bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis of negative regulation of CRISPR-Cas7-11 by TPR-CHAT
Authors: Hong Tian , Luo Qinghua , Ma Haiyun , Wang Xin , Li Xinqiong , Shen Chongrong , Pang Jie , Wang Yan , Chen Yuejia , Zhang Changbin , Su Zhaoming , Dong Haohao , Tang Xiaodi 
Published: May 2024

AbstractCRISPR‒Cas7-11 is a Type III-E CRISPR-associated nuclease that functions as a potent RNA editing tool. Tetratrico-peptide repeat fused with Cas/HEF1-associated signal transducer (TPR-CHAT) acts as a regulatory protein that interacts with CRISPR RNA (crRNA)-bound Cas7-11 to form a CRISPR-guided caspase complex (Craspase). However, the precise modulation of Cas7-11’s nuclease activity by TPR-CHAT to enhance its utility requires further study. Here, we report cryo-electron microscopy (cryo-EM) structures of Desulfonema ishimotonii (Di) Cas7-11-crRNA, complexed with or without the full length or the N-terminus of TPR-CHAT. These structures unveil the molecular features of the Craspase complex. Structural analysis, combined with in vitro nuclease assay and electrophoretic mobility shift assay, reveals that DiTPR-CHAT negatively regulates the activity of DiCas7-11 by preventing target RNA from binding through the N-terminal 65 amino acids of DiTPR-CHAT (DiTPR-CHATNTD). Our work demonstrates that DiTPR-CHATNTD can function as a small unit of DiCas7-11 regulator, potentially enabling safe applications to prevent overcutting and off-target effects of the CRISPR‒Cas7-11 system.
XIST and MUC1-C form an auto-regulatory pathway in driving cancer progression
Authors: Wang Keyi , Bhattacharya Atrayee , Haratake Naoki , Daimon Tatsuaki , Nakashoji Ayako , Ozawa Hiroki , Peng Bo , Li Wei , Kufe Donald 
Published: May 2024

AbstractThe long non-coding RNA X-inactive specific transcript (lncRNA XIST) and MUC1 gene are dysregulated in chronic inflammation and cancer; however, there is no known interaction of their functions. The present studies demonstrate that MUC1-C regulates XIST lncRNA levels by suppressing the RBM15/B, WTAP and METTL3/14 components of the m6A methylation complex that associate with XIST A repeats. MUC1-C also suppresses the YTHDF2-CNOT1 deadenylase complex that recognizes m6A sites and contributes to XIST decay with increases in XIST stability and expression. In support of an auto-regulatory pathway, we show that XIST regulates MUC1-C expression by promoting NF-κB-mediated activation of the MUC1 gene. Of significance, MUC1-C and XIST regulate common genes associated with inflammation and stemness, including (i) miR-21 which is upregulated across pan-cancers, and (ii) TDP-43 which associates with the XIST E repeats. Our results further demonstrate that the MUC1-C/XIST pathway (i) is regulated by TDP-43, (ii) drives stemness-associated genes, and (iii) is necessary for self-renewal capacity. These findings indicate that the MUC1-C/XIST auto-regulatory axis is of importance in cancer progression.
FOXP4-mediated induction of PTK7 activates the Wnt/β-catenin pathway and promotes ovarian cancer development
Authors: Ji Jing , Qian Qilan , Cheng Wenhao , Ye Xiaoqing , Jing Aixin , Ma Shaojie , Ding Yuanyuan , Ma Xinhui , Wang Yasong , Sun Qian , Wang Xiujun , Chen Yulu , Zhu Lan , Yuan Qing , Xu Menghan , Qin Jingting , Ma Lin , Yang Jiayan , Zhang Meiqi , Geng Ting , Wang Sen , Wang Dan , Song Yizhuo , Zhang Boyu , Xu Yuting , Xu Linyu , Liu Shunfang , Liu Wei , Liu Bin 
Published: May 2024

