bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysfunctional endocannabinoid CB1 receptor expression and signaling contribute to skeletal muscle cell toxicity induced by simvastatin
Authors: Kalkan Hilal , Panza Elisabetta , Pagano Ester , Ercolano Giuseppe , Moriello Claudia , Piscitelli Fabiana , Sztretye Mónika , Capasso Raffaele , Di Marzo Vincenzo , Iannotti Fabio Arturo 
Published: August 2023

AbstractStatins are the most prescribed lipid-lowering agents worldwide. Their use is generally safe, although muscular toxicity occurs in about 1 in 10.000 patients. In this study, we explored the role of the endocannabinoid system (ECS) during muscle toxicity induced by simvastatin. In murine C2C12 myoblasts exposed to simvastatin, levels of the endocannabinoids AEA and 2-AG as well the expression of specific miRNAs (in particular miR-152) targeting the endocannabinoid CB1 gene were increased in a time-dependent manner. Rimonabant, a selective CB1 antagonist, exacerbated simvastatin-induced toxicity in myoblasts, while only a weak opposite effect was observed with ACEA and GAT211, selective orthosteric and allosteric agonists of CB1 receptor, respectively. In antagomiR152-transfected myoblasts, simvastatin toxicity was in part prevented together with the functional rescue of CB1. Further analyses revealed that simvastatin in C2C12 cells also suppresses PKC and ERK signaling pathways, which are instead activated downstream of CB1 receptor stimulation, thus adding more insight into the mechanism causing CB1 functional inactivation. Importantly, simvastatin induced similar alterations in skeletal muscles of C57BL/6 J mice and primary human myoblasts. In sum, we identified the dysregulated expression of the endocannabinoid CB1 receptor as well as the impairment of its downstream signaling pathways as a novel pathological mechanism involved in statin-induced myopathy.
Haspin balances the ratio of asymmetric cell division through Wnt5a and regulates cell fate decisions in mouse embryonic stem cells
Authors: Gao Yingying , Ma Bin , Li Yifan , Wu Xiangyu , Zhao Shifeng , Guo Huiping , Wang Yiwei , Sun Lihua , Xie Jing 
Published: August 2023

AbstractMany different types of stem cells utilize asymmetric cell division (ACD) to produce two daughter cells with distinct fates. Haspin-catalyzed phosphorylation of histone H3 at Thr3 (H3T3ph) plays important roles during mitosis, including ACD in stem cells. However, whether and how Haspin functions in ACD regulation remains unclear. Here, we report that Haspin knockout (Haspin-KO) mouse embryonic stem cells (mESCs) had increased ratio of ACD, which cumulatively regulates cell fate decisions. Furthermore, Wnt5a is significantly downregulated due to decreased Pax2 in Haspin-KO mESCs. Wnt5a knockdown mESCs phenocopied Haspin-KO cells while overexpression of Wnt5a in Haspin-KO cells rescued disproportionated ACD. Collectively, Haspin is indispensable for mESCs to maintain a balanced ratio of ACD, which is essential for normal development and homeostasis.
Persistent symptoms after COVID-19 are not associated with differential SARS-CoV-2 antibody or T cell immunity
Authors: Altmann Daniel M. , Reynolds Catherine J. , Joy George , Otter Ashley D. , Gibbons Joseph M. , Pade Corinna , Swadling Leo , Maini Mala K. , Brooks Tim , Semper Amanda , McKnight Áine , Noursadeghi Mahdad , Manisty Charlotte , Treibel Thomas A. , Moon James C. ,   COVIDsortium investigators, Boyton Rosemary J. 
Published: August 2023

AbstractAmong the unknowns in decoding the pathogenesis of SARS-CoV-2 persistent symptoms in Long Covid is whether there is a contributory role of abnormal immunity during acute infection. It has been proposed that Long Covid is a consequence of either an excessive or inadequate initial immune response. Here, we analyze SARS-CoV-2 humoral and cellular immunity in 86 healthcare workers with laboratory confirmed mild or asymptomatic SARS-CoV-2 infection during the first wave. Symptom questionnaires allow stratification into those with persistent symptoms and those without for comparison. During the period up to 18-weeks post-infection, we observe no difference in antibody responses to spike RBD or nucleoprotein, virus neutralization, or T cell responses. Also, there is no difference in the profile of antibody waning. Analysis at 1-year, after two vaccine doses, comparing those with persistent symptoms to those without, again shows similar SARS-CoV-2 immunity. Thus, quantitative differences in these measured parameters of SARS-CoV-2 adaptive immunity following mild or asymptomatic acute infection are unlikely to have contributed to Long Covid causality. ClinicalTrials.gov (NCT04318314).
A circuit suppressing retinal drive to the optokinetic system during fast image motion
Authors: Mani Adam , Yang Xinzhu , Zhao Tiffany A. , Leyrer Megan L. , Schreck Daniel , Berson David M. 
Published: August 2023

