bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methylation across the central dogma in health and diseases: new therapeutic strategies
Authors: Liu Ruochen , Zhao Erhu , Yu Huijuan , Yuan Chaoyu , Abbas Muhammad Nadeem , Cui Hongjuan 
Published: August 2023

AbstractThe proper transfer of genetic information from DNA to RNA to protein is essential for cell-fate control, development, and health. Methylation of DNA, RNAs, histones, and non-histone proteins is a reversible post-synthesis modification that finetunes gene expression and function in diverse physiological processes. Aberrant methylation caused by genetic mutations or environmental stimuli promotes various diseases and accelerates aging, necessitating the development of therapies to correct the disease-driver methylation imbalance. In this Review, we summarize the operating system of methylation across the central dogma, which includes writers, erasers, readers, and reader-independent outputs. We then discuss how dysregulation of the system contributes to neurological disorders, cancer, and aging. Current small-molecule compounds that target the modifiers show modest success in certain cancers. The methylome-wide action and lack of specificity lead to undesirable biological effects and cytotoxicity, limiting their therapeutic application, especially for diseases with a monogenic cause or different directions of methylation changes. Emerging tools capable of site-specific methylation manipulation hold great promise to solve this dilemma. With the refinement of delivery vehicles, these new tools are well positioned to advance the basic research and clinical translation of the methylation field.
Synthetic viability induces resistance to immune checkpoint inhibitors in cancer cells
Authors: Liu Mingyue , Dong Qi , Chen Bo , Liu Kaidong , Zhao Zhangxiang , Wang Yuquan , Zhuang Shuping , Han Huiming , Shi Xingyang , Jin Zixin , Hui Yang , Gu Yunyan 
Published: August 2023

Abstract
Background
Immune checkpoint inhibitors (ICI) have revolutionized the treatment for multiple cancers. However, most of patients encounter resistance. Synthetic viability (SV) between genes could induce resistance. In this study, we established SV signature to predict the efficacy of ICI treatment for melanoma.

Methods
We collected features and predicted SV gene pairs by random forest classifier. This work prioritized SV gene pairs based on CRISPR/Cas9 screens. SV gene pairs signature were constructed to predict the response to ICI for melanoma patients.

Results
This study predicted robust SV gene pairs based on 14 features. Filtered by CRISPR/Cas9 screens, we identified 1,861 SV gene pairs, which were also related with prognosis across multiple cancer types. Next, we constructed the six SV pairs signature to predict resistance to ICI for melanoma patients. This study applied the six SV pairs signature to divide melanoma patients into high-risk and low-risk. High-risk melanoma patients were associated with worse response after ICI treatment. Immune landscape analysis revealed that high-risk melanoma patients had lower natural killer cells and CD8+ T cells infiltration.

Conclusions
In summary, the 14 features classifier accurately predicted robust SV gene pairs for cancer. The six SV pairs signature could predict resistance to ICI.
Nuclear localization of TET2 requires β-catenin activation and correlates with favourable prognosis in colorectal cancer
Authors: Li Changpeng , He Jingcai , Meng Fei , Wang Fuhui , Sun Hao , Zhang Huizhong , Dong Linna , Zhang Mengdan , Xu Qiaoran , Liang Lining , Li Yuan , Yang Tingting , He Meiai , Wang Tao , Lin Jiechun , Sun Jiaqi , Huang Qiuling , Guo Lin , Zhang Xiaofei , Mai Shijuan , Zheng Hui 
Published: August 2023

AbstractMutation-induced malfunction of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is widely reported in haematological malignancies. However, the role of TET2 in solid cancers, including colorectal cancer (CRC), is unclear. Here, we found that TET2 malfunction in CRC is mostly due to decreased nuclear localization and that nuclear localization of TET2 is correlated with better survival of patients. To explore the underlying mechanisms, 14 immortalized solid tumour cell lines and 12 primary CRC cell lines were used. TET2 was mostly detected in the nucleus, and it induced significant DNA demethylation and suppressed cell growth by demethylating RORA and SPARC in cell lines like SW480. While in cell lines like SW620, TET2 was observed in the cytosol and did not affect DNA methylation or cell growth. Further examination with immunoprecipitation–mass spectrometry illustrated that β-catenin activation was indispensable for the nuclear localization and tumour suppression effects of TET2. In addition, the β-catenin pathway activator IM12 and the TET2 activator vitamin C were used simultaneously to enhance the effects of TET2 under low-expression conditions, and synergistic inhibitory effects on the growth of cancer were observed both in vitro and in vivo. Collectively, these data suggest that β-catenin-mediated nuclear localization of TET2 is an important therapeutic target for solid tumours.
Vemurafenib inhibits necroptosis in normal and pathological conditions as a RIPK1 antagonist
Authors: Sun Mayu , Ma Xueqi , Mu Wei , Li Haonan , Zhao Xiaoming , Zhu Tengfei , Li Jingquan , Yang Yongliang , Zhang Haibing , Ba Qian , Wang Hui 
Published: August 2023

