bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for Kilometer‐Scale Biophysical Features at the Gulf Stream Front
Authors: Gray Patrick Clifton , Savelyev Ivan , Cassar Nicolas , Lévy Marina , Boss Emmanuel , Lehahn Yoav , Bourdin Guillaume , Thompson Kate A. , Windle Anna , Gronniger Jessica , Floge Sheri , Hunt Dana E. , Silsbe Greg , Johnson Zackary I. , Johnston David W. 
Published: March 2024

AbstractUnderstanding the interplay of ocean physics and biology at the submesoscale and below (<30 km) is an ongoing challenge in oceanography. While poorly constrained, these scales may be of critical importance for understanding how changing ocean dynamics will impact marine ecosystems. Fronts in the ocean, regions where two disparate water masses meet and isopycnals become tilted toward vertical, are considered hotspots for biophysical interaction, but there is limited observational evidence at the appropriate scales to assess their importance. Fronts around western boundary currents like the Gulf Stream are of particular interest as these dynamic physical regions are thought to influence both productivity and composition of primary producers; however, how exactly this plays out is not well known. Using satellite data and 2 years of in situ observations across the Gulf Stream front near Cape Hatteras, North Carolina, we investigate how submesoscale frontal dynamics could affect biological communities and generate hotspots of productivity and export. We assess the seasonality and phenology of the region, generalize the kilometer‐scale structure of the front, and analyze 69 transects to assess two physical processes of potential biogeochemical importance: cold shelf filament subduction and high salinity Sargasso Sea obduction. We link these processes observationally to meanders in the Gulf Stream and discuss how cold filament subduction could be exporting carbon and how obduction of high salinity water from depth is connected with high chlorophyll‐a. Finally, we report on phytoplankton community composition in each of these features and integrate these observations into our understanding of frontal submesoscale dynamics.
Modeling the Global Water Cycle—The Effect of Mg‐Sursassite and Phase A on Deep Slab Dehydration and the Global Subduction Zone Water Budget
Authors: Gies Nils Benjamin , Konrad‐Schmolke Matthias , Hermann Jörg 
Published: March 2024

AbstractWe study the interplay of the thermal structure within subducted oceanic slabs together with the stability fields of hydrous phases that control slab dehydration and the amount of water transported into the deeper mantle. We implement different published thermodynamic data for phase A and Mg‐sursassite into a model of 56 subduction zones and evaluate the effect of these phases on the global water budget. We modeled vertical fluid fluxes within the slab such that dehydration‐derived fluid was allowed to react with fluid‐undersaturated rocks in other parts of the slab. The effect of Mg‐sursassite on the global water budget is limited, because the Clapeyron slope of this dehydration reaction is steeper than most pressure‐temperature trajectories in subduction zones. Two sets of published thermodynamic data for phase A yield significantly different values for the amount of deeply subducted water, ranging between 8 × 108 Tg/Ma and 1.4 × 109 Tg/Ma. In some subduction zones, the differences span several orders of magnitude. The absolute modeled amount of deeply subducted water strongly depends on the depth and intensity of slab mantle hydration, but a comparison of modeled and experimental data indicates that the thermodynamic dataset that yielded higher values is more reliable and should be implemented in future thermodynamic models. Our results show that the stable phases around the choke point as well as the slope and position of the phase A‐out reaction influence the deep water release from the slab, but the slope and position of the phase A dehydration reaction mainly control the recycling of water into the deep mantle.
Loss of RNA-binding protein CELF2 promotes acute leukemia development via FAT10-mTORC1
Authors: Guo Tengxiao , Wang Yuxia , Sun Xiaolu , Hou Shuaibing , Lan Yanjie , Yuan Shengnan , Yang Shuang , Zhao Fei , Chu Yajing , Ma Yuanwu , Cheng Tao , Yu Jia , Liu Bing , Yuan Weiping , Wang Xiaomin 
Published: March 2024