AbstractOptokinetic nystagmus (OKN) assists stabilization of the retinal image during head rotation. OKN is driven by ON direction selective retinal ganglion cells (ON DSGCs), which encode both the direction and speed of global retinal slip. The synaptic circuits responsible for the direction selectivity of ON DSGCs are well understood, but those sculpting their slow-speed preference remain enigmatic. Here, we probe this mechanism in mouse retina through patch clamp recordings, functional imaging, genetic manipulation, and electron microscopic reconstructions. We confirm earlier evidence that feedforward glycinergic inhibition is the main suppressor of ON DSGC responses to fast motion, and reveal the source for this inhibition—the VGluT3 amacrine cell, a dual neurotransmitter, excitatory/inhibitory interneuron. Together, our results identify a role for VGluT3 cells in limiting the speed range of OKN. More broadly, they suggest VGluT3 cells shape the response of many retinal cell types to fast motion, suppressing it in some while enhancing it in others.
Data-mining unveils structure–property–activity correlation of viral infectivity enhancing self-assembling peptides
Authors: Kaygisiz Kübra , Rauch-Wirth Lena , Dutta Arghya , Yu Xiaoqing , Nagata Yuki , Bereau Tristan , Münch Jan , Synatschke Christopher V. , Weil Tanja 
Published: August 2023

AbstractGene therapy via retroviral vectors holds great promise for treating a variety of serious diseases. It requires the use of additives to boost infectivity. Amyloid-like peptide nanofibers (PNFs) were shown to efficiently enhance retroviral gene transfer. However, the underlying mode of action of these peptides remains largely unknown. Data-mining is an efficient method to systematically study structure–function relationship and unveil patterns in a database. This data-mining study elucidates the multi-scale structure–property–activity relationship of transduction enhancing peptides for retroviral gene transfer. In contrast to previous reports, we find that not the amyloid fibrils themselves, but rather µm-sized β-sheet rich aggregates enhance infectivity. Specifically, microscopic aggregation of β-sheet rich amyloid structures with a hydrophobic surface pattern and positive surface charge are identified as key material properties. We validate the reliability of the amphiphilic sequence pattern and the general applicability of the key properties by rationally creating new active sequences and identifying short amyloidal peptides from various pathogenic and functional origin. Data-mining—even for small datasets—enables the development of new efficient retroviral transduction enhancers and provides important insights into the diverse bioactivity of the functional material class of amyloids.
Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease
Authors: Langella Stephanie , Barksdale N. Gil , Vasquez Daniel , Aguillon David , Chen Yinghua , Su Yi , Acosta-Baena Natalia , Acosta-Uribe Juliana , Baena Ana Y. , Garcia-Ospina Gloria , Giraldo-Chica Margarita , Tirado Victoria , Muñoz Claudia , Ríos-Romenets Silvia , Guzman-Martínez Claudia , Oliveira Gabriel , Yang Hyun-Sik , Vila-Castelar Clara , Pruzin Jeremy J. , Ghisays Valentina , Arboleda-Velasquez Joseph F. , Kosik Kenneth S. , Reiman Eric M. , Lopera Francisco , Quiroz Yakeel T. 
Published: August 2023

AbstractAutosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects ofAPOEand educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have anAPOEe4 allele compared to those who do not and delayed in mutation carriers who also have anAPOEe2 allele compared to those who do not. Educational attainment is protective and moderates the effect ofAPOEon cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.
Cell type-specific delivery by modular envelope design
Authors: Strebinger Daniel , Frangieh Chris J. , Friedrich Mirco J. , Faure Guilhem , Macrae Rhiannon K. , Zhang Feng 
Published: August 2023