AbstractNecroptosis, a programmed cell death with necrotic-like morphology, has been recognized as an important driver in various inflammatory diseases. Inhibition of necroptosis has shown potential promise in the therapy of multiple human diseases. However, very few necroptosis inhibitors are available for clinical use as yet. Here, we identified an FDA-approved anti-cancer drug, Vemurafenib, as a potent inhibitor of necroptosis. Through direct binding, Vemurafenib blocked the kinase activity of receptor-interacting protein kinases 1 (RIPK1), impeded the downstream signaling and necrosome complex assembly, and inhibited necroptosis. Compared with Necrostain-1, Vemurafenib stabilized RIPK1 in an inactive DLG-out conformation by occupying a distinct allosteric hydrophobic pocket. Furthermore, pretreatment with Vemurafenib provided strong protection against necroptosis-associated diseases in vivo. Altogether, our results demonstrate that Vemurafenib is an effective RIPK1 antagonist and provide rationale and preclinical evidence for the potential application of approved drug in necroptosis-related diseases.
Clinical-mediated discovery of pyroptosis in CD8+ T cell and NK cell reveals melanoma heterogeneity by single-cell and bulk sequence
Authors: Zhang Ying , Bai Yun , Ma Xiao-Xuan , Song Jian-Kun , Luo Yue , Fei Xiao-Ya , Ru Yi , Luo Ying , Jiang Jing-Si , Zhang Zhan , Yang Dan , Xue Ting-Ting , Zhang Hui-Ping , Liu Tai-Yi , Xiang Yan-Wei , Kuai Le , Liu Ye-Qiang , Li Bin 
Published: August 2023

AbstractHistologically, melanoma tissues had fewer positive cells percentage of pyroptosis-related genes (PRGs), GZMA, GSDMB, NLRP1, IL18, and CHMP4A in epidermal than in normal skin. Pyroptosis, a new frontier in cancer, affects the tumor microenvironment and tumor immunotherapy. Nevertheless, the role of pyroptosis remains controversial, which reason is partly due to the heterogeneity of the cellular composition in melanoma. In this study, we present a comprehensive analysis of the single-cell transcriptome landscape of pyroptosis in melanoma specimens. Our findings reveal dysregulation in the expression of PRGs, particularly in immune cells, such as CD8+ cells (representing CD8+ T cells) and CD57+ cells (representing NK cells). Additionally, the immunohistochemical and multiplex immunofluorescence staining experiments results further confirmed GZMA+ cells and GSDMB+ cells were predominantly expressed in immune cells, especially in CD8 + T cells and NK cells. Melanoma specimens secreted a minimal presence of GZMA+ merged CD8+ T cells (0.11%) and GSDMB+ merged CD57+ cells (0.08%), compared to the control groups exhibiting proportions of 4.02% and 0.62%, respectively. The aforementioned findings indicate that a reduced presence of immune cells within tumors may play a role in diminishing the ability of pyroptosis, consequently posing a potential risk to the anti-melanoma properties. To quantify clinical relevance, we constructed a prognostic risk model and an individualized nomogram (C-index=0.58, P = 0.002), suggesting a potential role of PRGs in malignant melanoma prevention. In conclusion, our integrated single-cell and bulk RNA-seq analysis identified immune cell clusters and immune gene modules with experiment validation, contributing to our better understanding of pyroptosis in melanoma.
A HER2-targeting antibody-MMAE conjugate RC48 sensitizes immunotherapy in HER2-positive colon cancer by triggering the cGAS-STING pathway
Authors: Wu Xiaohan , Xu Lingyan , Li Xiaofei , Zhou Yirui , Han Xiao , Zhang Wei , Wang Weicheng , Guo Wenjie , Liu Wen , Xu Qiang , Gu Yanhong 
Published: August 2023