AbstractRNA-binding proteins (RBPs) are critical regulators for RNA transcription and translation. As a key member of RBPs, ELAV-like family protein 2 (CELF2) has been shown to regulate RNA splicing and embryonic hematopoietic development and was frequently seen dysregulated in acute myeloid leukemia (AML). However, the functional role(s) of CELF2 in hematopoiesis and leukemogenesis has not been fully elucidated. In the current study, we showed that Celf2 deficiency in hematopoietic system led to enhanced HSCs self-renewal and differentiation toward myeloid cells in mice. Loss of Celf2 accelerated myeloid cell transformation and AML development in MLL-AF9-induced AML murine models. Gene expression profiling integrated with RNA immunoprecipitation sequencing (RIP-Seq), together with biochemical experiments revealed that CELF2 deficiency stabilizes FAT10 mRNA, promotes FAT10 translation, thereby increases AKT phosphorylation and mTORC1 signaling pathway activation. Notably, combination therapy with a mTORC1 inhibitor (Rapamycin) and a MA9/DOTL1 inhibitor (EPZ-5676) reduced the leukemia burden in MLL-AF9 mice lacking Celf2 in vivo. Our study elucidated a novel mechanism by which the CELF2/FAT10-AKT/mTORC1 axis regulates the proliferation of normal blood cells and the development of AML, thus providing potential therapeutic targets for myeloid leukemia suppression.
RIPK3 cleavage is dispensable for necroptosis inhibition but restricts NLRP3 inflammasome activation
Authors: Tran Hong Tri , Kratina Tobias , Coutansais Auriane , Michalek Dominika , Hogan Benjamin M. , Lawlor Kate E. , Vince James E. , Silke John , Lalaoui Najoua 
Published: March 2024

AbstractCaspase-8 activity is required to inhibit necroptosis during embryogenesis in mice. In vitro studies have suggested that caspase-8 directly cleaves RIPK1, CYLD and the key necroptotic effector kinase RIPK3 to repress necroptosis. However, recent studies have shown that mice expressing uncleavable RIPK1 die during embryogenesis due to excessive apoptosis, while uncleavable CYLD mice are viable. Therefore, these results raise important questions about the role of RIPK3 cleavage. To evaluate the physiological significance of RIPK3 cleavage, we generated Ripk3D333A/D333A mice harbouring a point mutation in the conserved caspase-8 cleavage site. These mice are viable, demonstrating that RIPK3 cleavage is not essential for blocking necroptosis during development. Furthermore, unlike RIPK1 cleavage-resistant cells, Ripk3D333A/D333A cells were not significantly more sensitive to necroptotic stimuli. Instead, we found that the cleavage of RIPK3 by caspase-8 restricts NLRP3 inflammasome activation-dependent pyroptosis and IL-1β secretion when Inhibitors of APoptosis (IAP) are limited. These results demonstrate that caspase-8 does not inhibit necroptosis by directly cleaving RIPK3 and further underscore a role for RIPK3 in regulating the NLRP3 inflammasome.
The EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression
Authors: Jin Huilin , Huang Xiaoling , Pan Qihao , Ma Ning , Xie Xiaoshan , Wei Yue , Yu Fenghai , Wen Weijie , Zhang Boyu , Zhang Peng , Chen Xijie , Wang Jie , Liu Ran-yi , Lin Junzhong , Meng Xiangqi , Lee Mong-Hong 
Published: March 2024