AbstractOvarian cancer (OV) poses a significant challenge in clinical settings due to its difficulty in early diagnosis and treatment resistance. FOXP4, belonging to the FOXP subfamily, plays a pivotal role in various biological processes including cancer, cell cycle regulation, and embryonic development. However, the specific role and importance of FOXP4 in OV have remained unclear. Our research showed that FOXP4 is highly expressed in OV tissues, with its elevated levels correlating with poor prognosis. We further explored FOXP4’s function through RNA sequencing and functional analysis in FOXP4-deficient cells, revealing its critical role in activating the Wnt signaling pathway. This activation exacerbates the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, which causes abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OV cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings underscore the significance of the FOXP4-induced Wnt pathway activation in OV, suggesting the therapeutic potential of targeting this pathway in OV treatment.
Reduction of spermine synthase enhances autophagy to suppress Tau accumulation
Authors: Tao Xianzun , Liu Jiaqi , Diaz-Perez Zoraida , Foley Jackson R. , Nwafor Ashley , Stewart Tracy Murray , Casero Robert A. , Zhai R. Grace 
Published: May 2024

AbstractPrecise polyamine metabolism regulation is vital for cells and organisms. Mutations in spermine synthase (SMS) cause Snyder–Robinson intellectual disability syndrome (SRS), characterized by significant spermidine accumulation and autophagy blockage in the nervous system. Emerging evidence connects polyamine metabolism with other autophagy-related diseases, such as Tauopathy, however, the functional intersection between polyamine metabolism and autophagy in the context of these diseases remains unclear. Here, we altered SMS expression level to investigate the regulation of autophagy by modulated polyamine metabolism in Tauopathy in Drosophila and human cellular models. Interestingly, while complete loss of Drosophila spermine synthase (dSms) impairs lysosomal function and blocks autophagic flux recapitulating SRS disease phenotype, partial loss of dSms enhanced autophagic flux, reduced Tau protein accumulation, and led to extended lifespan and improved climbing performance in Tauopathy flies. Measurement of polyamine levels detected a mild elevation of spermidine in flies with partial loss of dSms. Similarly, in human neuronal or glial cells, partial loss of SMS by siRNA-mediated knockdown upregulated autophagic flux and reduced Tau protein accumulation. Importantly, proteomics analysis of postmortem brain tissue from Alzheimer’s disease (AD) patients showed a significant albeit modest elevation of SMS level. Taken together, our study uncovers a functional correlation between polyamine metabolism and autophagy in AD: SMS reduction upregulates autophagy, suppresses Tau accumulation, and ameliorates neurodegeneration and cell death. These findings provide a new potential therapeutic target for AD.
HTRA1 interacts with SLC7A11 to modulate colorectal cancer chemosensitivity by inhibiting ferroptosis
Authors: Liu Weiwei , Liu Chaoqun , Xiao Jun , Qian Cheng , Chen Zhilin , Lin Wandie , Zhang Yujie , Wu Jianghua , Zhou Rui , Zhao Liang 
Published: May 2024

AbstractChemotherapy is an important therapuetic strategy for colorectal cancer (CRC), but chemoresistance severely affects its efficacy, and the underlying mechanism has not been fully elucidated. Increasing evidence suggests that lipid peroxidation imbalance-mediated ferroptosis is closely associated with chemoresistance. Hence, targeting ferroptosis pathways or modulating the tolerance to oxidative stress might be an effective strategy to reverse tumor chemoresistance. HtrA serine protease 1 (HTRA1) was screened out as a CRC progression- and chemoresistance-related gene. It is highly expressed in CRC cells and negatively correlated with the prognosis of CRC patients. Gain- and loss-of-function analyses demonstrated a stimulatory role of HTRA1 on the proliferation of CRC cells. The enrichment analysis of HTRA1-interacting proteins indicated the involvement of ferroptosis in the HTRA1-mediated chemoresistance. Moreover, electron microscope analysis, as well as the ROS and MDA levels in CRC cells also confirmed the effect of HTRA1 on ferroptosis. We also verified that HTRA1 could interact with SLC7A11 through its Kazal structural domain and up-regulate the expression of SLC7A11, which in turn inhibited the ferroptosis and leaded to the chemoresistance of CRC cells to 5-FU/L-OHP. Hence, we propose that HTRA1 may be a potential therapeutic target and a prognostic indicator in CRC.
IL-17a promotes hepatocellular carcinoma by increasing FAP expression in hepatic stellate cells via activation of the STAT3 signaling pathway
Authors: Sun Dapeng , Li Wen , Ding Dongyang , Tan Kunjiang , Ding Wenbin , Wang Zongyan , Fu Siyuan , Hou Guojun , Zhou Wei-ping , Gu Fangming 
Published: May 2024