AbstractHuman epidermal growth factor receptor 2 (HER2) is a protein that is overexpressed in some types of cancer, including breast and urothelial cancer. Here we found that HER2 was present in a portion of colon cancer patients, raising the possibility of using anti-HER2 therapy. RC48, a novel antibody-drug conjugate (ADC) comprising cytotoxic monomethyl auristatin E (MMAE) and an anti-HER2 antibody tethered via a linker, showed a comparable therapeutic effect in both HER2 low expressed (IHC2+/FISH- or IHC+) and high expressed urothelial cancer patients. In vitro studies using colon cancer cell lines showed that RC48 effectively impeded the proliferation of HER2-positive cells, indicating its potential as a treatment for HER2-positive colon cancer. Mechanism study showed that RC48 not only induces cell cycle arrest but also disrupts HER2-mediated restain of cGAS-STING signaling, potentially activating an immune response against the cancer cells. The administration of RC48 significantly reduced the growth of HER2-positive colon cancer and made HER2-positive colon cancer cells more susceptible to immunotherapy. The results of our study will contribute to determining the feasibility of RC48 as a therapeutic option for HER2-positive colon cancer.
Expression of Cyclin E1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in mice
Authors: Otto Julia , Verwaayen Anna , Penners Christian , Hundertmark Jana , Lin Cheng , Kallen Carina , Paffen Daniela , Otto Tobias , Berger Hilmar , Tacke Frank , Weiskirchen Ralf , Nevzorova Yulia A. , Bartneck Matthias , Trautwein Christian , Sonntag Roland , Liedtke Christian 
Published: August 2023

AbstractHepatocellular carcinoma (HCC) is one of the most severe malignancies with increasing incidence and limited treatment options. Typically, HCC develops during a multistep process involving chronic liver inflammation and liver fibrosis. The latter is characterized by the accumulation of extracellular matrix produced by Hepatic Stellate Cells (HSCs). This process involves cell cycle re-entry and proliferation of normally quiescent HSCs in an ordered sequence that is highly regulated by cyclins and associated cyclin-dependent kinases (CDKs) such as the Cyclin E1 (CCNE1)/CDK2 kinase complex. In the present study, we examined the role of Cyclin E1 (Ccne1) and Cdk2 genes in HSCs for liver fibrogenesis and hepatocarcinogenesis. To this end, we generated conditional knockout mice lacking Ccne1 or Cdk2 specifically in HSCs (Ccne1∆HSC or Cdk2∆HSC). Ccne1∆HSC mice showed significantly reduced liver fibrosis formation and attenuated HSC activation in the carbon tetrachloride (CCl4) model. In a combined model of fibrosis-driven hepatocarcinogenesis, Ccne1∆HSC mice revealed decreased HSC activation even after long-term observation and substantially reduced tumor load in the liver when compared to wild-type controls. Importantly, the deletion of Cdk2 in HSCs also resulted in attenuated liver fibrosis after chronic CCl4 treatment. Single-cell RNA sequencing revealed that only a small fraction of HSCs expressed Ccne1/Cdk2 at a distinct time point after CCl4 treatment. In summary, we provide evidence that Ccne1 expression in a small population of HSCs is sufficient to trigger extensive liver fibrosis and hepatocarcinogenesis in a Cdk2-dependent manner. Thus, HSC-specific targeting of Ccne1 or Cdk2 in patients with liver fibrosis and high risk for HCC development could be therapeutically beneficial.
Targeting ANXA7/LAMP5-mTOR axis attenuates spinal cord injury by inhibiting neuronal apoptosis via enhancing autophagy in mice
Authors: Li Na , Chen Lu , Zhao Xiaoqing , Gu Chi , Chang Yong , Feng Shiqing 
Published: August 2023

AbstractSpinal cord injury (SCI) could lead to severe disabilities in motor and sensory functions, and cause a heavy burden on patient physiology and psychology due to lack of specific repair measures so far. ANXA7 is an annexin with Ca2+ -dependent GTPase activity, which were mainly expressed in neuron in spinal cord and downregulated significantly after SCI in mice. In our study, GTPase activity activation of ANXA7 plays the protective role in neuron after OGD/R through inhibiting neuron apoptosis, which mediated by enhancing autophagy via mTOR/TFEB pathway. We also discovered that ANXA7 has significant interaction with neural-specific lysosomal-associated membrane protein LAMP5, which together with ANXA7 regulates autophagy and apoptosis. Asp411 mutation of ANXA7 obviously impaired the interaction of ANXA7 and LAMP5 compared with the wild type. Furthermore, it was found that activation of ANXA7 could help to stabilize the protein expression of LAMP5. Overexpression of LAMP5 could attenuate the destruction of lysosomal acidic environment, inhibition of autophagy and activation of apoptosis caused by ANXA7 downregulation after OGD/R. We verified that injecting ANXA7 overexpression lentivirus and activation of ANXA7 both have significant repair effects on SCI mice by using CatWalk assay and immunohistochemistry staining. In summary, our findings clarify the new role of ANXA7 and LAMP5 in SCI, provided a new specific target of neuronal repair and discovered new molecular mechanisms of ANXA7 to regulate autophagy and apoptosis. Targeting ANXA7 may be a prospective therapeutic strategy for SCI in future.
Metal-mediated DNA strand displacement and molecular device operations based on base-pair switching of 5-hydroxyuracil nucleobases
Authors: Takezawa Yusuke , Mori Keita , Huang Wei-En , Nishiyama Kotaro , Xing Tong , Nakama Takahiro , Shionoya Mitsuhiko 
Published: August 2023