AbstractEukaryotic initiation translation factor 3 subunit h (EIF3H) plays critical roles in regulating translational initiation and predicts poor cancer prognosis, but the mechanism underlying EIF3H tumorigenesis remains to be further elucidated. Here, we report that EIF3H is overexpressed in colorectal cancer (CRC) and correlates with poor prognosis. Conditional Eif3h deletion suppresses colorectal tumorigenesis in AOM/DSS model. Mechanistically, EIF3H functions as a deubiquitinase for HAX1 and stabilizes HAX1 via antagonizing βTrCP-mediated ubiquitination, which enhances the interaction between RAF1, MEK1 and ERK1, thereby potentiating phosphorylation of ERK1/2. In addition, activation of Wnt/β-catenin signaling induces EIF3H expression. EIF3H/HAX1 axis promotes CRC tumorigenesis and metastasis in mouse orthotopic cancer model. Significantly, combined targeting Wnt and RAF1-ERK1/2 signaling synergistically inhibits tumor growth in EIF3H-high patient-derived xenografts. These results uncover the important roles of EIF3H in mediating CRC progression through regulating HAX1 and RAF1-ERK1/2 signaling. EIF3H represents a promising therapeutic target and prognostic marker in CRC.
Immunization with V987H-stabilized Spike glycoprotein protects K18-hACE2 mice and golden Syrian hamsters upon SARS-CoV-2 infection
Authors: Ávila-Nieto Carlos , Vergara-Alert Júlia , Amengual-Rigo Pep , Ainsua-Enrich Erola , Brustolin Marco , Rodríguez de la Concepción María Luisa , Pedreño-Lopez Núria , Rodon Jordi , Urrea Victor , Pradenas Edwards , Marfil Silvia , Ballana Ester , Riveira-Muñoz Eva , Pérez Mònica , Roca Núria , Tarrés-Freixas Ferran , Cantero Guillermo , Pons-Grífols Anna , Rovirosa Carla , Aguilar-Gurrieri Carmen , Ortiz Raquel , Barajas Ana , Trinité Benjamin , Lepore Rosalba , Muñoz-Basagoiti Jordana , Perez-Zsolt Daniel , Izquierdo-Useros Nuria , Valencia Alfonso , Blanco Julià , Guallar Victor , Clotet Bonaventura , Segalés Joaquim , Carrillo Jorge 
Published: March 2024

AbstractSafe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are crucial to fight against the coronavirus disease 2019 pandemic. Most vaccines are based on a mutated version of the Spike glycoprotein [K986P/V987P (S-2P)] with improved stability, yield and immunogenicity. However, S-2P is still produced at low levels. Here, we describe the V987H mutation that increases by two-fold the production of the recombinant Spike and the exposure of the receptor binding domain (RBD). S-V987H immunogenicity is similar to S-2P in mice and golden Syrian hamsters (GSH), and superior to a monomeric RBD. S-V987H immunization confer full protection against severe disease in K18-hACE2 mice and GSH upon SARS-CoV-2 challenge (D614G or B.1.351 variants). Furthermore, S-V987H immunized K18-hACE2 mice show a faster tissue viral clearance than RBD- or S-2P-vaccinated animals challenged with D614G, B.1.351 or Omicron BQ1.1 variants. Thus, S-V987H protein might be considered for future SARS-CoV-2 vaccines development.
Aberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma
Authors: Ang Daniel A. , Carter Jean-Michel , Deka Kamalakshi , Tan Joel H. L. , Zhou Jianbiao , Chen Qingfeng , Chng Wee Joo , Harmston Nathan , Li Yinghui 
Published: March 2024

AbstractIn multiple myeloma, abnormal plasma cells establish oncogenic niches within the bone marrow by engaging the NF-κB pathway to nurture their survival while they accumulate pro-proliferative mutations. Under these conditions, many cases eventually develop genetic abnormalities endowing them with constitutive NF-κB activation. Here, we find that sustained NF-κB/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis-regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-κB signalling potentiates transcriptional programs beneficial for multiple myeloma progression.
Switching action modes of miR408-5p mediates auxin signaling in rice
Authors: Rong Fuxi , Lv Yusong , Deng Pingchuan , Wu Xia , Zhang Yaqi , Yue Erkui , Shen Yuxin , Muhammad Sajid , Ni Fangrui , Bian Hongwu , Wei Xiangjin , Zhou Weijun , Hu Peisong , Wu Liang 
Published: March 2024

AbstractMicroRNAs (miRNAs) play fundamental roles in many developmental and physiological processes in eukaryotes. MiRNAs in plants generally regulate their targets via either mRNA cleavage or translation repression; however, which approach plays a major role and whether these two function modes can shift remains elusive. Here, we identify a miRNA, miR408-5p that regulates AUXIN/INDOLE ACETIC ACID 30 (IAA30), a critical repressor in the auxin pathway via switching action modes in rice. We find that miR408-5p usually inhibits IAA30 protein translation, but in a high auxin environment, it promotes the decay of IAA30 mRNA when it is overproduced. We further demonstrate that IDEAL PLANT ARCHITECTURE1 (IPA1), an SPL transcription factor regulated by miR156, mediates leaf inclination through association with miR408-5p precursor promoter. We finally show that the miR156-IPA1-miR408-5p-IAA30 module could be controlled by miR393, which silences auxin receptors. Together, our results define an alternative auxin transduction signaling pathway in rice that involves the switching of function modes by miR408-5p, which contributes to a better understanding of the action machinery as well as the cooperative network of miRNAs in plants.
Toward sub-second solution exchange dynamics in flow reactors for liquid-phase transmission electron microscopy
Authors: Merkens Stefan , Tollan Christopher , De Salvo Giuseppe , Bejtka Katarzyna , Fontana Marco , Chiodoni Angelica , Kruse Joscha , Iriarte-Alonso Maiara Aime , Grzelczak Marek , Seifert Andreas , Chuvilin Andrey 
Published: March 2024