AbstractStudies have shown that hepatic stellate cells (HSCs) and interleukin-17a (IL-17a) play important roles in liver tumorigenesis. In addition, fibroblast activation protein-α (FAP) has been shown to be a key regulator of hepatic stellate cell activation. In this study, in vivo and in vitro experiments were performed to verify the promoting effects of IL-17a administration, IL-17a overexpression, and FAP upregulation in HSCs on liver fibrosis and liver tumorigenesis. The cleavage under targets & release using nuclease (CUT&RUN) technique was used to verify the binding status of STAT3 to the FAP promoter. The in vitro studies showed that IL-17a activated HSCs and promoted HCC development and progression. FAP and IL-17a overexpression also activated HSCs, promoted HCC cell proliferation and migration, and inhibited HCC cell apoptosis. The in vivo studies suggested that IL-17a and FAP overexpression in HSCs facilitated liver tumor development and progression. The CUT&RUN results indicated that FAP expression was regulated by STAT3, which could bind to the FAP promoter region and regulate its transcription status. We concluded that IL-17a promoted HCC by increasing FAP expression in HSCs via activation of the STAT3 signaling pathway.
Platelets favor the outgrowth of established metastases
Authors: Garcia-Leon Maria J. , Liboni Cristina , Mittelheisser Vincent , Bochler Louis , Follain Gautier , Mouriaux Clarisse , Busnelli Ignacio , Larnicol Annabel , Colin Florent , Peralta Marina , Osmani Naël , Gensbittel Valentin , Bourdon Catherine , Samaniego Rafael , Pichot Angélique , Paul Nicodème , Molitor Anne , Carapito Raphaël , Jandrot-Perrus Martine , Lefebvre Olivier , Mangin Pierre H. , Goetz Jacky G. 
Published: May 2024

AbstractDespite abundant evidence demonstrating that platelets foster metastasis, anti-platelet agents have low therapeutic potential due to the risk of hemorrhages. In addition, whether platelets can regulate metastasis at the late stages of the disease remains unknown. In this study, we subject syngeneic models of metastasis to various thrombocytopenic regimes to show that platelets provide a biphasic contribution to metastasis. While potent intravascular binding of platelets to tumor cells efficiently promotes metastasis, platelets further support the outgrowth of established metastases via immune suppression. Genetic depletion and pharmacological targeting of the glycoprotein VI (GPVI) platelet-specific receptor in humanized mouse models efficiently reduce the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study demonstrates therapeutic efficacy when targeting animals bearing growing metastases. It further identifies GPVI as a molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations.
Gene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo
Authors: Aubert Martine , Haick Anoria K. , Strongin Daniel E. , Klouser Lindsay M. , Loprieno Michelle A. , Stensland Laurence , Santo Tracy K. , Huang Meei-Li , Hyrien Ollivier , Stone Daniel , Jerome Keith R. 
Published: May 2024

Abstract
Anti-HSV therapies are only suppressive because they do not eliminate latent HSV present in ganglionic neurons, the source of recurrent disease. We have developed a potentially curative approach against HSV infection, based on gene editing using HSV-specific meganucleases delivered by adeno-associated virus (AAV) vectors. Gene editing performed with two anti-HSV-1 meganucleases delivered by a combination of AAV9, AAV-Dj/8, and AAV-Rh10 can eliminate 90% or more of latent HSV DNA in mouse models of orofacial infection, and up to 97% of latent HSV DNA in mouse models of genital infection. Using a pharmacological approach to reactivate latent HSV-1, we demonstrate that ganglionic viral load reduction leads to a significant decrease of viral shedding in treated female mice. While therapy is well tolerated, in some instances, we observe hepatotoxicity at high doses and subtle histological evidence of neuronal injury without observable neurological signs or deficits. Simplification of the regimen through use of a single serotype (AAV9) delivering single meganuclease targeting a duplicated region of the HSV genome, dose reduction, and use of a neuron-specific promoter each results in improved tolerability while retaining efficacy. These results reinforce the curative potential of gene editing for HSV disease.
Mammographic density mediates the protective effect of early-life body size on breast cancer risk
Authors: Vabistsevits Marina , Davey Smith George , Richardson Tom G. , Richmond Rebecca C. , Sieh Weiva , Rothstein Joseph H. , Habel Laurel A. , Alexeeff Stacey E. , Lloyd-Lewis Bethan , Sanderson Eleanor 
Published: May 2024