AbstractRational design of self-assembled DNA nanostructures has become one of the fastest-growing research areas in molecular science. Particular attention is focused on the development of dynamic DNA nanodevices whose configuration and function are regulated by specific chemical inputs. Herein, we demonstrate the concept of metal-mediated base-pair switching to induce inter- and intramolecular DNA strand displacement in a metal-responsive manner. The 5-hydroxyuracil (UOH) nucleobase is employed as a metal-responsive unit, forming both a hydrogen-bonded UOH–A base pair and a metal-mediated UOH–GdIII–UOH base pair. Metal-mediated strand displacement reactions are demonstrated under isothermal conditions based on the base-pair switching between UOH–A and UOH–GdIII–UOH. Furthermore, metal-responsive DNA tweezers and allosteric DNAzymes are developed as typical models for DNA nanodevices simply by incorporating UOH bases into the sequence. The metal-mediated base-pair switching will become a versatile strategy for constructing stimuli-responsive DNA nanostructures, expanding the scope of dynamic DNA nanotechnology.
Structural basis of peptidoglycan synthesis by E. coli RodA-PBP2 complex
Authors: Nygaard Rie , Graham Chris L. B. , Belcher Dufrisne Meagan , Colburn Jonathan D. , Pepe Joseph , Hydorn Molly A. , Corradi Silvia , Brown Chelsea M. , Ashraf Khuram U. , Vickery Owen N. , Briggs Nicholas S. , Deering John J. , Kloss Brian , Botta Bruno , Clarke Oliver B. , Columbus Linda , Dworkin Jonathan , Stansfeld Phillip J. , Roper David I. , Mancia Filippo 
Published: August 2023

AbstractPeptidoglycan (PG) is an essential structural component of the bacterial cell wall that is synthetized during cell division and elongation. PG forms an extracellular polymer crucial for cellular viability, the synthesis of which is the target of many antibiotics. PG assembly requires a glycosyltransferase (GT) to generate a glycan polymer using a Lipid II substrate, which is then crosslinked to the existing PG via a transpeptidase (TP) reaction. A Shape, Elongation, Division and Sporulation (SEDS) GT enzyme and a Class B Penicillin Binding Protein (PBP) form the core of the multi-protein complex required for PG assembly. Here we used single particle cryo-electron microscopy to determine the structure of a cell elongation-specific E. coli RodA-PBP2 complex. We combine this information with biochemical, genetic, spectroscopic, and computational analyses to identify the Lipid II binding sites and propose a mechanism for Lipid II polymerization. Our data suggest a hypothesis for the movement of the glycan strand from the Lipid II polymerization site of RodA towards the TP site of PBP2, functionally linking these two central enzymatic activities required for cell wall peptidoglycan biosynthesis.
Multiscale dynamics of charging and plating in graphite electrodes coupling operando microscopy and phase-field modelling
Authors: Lu Xuekun , Lagnoni Marco , Bertei Antonio , Das Supratim , Owen Rhodri E. , Li Qi , O’Regan Kieran , Wade Aaron , Finegan Donal P. , Kendrick Emma , Bazant Martin Z. , Brett Dan J. L. , Shearing Paul R. 
Published: August 2023