AbstractLiquid-phase transmission electron microscopy is a burgeoning experimental technique for monitoring nanoscale dynamics in a liquid environment, increasingly employing microfluidic reactors to control the composition of the sample solution. Current challenges comprise fast mass transport dynamics inside the central nanochannel of the liquid cell, typically flow cells, and reliable fixation of the specimen in the limited imaging area. In this work, we present a liquid cell concept – the diffusion cell – that satisfies these seemingly contradictory requirements by providing additional on-chip bypasses to allow high convective transport around the nanochannel in which diffusive transport predominates. Diffusion cell prototypes are developed using numerical mass transport models and fabricated on the basis of existing two-chip setups. Important hydrodynamic parameters, i.e., the total flow resistance, the flow velocity in the imaging area, and the time constants of mixing, are improved by 2-3 orders of magnitude compared to existing setups. The solution replacement dynamics achieved within seconds already match the mixing timescales of many ex-situ scenarios, and further improvements are possible. Diffusion cells can be easily integrated into existing liquid-phase transmission electron microscopy workflows, provide correlation of results with ex-situ experiments, and can create additional research directions addressing fast nanoscale processes.
p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice
Authors: Hill Ross J. , Bona Nazareno , Smink Job , Webb Hannah K. , Crisp Alastair , Garaycoechea Juan I. , Crossan Gerry P. 
Published: March 2024

AbstractDNA repair deficiency can lead to segmental phenotypes in humans and mice, in which certain tissues lose homeostasis while others remain seemingly unaffected. This may be due to different tissues facing varying levels of damage or having different reliance on specific DNA repair pathways. However, we find that the cellular response to DNA damage determines different tissue-specific outcomes. Here, we use a mouse model of the human XPF-ERCC1 progeroid syndrome (XFE) caused by loss of DNA repair. We find that p53, a central regulator of the cellular response to DNA damage, regulates tissue dysfunction in Ercc1-/- mice in different ways. We show that ablation of p53 rescues the loss of hematopoietic stem cells, and has no effect on kidney, germ cell or brain dysfunction, but exacerbates liver pathology and polyploidisation. Mechanistically, we find that p53 ablation led to the loss of cell-cycle regulation in the liver, with reduced p21 expression. Eventually, p16/Cdkn2a expression is induced, serving as a fail-safe brake to proliferation in the absence of the p53-p21 axis. Taken together, our data show that distinct and tissue-specific functions of p53, in response to DNA damage, play a crucial role in regulating tissue-specific phenotypes.
Squeezing formaldehyde into C60 fullerene
Authors: Vyas Vijyesh K. , Bacanu George R. , Soundararajan Murari , Marsden Elizabeth S. , Jafari Tanzeeha , Shugai Anna , Light Mark E. , Nagel Urmas , Rõõm Toomas , Levitt Malcolm H. , Whitby Richard J. 
Published: March 2024

AbstractThe cavity inside fullerene C60 provides a highly symmetric and inert environment for housing atoms and small molecules. Here we report the encapsulation of formaldehyde inside C60 by molecular surgery, yielding the supermolecular complex CH2O@C60, despite the 4.4 Å van der Waals length of CH2O exceeding the 3.7 Å internal diameter of C60. The presence of CH2O significantly reduces the cage HOMO-LUMO gap. Nuclear spin-spin couplings are observed between the fullerene host and the formaldehyde guest. The rapid spin-lattice relaxation of the formaldehyde 13C nuclei is attributed to a dominant spin-rotation mechanism. Despite being squeezed so tightly, the encapsulated formaldehyde molecules rotate freely about their long axes even at cryogenic temperatures, allowing observation of the ortho-to-para spin isomer conversion by infrared spectroscopy. The particle in a box nature of the system is demonstrated by the observation of two quantised translational modes in the cryogenic THz spectra.
Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis
Authors: Kohlmayr Johanna M. , Grabner Gernot F. , Nusser Anna , Höll Anna , Manojlović Verina , Halwachs Bettina , Masser Sarah , Jany-Luig Evelyne , Engelke Hanna , Zimmermann Robert , Stelzl Ulrich 
Published: March 2024

AbstractATGL is a key enzyme in intracellular lipolysis and plays an important role in metabolic and cardiovascular diseases. ATGL is tightly regulated by a known set of protein-protein interaction partners with activating or inhibiting functions in the control of lipolysis. Here, we use deep mutational protein interaction perturbation scanning and generate comprehensive profiles of single amino acid variants that affect the interactions of ATGL with its regulatory partners: CGI-58, G0S2, PLIN1, PLIN5 and CIDEC. Twenty-three ATGL amino acid variants yield a specific interaction perturbation pattern when validated in co-immunoprecipitation experiments in mammalian cells. We identify and characterize eleven highly selective ATGL switch mutations which affect the interaction of one of the five partners without affecting the others. Switch mutations thus provide distinct interaction determinants for ATGL’s key regulatory proteins at an amino acid resolution. When we test triglyceride hydrolase activity in vitro and lipolysis in cells, the activity patterns of the ATGL switch variants trace to their protein interaction profile. In the context of structural data, the integration of variant binding and activity profiles provides insights into the regulation of lipolysis and the impact of mutations in human disease.
A concise and scalable chemoenzymatic synthesis of prostaglandins
Authors: Yin Yunpeng , Wang Jinxin , Li Jian 
Published: March 2024

AbstractProstaglandins have garnered significant attention from synthetic chemists due to their exceptional biological activities. In this report, we present a concise chemoenzymatic synthesis method for several representative prostaglandins, achieved in 5 to 7 steps. Notably, the common intermediate bromohydrin, a radical equivalent of Corey lactone, is chemoenzymatically synthesized in only two steps, which allows us to complete the synthesis of prostaglandin F2α in five steps on a 10-gram scale. The chiral cyclopentane core is introduced with high enantioselectivity, while the lipid chains are sequentially incorporated through a cost-effective process involving bromohydrin formation, nickel-catalyzed cross-couplings, and Wittig reactions. This cost-efficient synthesis route for prostaglandins holds the potential to make prostaglandin-related drugs more affordable and facilitate easier access to their analogues.
Risk prediction and interaction analysis using polygenic risk score of type 2 diabetes in a Korean population
Authors: Song Minsun , Kwak Soo Heon , Kim Jihyun 
Published: March 2024

AbstractJoint modelling of genetic and environmental risk factors can provide important information to predict the risk of type 2 diabetes (T2D). Therefore, to predict the genetic risk of T2D, we constructed a polygenic risk score (PRS) using genotype data of one Korean cohort, KARE (745 cases and 2549 controls), and the genome-wide association study summary statistics of Biobank Japan. We evaluated the performance of PRS in an independent Korean cohort, HEXA (5684 cases and 35,703 controls). Individuals with T2D had a significantly higher mean PRS than controls (0.492 vs. − 0.078, p$$\approx 0$$

≈
0

). PRS predicted the risk of T2D with an AUC of 0.658 (95% CI 0.651–0.666). We also evaluated interaction between PRS and waist circumference (WC) in the HEXA cohort. PRS exhibited a significant sub-multiplicative interaction with WC (ORinteraction 0.991, 95% CI 0.987–0.995, pinteraction = 4.93 × 10–6) in T2D. The effect of WC on T2D decreased as PRS increased. The sex-specific analyses produced similar interaction results, revealing a decreased WC effect on T2D as the PRS increased. In conclusion, the risk of WC for T2D may differ depending on PRS and those with a high PRS might develop T2D with a lower WC threshold. Our findings are expected to improve risk prediction for T2D and facilitate the identification of individuals at an increased risk of T2D.