AbstractThe unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%–79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.
Optical vectorial-mode parity Hall effect: a case study with cylindrical vector beams
Authors: Zhou Changyu , Liang Weili , Xie Zhenwei , Ma Jia , Yang Hui , Yang Xing , Hu Yueqiang , Duan Huigao , Yuan Xiaocong 
Published: May 2024

AbstractThe vectorial optical field (VOF) assumes a pivotal role in light-matter interactions. Beyond its inherent polarization topology, the VOF also encompasses an intrinsic degree of freedom associated with parity (even or odd), corresponding to a pair of degenerate orthogonal modes. However, previous research has not delved into the simultaneous manipulation of both even and odd parities. In this study, we introduce and validate the previously unexplored parity Hall effect for vectorial modes using a metasurface design. Our focus lies on a cylindrical vector beam (CVB) as a representative case. Through the tailored metasurface, we effectively separate two degenerate CVBs with distinct parities in divergent directions, akin to the observed spin states split in the spin Hall effect. Additionally, we provide experimental evidence showcasing the capabilities of this effect in multi-order CVB demultiplexing and parity-demultiplexed CVB-encoded holography. This effect unveils promising opportunities for various applications, including optical communication and imaging.
Rapid and scalable photocatalytic C(sp2)–C(sp3) Suzuki−Miyaura cross-coupling of aryl bromides with alkyl boranes
Authors: Wan Ting , Capaldo Luca , Djossou Jonas , Staffa Angela , de Zwart Felix J. , de Bruin Bas , Noël Timothy 
Published: May 2024

AbstractIn recent years, there has been a growing demand for drug design approaches that incorporate a higher number of sp3-hybridized carbons, necessitating the development of innovative cross-coupling strategies to reliably introduce aliphatic fragments. Here, we present a powerful approach for the light-mediated B-alkyl Suzuki−Miyaura cross-coupling between alkyl boranes and aryl bromides. Alkyl boranes were easily generated via hydroboration from readily available alkenes, exhibiting excellent regioselectivity and enabling the selective transfer of a diverse range of primary alkyl fragments onto the arene ring under photocatalytic conditions. This methodology eliminates the need for expensive catalytic systems and sensitive organometallic compounds, operating efficiently at room temperature within just 30 min. We further demonstrate the translation of the present protocol to continuous-flow conditions, enhancing scalability, safety, and overall efficiency of the method. This versatile approach offers significant potential for accelerating drug discovery efforts by enabling the introduction of complex aliphatic fragments in a straightforward and reliable manner.
Analysis of early intermediate states of the nitrogenase reaction by regularization of EPR spectra
Authors: Heidinger Lorenz , Perez Kathryn , Spatzal Thomas , Einsle Oliver , Weber Stefan , Rees Douglas C. , Schleicher Erik 
Published: May 2024

AbstractDue to the complexity of the catalytic FeMo cofactor site in nitrogenases that mediates the reduction of molecular nitrogen to ammonium, mechanistic details of this reaction remain under debate. In this study, selenium- and sulfur-incorporated FeMo cofactors of the catalytic MoFe protein component from Azotobacter vinelandii are prepared under turnover conditions and investigated by using different EPR methods. Complex signal patterns are observed in the continuous wave EPR spectra of selenium-incorporated samples, which are analyzed by Tikhonov regularization, a method that has not yet been applied to high spin systems of transition metal cofactors, and by an already established grid-of-error approach. Both methods yield similar probability distributions that reveal the presence of at least four other species with different electronic structures in addition to the ground state E0. Two of these species were preliminary assigned to hydrogenated E2 states. In addition, advanced pulsed-EPR experiments are utilized to verify the incorporation of sulfur and selenium into the FeMo cofactor, and to assign hyperfine couplings of 33S and 77Se that directly couple to the FeMo cluster. With this analysis, we report selenium incorporation under turnover conditions as a straightforward approach to stabilize and analyze early intermediate states of the FeMo cofactor.
Snail-inspired water-enhanced soft sliding suction for climbing robots
Authors: Yue Tianqi , Bloomfield-Gadêlha Hermes , Rossiter Jonathan 
Published: May 2024

AbstractSnails can stably slide across a surface with only a single high-payload sucker, offering an efficient adhesive locomotion mechanism for next-generation climbing robots. The critical factor for snails’ sliding suction behaviour is mucus secretion, which reduces friction and enhances suction. Inspired by this, we proposed an artificial sliding suction mechanism. The sliding suction utilizes water as an artificial mucus, which is widely available and evaporates with no residue. The sliding suction allows a lightweight robot (96 g) to slide vertically and upside down, achieving high speeds (rotation of 53°/s and translation of 19 mm/s) and high payload (1 kg as tested and 5.03 kg in theory), and does not require energy during adhesion. Here, we show that the sliding suction is a low-cost, energy-efficient, high-payload and clean adhesive locomotion strategy, which has high potential for use in climbing robots, outdoor inspection robots and robotic transportation.
Tuning instability in suspended monolayer 2D materials
Authors: Hou Yuan , Zhou Jingzhuo , He Zezhou , Chen Juzheng , Zhu Mengya , Wu HengAn , Lu Yang 
Published: May 2024

AbstractMonolayer two-dimensional (2D) materials possess excellent in-plane mechanical strength yet extremely low bending stiffness, making them particularly susceptible to instability, which is anticipated to have a substantial impact on their physical functionalities such as 2D-based Micro/Nanoelectromechanical systems (M/NEMS), nanochannels, and proton transport membrane. In this work, we achieve quantitatively tuning instability in suspended 2D materials including monolayer graphene and MoS2 by employing a push-to-shear strategy. We comprehensively examine the dynamic wrinkling-splitting-smoothing process and find that monolayer 2D materials experience stepwise instabilities along with different recovery processes. These stepwise instabilities are governed by the materials’ geometry, pretension, and the elastic nonlinearity. We attribute the different instability and recovery paths to the local stress redistribution in monolayer 2D materials. The tunable instability behavior of suspended monolayer 2D materials not only allows measuring their bending stiffness but also opens up new opportunities for programming the nanoscale instability pattern and even physical properties of atomically thin films.
Single-site iron-anchored amyloid hydrogels as catalytic platforms for alcohol detoxification
Authors: Su Jiaqi , Wang Pengjie , Zhou Wei , Peydayesh Mohammad , Zhou Jiangtao , Jin Tonghui , Donat Felix , Jin Cuiyuan , Xia Lu , Wang Kaiwen , Ren Fazheng , Van der Meeren Paul , García de Arquer F. Pelayo , Mezzenga Raffaele 
Published: May 2024

AbstractConstructing effective antidotes to reduce global health impacts induced by alcohol prevalence is a challenging topic. Despite the positive effects observed with intravenous applications of natural enzyme complexes, their insufficient activities and complicated usage often result in the accumulation of toxic acetaldehyde, which raises important clinical concerns, highlighting the pressing need for stable oral strategies. Here we present an effective solution for alcohol detoxification by employing a biomimetic-nanozyme amyloid hydrogel as an orally administered catalytic platform. We exploit amyloid fibrils derived from β-lactoglobulin, a readily accessible milk protein that is rich in coordinable nitrogen atoms, as a nanocarrier to stabilize atomically dispersed iron (ferrous-dominated). By emulating the coordination structure of the horseradish peroxidase enzyme, the single-site iron nanozyme demonstrates the capability to selectively catalyse alcohol oxidation into acetic acid, as opposed to the more toxic acetaldehyde. Administering the gelatinous nanozyme to mice suffering from alcohol intoxication significantly reduced their blood-alcohol levels (decreased by 55.8% 300 min post-alcohol intake) without causing additional acetaldehyde build-up. Our hydrogel further demonstrates a protective effect on the liver, while simultaneously mitigating intestinal damage and dysbiosis associated with chronic alcohol consumption, introducing a promising strategy in effective alcohol detoxification.