AbstractThe phase separation dynamics in graphitic anodes significantly affects lithium plating propensity, which is the major degradation mechanism that impairs the safety and fast charge capabilities of automotive lithium-ion batteries. In this study, we present comprehensive investigation employing operando high-resolution optical microscopy combined with non-equilibrium thermodynamics implemented in a multi-dimensional (1D+1D to 3D) phase-field modeling framework to reveal the rate-dependent spatial dynamics of phase separation and plating in graphite electrodes. Here we visualize and provide mechanistic understanding of the multistage phase separation, plating, inter/intra-particle lithium exchange and plated lithium back-intercalation phenomena. A strong dependence of intra-particle lithiation heterogeneity on the particle size, shape, orientation, surface condition and C-rate at the particle level is observed, which leads to early onset of plating spatially resolved by a 3D image-based phase-field model. Moreover, we highlight the distinct relaxation processes at different state-of-charges (SOCs), wherein thermodynamically unstable graphite particles undergo a drastic intra-particle lithium redistribution and inter-particle lithium exchange at intermediate SOCs, whereas the electrode equilibrates much slower at low and high SOCs. These physics-based insights into the distinct SOC-dependent relaxation efficiency provide new perspective towards developing advanced fast charge protocols to suppress plating and shorten the constant voltage regime.
Room temperature energy-efficient spin-orbit torque switching in two-dimensional van der Waals Fe3GeTe2 induced by topological insulators
Authors: Wang Haiyu , Wu Hao , Zhang Jie , Liu Yingjie , Chen Dongdong , Pandey Chandan , Yin Jialiang , Wei Dahai , Lei Na , Shi Shuyuan , Lu Haichang , Li Peng , Fert Albert , Wang Kang L. , Nie Tianxiao , Zhao Weisheng 
Published: August 2023

AbstractTwo-dimensional (2D) ferromagnetic materials with unique magnetic properties have great potential for next-generation spintronic devices with high flexibility, easy controllability, and high heretointegrability. However, realizing magnetic switching with low power consumption at room temperature is challenging. Here, we demonstrate the room-temperature spin-orbit torque (SOT) driven magnetization switching in an all-van der Waals (vdW) heterostructure using an optimized epitaxial growth approach. The topological insulator Bi2Te3 not only raises the Curie temperature of Fe3GeTe2 (FGT) through interfacial exchange coupling but also works as a spin current source allowing the FGT to switch at a low current density of ~2.2×106 A/cm2. The SOT efficiency is ~2.69, measured at room temperature. The temperature and thickness-dependent SOT efficiency prove that the larger SOT in our system mainly originates from the nontrivial topological origin of the heterostructure. Our experiments enable an all-vdW SOT structure and provides a solid foundation for the implementation of room-temperature all-vdW spintronic devices in the future.
Magnetization reversal through an antiferromagnetic state
Authors: Ghara Somnath , Barts Evgenii , Vasin Kirill , Kamenskyi Dmytro , Prodan Lilian , Tsurkan Vladimir , Kézsmárki István , Mostovoy Maxim , Deisenhofer Joachim 
Published: August 2023

AbstractMagnetization reversal in ferro- and ferrimagnets is a well-known archetype of non-equilibrium processes, where the volume fractions of the oppositely magnetized domains vary and perfectly compensate each other at the coercive magnetic field. Here, we report on a fundamentally new pathway for magnetization reversal that is mediated by an antiferromagnetic state. Consequently, an atomic-scale compensation of the magnetization is realized at the coercive field, instead of the mesoscopic or macroscopic domain cancellation in canonical reversal processes. We demonstrate this unusual magnetization reversal on the Zn-doped polar magnet Fe2Mo3O8. Hidden behind the conventional ferrimagnetic hysteresis loop, the surprising emergence of the antiferromagnetic phase at the coercive fields is disclosed by a sharp peak in the field-dependence of the electric polarization. In addition, at the magnetization reversal our THz spectroscopy studies reveal the reappearance of the magnon mode that is only present in the pristine antiferromagnetic state. According to our microscopic calculations, this unusual process is governed by the dominant intralayer coupling, strong easy-axis anisotropy and spin fluctuations, which result in a complex interplay between the ferrimagnetic and antiferromagnetic phases. Such antiferro-state-mediated reversal processes offer novel concepts for magnetization control, and may also emerge for other ferroic orders.
Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13
Authors: Liu Shenping , Sommese Ruth F. , Nedoma Nicole L. , Stevens Lucy Mae , Dutra Jason K. , Zhang Liying , Edmonds David J. , Wang Yang , Garnsey Michelle , Clasquin Michelle F. 
Published: August 2023

AbstractHydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Recently, there have been several reports that predicted loss of function variants in HSD17B13 protect against the progression of steatosis to non-alcoholic steatohepatitis with fibrosis and hepatocellular carcinoma. Here we report crystal structures of full length HSD17B13 in complex with its NAD+ cofactor, and with lipid/detergent molecules and small molecule inhibitors from two distinct series in the ligand binding pocket. These structures provide insights into a mechanism for lipid droplet-associated proteins anchoring to membranes as well as a basis for HSD17B13 variants disrupting function. Two series of inhibitors interact with the active site residues and the bound cofactor similarly, yet they occupy different paths leading to the active site. These structures provide ideas for structure-based design of inhibitors that may be used in the treatment of liver disease.