber Maximilian , Casares-Arias Javier , Fässler Reinhard , Müller Daniel J. , Strohmeyer Nico 
Published: April 2023

AbstractTo enter mitosis, most adherent animal cells reduce adhesion, which is followed by cell rounding. How mitotic cells regulate adhesion to neighboring cells and extracellular matrix (ECM) proteins is poorly understood. Here we report that, similar to interphase, mitotic cells can employ integrins to initiate adhesion to the ECM in a kindlin- and talin-dependent manner. However, unlike interphase cells, we find that mitotic cells cannot engage newly bound integrins to actomyosin via talin or vinculin to reinforce adhesion. We show that the missing actin connection of newly bound integrins leads to transient ECM-binding and prevents cell spreading during mitosis. Furthermore, β1 integrins strengthen the adhesion of mitotic cells to adjacent cells, which is supported by vinculin, kindlin, and talin1. We conclude that this dual role of integrins in mitosis weakens the cell-ECM adhesion and strengthens the cell-cell adhesion to prevent delamination of the rounding and dividing cell.
Photoacoustic 2D actuator via femtosecond pulsed laser action on van der Waals interfaces
Authors: Chen Xin , Kislyakov Ivan M. , Wang Tiejun , Xie Yafeng , Wang Yan , Zhang Long , Wang Jun 
Published: April 2023

AbstractAchieving optically controlled nanomachine engineering can satisfy the touch-free and non-invasive demands of optoelectronics, nanotechnology, and biology. Traditional optical manipulations are mainly based on optical and photophoresis forces, and they usually drive particles in gas or liquid environments. However, the development of an optical drive in a non-fluidic environment, such as on a strong van der Waals interface, remains difficult. Herein, we describe an efficient 2D nanosheet actuator directed by an orthogonal femtosecond laser, where 2D VSe2 and TiSe2 nanosheets deposited on sapphire substrates can overcome the interface van der Waals forces (tens and hundreds of megapascals of surface density) and move on the horizontal surfaces. We attribute the observed optical actuation to the momentum generated by the laser-induced asymmetric thermal stress and surface acoustic waves inside the nanosheets. 2D semimetals with high absorption coefficient can enrich the family of materials suitable to implement optically controlled nanomachines on flat surfaces.
OBERON3 and SUPPRESSOR OF MAX2 1-LIKE proteins form a regulatory module driving phloem development
Authors: Wallner Eva-Sophie , Tonn Nina , Shi Dongbo , Luzzietti Laura , Wanke Friederike , Hunziker Pascal , Xu Yingqiang , Jung Ilona , Lopéz-Salmerón Vadir , Gebert Michael , Wenzl Christian , Lohmann Jan U. , Harter Klaus , Greb Thomas 
Published: April 2023

AbstractSpatial specificity of cell fate decisions is central for organismal development. The phloem tissue mediates long-distance transport of energy metabolites along plant bodies and is characterized by an exceptional degree of cellular specialization. How a phloem-specific developmental program is implemented is, however, unknown. Here we reveal that the ubiquitously expressed PHD-finger protein OBE3 forms a central module with the phloem-specific SMXL5 protein for establishing the phloem developmental program in Arabidopsis thaliana. By protein interaction studies and phloem-specific ATAC-seq analyses, we show that OBE3 and SMXL5 proteins form a complex in nuclei of phloem stem cells where they promote a phloem-specific chromatin profile. This profile allows expression of OPS, BRX, BAM3, and CVP2 genes acting as mediators of phloem differentiation. Our findings demonstrate that OBE3/SMXL5 protein complexes establish nuclear features essential for determining phloem cell fate and highlight how a combination of ubiquitous and local regulators generate specificity of developmental decisions in plants.
Priming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors
Authors: Kim Dae Joong , Anandh Swetha , Null Jamie L. , Przanowski Piotr , Bhatnagar Sanchita , Kumar Pankaj , Shelton Sarah E. , Grundy Erin E. , Chiappinelli Katherine B. , Kamm Roger D. , Barbie David A. , Dudley Andrew C. 
Published: April 2023

AbstractTargeting DNA methyltransferase 1 (DNMT1) has immunomodulatory and anti-neoplastic activity, especially when paired with cancer immunotherapies. Here we explore the immunoregulatory functions of DNMT1 in the tumor vasculature of female mice. Dnmt1 deletion in endothelial cells (ECs) impairs tumor growth while priming expression of cytokine-driven cell adhesion molecules and chemokines important for CD8+ T-cell trafficking across the vasculature; consequently, the efficacy of immune checkpoint blockade (ICB) is enhanced. We find that the proangiogenic factor FGF2 promotes ERK-mediated DNMT1 phosphorylation and nuclear translocation to repress transcription of the chemokines Cxcl9/Cxcl10 in ECs. Targeting Dnmt1 in ECs reduces proliferation but augments Th1 chemokine production and extravasation of CD8+ T-cells, suggesting DNMT1 programs immunologically anergic tumor vasculature. Our study is in good accord with preclinical observations that pharmacologically disrupting DNMT1 enhances the activity of ICB but suggests an epigenetic pathway presumed to be targeted in cancer cells is also operative in the tumor vasculature.
Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics
Authors: Xu Xinyu , Shonberg Jeremy , Kaindl Jonas , Clark Mary J. , Stößel Anne , Maul Luis , Mayer Daniel , Hübner Harald , Hirata Kunio , Venkatakrishnan A. J. , Dror Ron O. , Kobilka Brian K. , Sunahara Roger K. , Liu Xiangyu , Gmeiner Peter 
Published: April 2023

AbstractG protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β1and β2adrenergic receptors (β1AR and β2AR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the β2AR over the β1AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the β2AR, as well as a less stable binding pocket for constrained epinephrine in the β1AR. The differences in the amino acid sequence of the extracellular vestibule of the β1AR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the β2AR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs.