bluuebunny/crossref_metadata_2025_split huggingface dataset:
UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma
Authors: Kuser-Abali Gamze , Zhang Youfang , Szeto Pacman , Zhao Peinan , Masoumi-Moghaddam Samar , Fedele Clare G. , Leece Isobel , Huang Cheng , Cheung Jen G. , Ameratunga Malaka , Noguchi Fumihito , Andrews Miles C. , Wong Nicholas C. , Schittenhelm Ralf B. , Shackleton Mark 
Published: March 2023

AbstractCellular heterogeneity in cancer is linked to disease progression and therapy response, although mechanisms regulating distinct cellular states within tumors are not well understood. We identified melanin pigment content as a major source of cellular heterogeneity in melanoma and compared RNAseq data from high-pigmented (HPCs) and low-pigmented melanoma cells (LPCs), suggesting EZH2 as a master regulator of these states. EZH2 protein was found to be upregulated in LPCs and inversely correlated with melanin deposition in pigmented patient melanomas. Surprisingly, conventional EZH2 methyltransferase inhibitors, GSK126 and EPZ6438, had no effect on LPC survival, clonogenicity and pigmentation, despite fully inhibiting methyltransferase activity. In contrast, EZH2 silencing by siRNA or degradation by DZNep or MS1943 inhibited growth of LPCs and induced HPCs. As the proteasomal inhibitor MG132 induced EZH2 protein in HPCs, we evaluated ubiquitin pathway proteins in HPC vs LPCs. Biochemical assays and animal studies demonstrated that in LPCs, the E2-conjugating enzyme UBE2L6 depletes EZH2 protein in cooperation with UBR4, an E3 ligase, via ubiquitination at EZH2’s K381 residue, and is downregulated in LPCs by UHRF1-mediated CpG methylation. Targeting UHRF1/UBE2L6/UBR4-mediated regulation of EZH2 offers potential for modulating the activity of this oncoprotein in contexts in which conventional EZH2 methyltransferase inhibitors are ineffective.
Activation of immune signals during organ transplantation
Authors: Li Qingwen , Lan Peixiang 
Published: March 2023

AbstractThe activation of host’s innate and adaptive immune systems can lead to acute and chronic graft rejection, which seriously impacts graft survival. Thus, it is particularly significant to clarify the immune signals, which are critical to the initiation and maintenance of rejection generated after transplantation. The initiation of response to graft is dependent on sensing of danger and stranger molecules. The ischemia and reperfusion of grafts lead to cell stress or death, followed by releasing a variety of damage-associated molecular patterns (DAMPs), which are recognized by pattern recognition receptors (PRRs) of host immune cells to activate intracellular immune signals and induce sterile inflammation. In addition to DAMPs, the graft exposed to ‘non-self’ antigens (stranger molecules) are recognized by the host immune system, stimulating a more intense immune response and further aggravating the graft damage. The polymorphism of MHC genes between different individuals is the key for host or donor immune cells to identify heterologous ‘non-self’ components in allogeneic and xenogeneic organ transplantation. The recognition of ‘non-self’ antigen by immune cells mediates the activation of immune signals between donor and host, resulting in adaptive memory immunity and innate trained immunity to the graft, which poses a challenge to the long-term survival of the graft. This review focuses on innate and adaptive immune cells receptor recognition of damage-associated molecular patterns, alloantigens and xenoantigens, which is described as danger model and stranger model. In this review, we also discuss the innate trained immunity in organ transplantation.
Vitamin B12 is not shared by all marine prototrophic bacteria with their environment
Authors: Sultana Sabiha , Bruns Stefan , Wilkes Heinz , Simon Meinhard , Wienhausen Gerrit 
Published: March 2023

Abstract
Vitamin B12 (cobalamin, herein B12) is an essential cofactor involved in amino acid synthesis and carbon resupply to the TCA cycle for most prokaryotes, eukaryotic microorganisms, and animals. Despite being required by most, B12 is produced by only a minor fraction of prokaryotes and therefore leads to complex interaction between prototrophs and auxotrophs. However, it is unknown how B12 is provided by prototrophs to auxotrophs. In this study, 33 B12 prototrophic alphaproteobacterial strains were grown in co-culture with Thalassiosira pseudonana, a B12 auxotrophic diatom, to determine the bacterial ability to support the growth of the diatom by sharing B12. Among these strains, 18 were identified to share B12 with the diatom, while nine were identified to retain B12 and not support growth of the diatom. The other bacteria either shared B12 with the diatom only with the addition of substrate or inhibited the growth of the diatom. Extracellular B12 measurements of B12-provider and B12-retainer strains confirmed that the cofactor could only be detected in the environment of the tested B12-provider strains. Intracellular B12 was measured by LC-MS and showed that the concentrations of the different B12-provider as well as B12-retainer strains differed substantially. Although B12 is essential for the vast majority of microorganisms, mechanisms that export this essential cofactor are still unknown. Our results suggest that a large proportion of bacteria that can synthesise B12de novo cannot share the cofactor with their environment.
Protein dynamics at invadopodia control invasion–migration transitions in melanoma cells
Authors: Legrand Marlène , Mousson Antoine , Carl Philippe , Rossé Léa , Justiniano Hélène , Gies Jean-Pierre , Bouvard Daniel , Sick Emilie , Dujardin Denis , Rondé Philippe 
Published: March 2023

AbstractCell invasion is a highly complex process that requires the coordination of cell migration and degradation of the extracellular matrix. In melanoma cells, as in many highly invasive cancer cell types these processes are driven by the regulated formation of adhesives structures such as focal adhesions and invasive structures like invadopodia. Structurally, focal adhesion and invadopodia are quite distinct, yet they share many protein constituents. However, quantitative understanding of the interaction of invadopodia with focal adhesion is lacking, and how invadopodia turn-over is associated with invasion-migration transition cycles remains unknown. In this study, we investigated the role of Pyk2, cortactin and Tks5 in invadopodia turnover and their relation with focal adhesions. We found that active Pyk2 and cortactin are localised at both focal adhesions and invadopodia. At invadopodia, localisation of active Pyk2 is correlated with ECM degradation. During invadopodia disassembly, Pyk2 and cortactin but not Tks5 are often relocated at nearby nascent adhesions. We also show that during ECM degradation, cell migration is reduced which is likely related to the sharing of common molecules within the two structures. Finally, we found that the dual FAK/Pyk2 inhibitor PF-431396 inhibits both focal adhesion and invadopodia activities thereby reducing both migration and ECM degradation.
PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma
Authors: Kang Lichun , Wang Dekun , Shen Tianyu , Liu Xuan , Dai Bo , Zhou Donghui , Shen Huan , Gong Junbo , Li Gang , Hu Yuanjing , Wang Peng , Mi Xue , Zhang Yuying , Tan Xiaoyue 
Published: March 2023

AbstractThe prognosis of renal cell carcinoma (RCC) remains poor due to metastases and resistance to chemotherapy. Salinomycin (Sal) exhibits the potential of antitumor, while the underlying mechanism is not completely clear. Here, we found that Sal induced ferroptosis in RCCs and identified Protein Disulfide Isomerase Family A Member 4 (PDIA4) as a mediator of Sal’s effect on ferroptosis. Sal suppressed PDIA4 by increasing its autophagic degradation. Downregulation of PDIA4 increased the sensitivity to ferroptosis, while ectopic overexpression of PDIA4 conferred ferroptosis resistance to RCCs. Our data showed that downregulation of PDIA4 suppressed activating transcription factor 4 (ATF4) and its downstream protein SLC7A11 (solute carrier family 7 member 11), thereby aggravating ferroptosis. In vivo, the administration of Sal promoted ferroptosis and suppressed tumor progress in the xenograft mouse model of RCC. Bioinformatical analyses based on clinical tumor samples and database indicated a positive correlation exists between PDIA4 and PERK/ATF4/SLC7A11 signaling pathway, as well as the malignant prognosis of RCCs. Together, our findings reveal that PDIA4 promotes ferroptosis resistance in RCCs. Treatment of Sal sensitizes RCC to ferroptosis via suppressing PDIA4, suggesting the potential therapeutical application in RCCs.
Emerging roles of TFE3 in metabolic regulation
Authors: Li Xingyu , Chen Yongming , Gong Siqiao , Chen Huixia , Liu Huafeng , Li Xiaoyu , Hao Junfeng 
Published: March 2023

AbstractTFE3 is a member of the MiT family of the bHLH-leucine zipper transcription factor. We previously focused on the role of TFE3 in autophagy and cancer. Recently, an increasing number of studies have revealed that TFE3 plays an important role in metabolic regulation. TFE3 participates in the metabolism of energy in the body by regulating pathways such as glucose and lipid metabolism, mitochondrial metabolism, and autophagy. This review summarizes and discusses the specific regulatory mechanisms of TFE3 in metabolism. We determined both the direct regulation of TFE3 on metabolically active cells, such as hepatocytes and skeletal muscle cells, and the indirect regulation of TFE3 through mitochondrial quality control and the autophagy–lysosome pathway. The role of TFE3 in tumor cell metabolism is also summarized in this review. Understanding the diverse roles of TFE3 in metabolic processes can provide new avenues for the treatment of some metabolism-related disorders.
Acidic graphene organocatalyst for the superior transformation of wastes into high-added-value chemicals
Authors: Cheruvathoor Poulose Aby , Medveď Miroslav , Bakuru Vasudeva Rao , Sharma Akashdeep , Singh Deepika , Kalidindi Suresh Babu , Bares Hugo , Otyepka Michal , Jayaramulu Kolleboyina , Bakandritsos Aristides , Zbořil Radek 
Published: March 2023

AbstractOur dependence on finite fossil fuels and the insecure energy supply chains have stimulated intensive research for sustainable technologies. Upcycling glycerol, produced from biomass fermentation and as a biodiesel formation byproduct, can substantially contribute in circular carbon economy. Here, we report glycerol’s solvent-free and room-temperature conversion to high-added-value chemicals via a reusable graphene catalyst (G-ASA), functionalized with a natural amino acid (taurine). Theoretical studies unveil that the superior performance of the catalyst (surpassing even homogeneous, industrial catalysts) is associated with the dual role of the covalently linked taurine, boosting the catalyst’s acidity and affinity for the reactants. Unlike previous catalysts, G-ASA exhibits excellent activity (7508 mmol g−1 h−1) and selectivity (99.9%) for glycerol conversion to solketal, an additive for improving fuels’ quality and a precursor of commodity and fine chemicals. Notably, the catalyst is also particularly active in converting oils to biodiesel, demonstrating its general applicability.
Mammalian-brain-inspired neuromorphic motion-cognition nerve achieves cross-modal perceptual enhancement
Authors: Jiang Chengpeng , Liu Jiaqi , Ni Yao , Qu Shangda , Liu Lu , Li Yue , Yang Lu , Xu Wentao 
Published: March 2023

AbstractPerceptual enhancement of neural and behavioral response due to combinations of multisensory stimuli are found in many animal species across different sensory modalities. By mimicking the multisensory integration of ocular-vestibular cues for enhanced spatial perception in macaques, a bioinspired motion-cognition nerve based on a flexible multisensory neuromorphic device is demonstrated. A fast, scalable and solution-processed fabrication strategy is developed to prepare a nanoparticle-doped two-dimensional (2D)-nanoflake thin film, exhibiting superior electrostatic gating capability and charge-carrier mobility. The multi-input neuromorphic device fabricated using this thin film shows history-dependent plasticity, stable linear modulation, and spatiotemporal integration capability. These characteristics ensure parallel, efficient processing of bimodal motion signals encoded as spikes and assigned with different perceptual weights. Motion-cognition function is realized by classifying the motion types using mean firing rates of encoded spikes and postsynaptic current of the device. Demonstrations of recognition of human activity types and drone flight modes reveal that the motion-cognition performance match the bio-plausible principles of perceptual enhancement by multisensory integration. Our system can be potentially applied in sensory robotics and smart wearables.
BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas
Authors: Moreno Victor , Vieito Maria , Sepulveda Juan Manuel , Galvao Vladimir , Hernández-Guerrero Tatiana , Doger Bernard , Saavedra Omar , Carlo-Stella Carmelo , Michot Jean-Marie , Italiano Antoine , Magagnoli Massimo , Carpio Cecilia , Pinto Antonio , Sarmiento Rafael , Amoroso Barbara , Aronchik Ida , Filvaroff Ellen , Hanna Bishoy , Wei Xin , Nikolova Zariana , Braña Irene 
Published: March 2023

AbstractBromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months’ duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8–33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0–8.6) and a CBR of 31.7% (95% CI, 18.1–48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.
Cryo-EM structures of human Cx36/GJD2 neuronal gap junction channel
Authors: Lee Seu-Na , Cho Hwa-Jin , Jeong Hyeongseop , Ryu Bumhan , Lee Hyuk-Joon , Kim Minsoo , Yoo Jejoong , Woo Jae-Sung , Lee Hyung Ho 
Published: March 2023

AbstractConnexin 36 (Cx36) is responsible for signal transmission in electrical synapses by forming interneuronal gap junctions. Despite the critical role of Cx36 in normal brain function, the molecular architecture of the Cx36 gap junction channel (GJC) is unknown. Here, we determine cryo-electron microscopy structures of Cx36 GJC at 2.2–3.6 Å resolutions, revealing a dynamic equilibrium between its closed and open states. In the closed state, channel pores are obstructed by lipids, while N-terminal helices (NTHs) are excluded from the pore. In the open state with pore-lining NTHs, the pore is more acidic than those in Cx26 and Cx46/50 GJCs, explaining its strong cation selectivity. The conformational change during channel opening also includes the α-to-π-helix transition of the first transmembrane helix, which weakens the protomer-protomer interaction. Our structural analyses provide high resolution information on the conformational flexibility of Cx36 GJC and suggest a potential role of lipids in the channel gating.
Rapid protection induced by a single-shot Lassa vaccine in male cynomolgus monkeys
Authors: Mateo Mathieu , Reynard Stéphanie , Pietrosemoli Natalia , Perthame Emeline , Journeaux Alexandra , Noy Kodie , Germain Clara , Carnec Xavier , Picard Caroline , Borges-Cardoso Virginie , Hortion Jimmy , Lopez-Maestre Hélène , Regnard Pierrick , Fellmann Lyne , Vallve Audrey , Barron Stéphane , Jourjon Ophélie , Lacroix Orianne , Duthey Aurélie , Dirheimer Manon , Daniau Maïlys , Legras-Lachuer Catherine , Carbonnelle Caroline , Raoul Hervé , Tangy Frédéric , Baize Sylvain 
Published: March 2023

AbstractLassa fever hits West African countries annually in the absence of licensed vaccine to limit the burden of this viral hemorrhagic fever. We previously developed MeV-NP, a single-shot vaccine protecting cynomolgus monkeys against divergent strains one month or more than a year before Lassa virus infection. Given the limited dissemination area during outbreaks and the risk of nosocomial transmission, a vaccine inducing rapid protection could be useful to protect exposed people during outbreaks in the absence of preventive vaccination. Here, we test whether the time to protection can be reduced after immunization by challenging measles virus pre-immune male cynomolgus monkeys sixteen or eight days after a single shot of MeV-NP. None of the immunized monkeys develop disease and they rapidly control viral replication. Animals immunized eight days before the challenge are the best controllers, producing a strong CD8 T-cell response against the viral glycoprotein. A group of animals was also vaccinated one hour after the challenge, but was not protected and succumbed to the disease as the control animals. This study demonstrates that MeV-NP can induce a rapid protective immune response against Lassa fever in the presence of MeV pre-existing immunity but can likely not be used as therapeutic vaccine.
Effects of acidification on nitrification and associated nitrous oxide emission in estuarine and coastal waters
Authors: Zhou Jie , Zheng Yanling , Hou Lijun , An Zhirui , Chen Feiyang , Liu Bolin , Wu Li , Qi Lin , Dong Hongpo , Han Ping , Yin Guoyu , Liang Xia , Yang Yi , Li Xiaofei , Gao Dengzhou , Li Ye , Liu Zhanfei , Bellerby Richard , Liu Min 
Published: March 2023

AbstractIn the context of an increasing atmospheric carbon dioxide (CO2) level, acidification of estuarine and coastal waters is greatly exacerbated by land-derived nutrient inputs, coastal upwelling, and complex biogeochemical processes. A deeper understanding of how nitrifiers respond to intensifying acidification is thus crucial to predict the response of estuarine and coastal ecosystems and their contribution to global climate change. Here, we show that acidification can significantly decrease nitrification rate but stimulate generation of byproduct nitrous oxide (N2O) in estuarine and coastal waters. By varying CO2concentration and pH independently, an expected beneficial effect of elevated CO2on activity of nitrifiers (“CO2-fertilization” effect) is excluded under acidification. Metatranscriptome data further demonstrate that nitrifiers could significantly up-regulate gene expressions associated with intracellular pH homeostasis to cope with acidification stress. This study highlights the molecular underpinnings of acidification effects on nitrification and associated greenhouse gas N2O emission, and helps predict the response and evolution of estuarine and coastal ecosystems under climate change and human activities.
Determinants of anemia severity levels among children aged 6–59 months in Ethiopia: Multilevel Bayesian statistical approach
Authors: Alamneh Tesfa Sewunet , Melesse Alemakef Wagnew , Gelaye Kassahun Alemu 
Published: March 2023

AbstractAnemia is a widespread public health problem that affects all stages of life particularly preschool children and pregnant mothers. Anemia among children had significant impact on their growth, development, school performance and mortality. Different strategies like deworming of young children, vitamin A supplementation for children aged 6–59 months, and ferrous sulphate supplementation and provision of insecticide treated bed net for pregnant women were designed to control and prevent anemia. Also, previous studies on anemia factors were conducted but they were not considering the ordered nature of anemia. Therefore, this study aimed to identify the factors of anemia severity levels among children aged 6–59 months in Ethiopia by using ordinal analysis based on Bayesian hierarchical statistical approach. A secondary data analysis was conducted using the 2016 Ethiopian Demographic and Health Survey data. A total of 8483 weighted children were included. Due to the ordered nature of the anemia and nested nature of DHS data, ordinal logistic regression model based on hierarchical Bayesian statistical approach was employed to identify the determinants of anemia severity levels. In this study, moderate anemia level was found to be the commonest type which accounts around 29.4%. Female children, poorer, middle, and richest wealth index, primary maternal education and having ANC visit had lower risk of having higher order of anemia. Moderate maternal anemia and stunted children had higher chance of having higher order of anemia. Children age had significant different effect on mild and moderate anemia. Meanwhile, multiple birth/s and deworming had effect on moderate anemia. In addition, normal birth weight had also significant and different effect on mild and severe anemia and history of feverlike illness on mild anemia. The prevalence of anemia among children aged 6–59 months anemia was found to be a severe public health problem. Children age, sex, maternal education, child stunting, history of fever, multiple birth, birth weight, provision of deworming and maternal anemia was found to be the most important factors for child anemia severity levels. Therefore, intervention efforts to control and prevent anemia in Ethiopia requires targeting of these hindering factors.