AbstractThe delivery of genetic cargo remains one of the largest obstacles to the successful translation of experimental therapies, in large part due to the absence of targetable delivery vectors. Enveloped delivery modalities use viral envelope proteins, which determine tropism and induce membrane fusion. Here we develop DIRECTED (Delivery to Intended REcipient Cells Through Envelope Design), a modular platform that consists of separate fusion and targeting components. To achieve high modularity and programmable cell type specificity, we develop multiple strategies to recruit or immobilize antibodies on the viral envelope, including a chimeric antibody binding protein and a SNAP-tag enabling the use of antibodies or other proteins as targeting molecules. Moreover, we show that fusogens from multiple viral families are compatible with DIRECTED and that DIRECTED components can target multiple delivery chassis (e.g., lentivirus and MMLV gag) to specific cell types, including primary human T cells in PBMCs and whole blood.
Type-2 CD8+ T-cell formation relies on interleukin-33 and is linked to asthma exacerbations
Authors: van der Ploeg Esmee K. , Krabbendam Lisette , Vroman Heleen , van Nimwegen Menno , de Bruijn Marjolein J. W. , de Boer Geertje M. , Bergen Ingrid M. , Kool Mirjam , Tramper-Standers Gerdien A. , Braunstahl Gert-Jan , Huylebroeck Danny , Hendriks Rudi W. , Stadhouders Ralph 
Published: August 2023

AbstractCD4+ T helper 2 (Th2) cells and group 2 innate lymphoid cells are considered the main producers of type-2 cytokines that fuel chronic airway inflammation in allergic asthma. However, CD8+ cytotoxic T (Tc) cells - critical for anti-viral defense - can also produce type-2 cytokines (referred to as ‘Tc2’ cells). The role of Tc cells in asthma and virus-induced disease exacerbations remains poorly understood, including which micro-environmental signals and cell types promote Tc2 cell formation. Here we show increased circulating Tc2 cell abundance in severe asthma patients, reaching peak levels during exacerbations and likely emerging from canonical IFNγ+ Tc cells through plasticity. Tc2 cell abundance is associated with increased disease burden, higher exacerbations rates and steroid insensitivity. Mouse models of asthma recapitulate the human disease by showing extensive type-2 skewing of lung Tc cells, which is controlled by conventional type-1 dendritic cells and IFNγ. Importantly, we demonstrate that the alarmin interleukin-33 (IL-33) critically promotes type-2 cytokine production by lung Tc cells in experimental allergic airway inflammation. Our data identify Tc cells as major producers of type-2 cytokines in severe asthma and during exacerbations that are remarkably sensitive to alterations in their inflammatory tissue micro-environment, with IL-33 emerging as an important regulator of Tc2 formation.
Trim33 masks a non-transcriptional function of E2f4 in replication fork progression
Authors: Rousseau Vanessa , Einig Elias , Jin Chao , Horn Julia , Riebold Mathias , Poth Tanja , Jarboui Mohamed-Ali , Flentje Michael , Popov Nikita 
Published: August 2023

AbstractReplicative stress promotes genomic instability and tumorigenesis but also presents an effective therapeutic endpoint, rationalizing detailed analysis of pathways that control DNA replication. We show here that the transcription factor E2f4 recruits the DNA helicase Recql to facilitate progression of DNA replication forks upon drug- or oncogene-induced replicative stress. In unperturbed cells, the Trim33 ubiquitin ligase targets E2f4 for degradation, limiting its genomic binding and interactions with Recql. Replicative stress blunts Trim33-dependent ubiquitination of E2f4, which stimulates transient Recql recruitment to chromatin and facilitates recovery of DNA synthesis. In contrast, deletion of Trim33 induces chronic genome-wide recruitment of Recql and strongly accelerates DNA replication under stress, compromising checkpoint signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis controls progression of DNA replication forks along transcriptionally active chromatin to maintain genome integrity.
Hypothermal opto-thermophoretic tweezers
Authors: Kollipara Pavana Siddhartha , Li Xiuying , Li Jingang , Chen Zhihan , Ding Hongru , Kim Youngsun , Huang Suichu , Qin Zhenpeng , Zheng Yuebing 
Published: August 2023

AbstractOptical tweezers have profound importance across fields ranging from manufacturing to biotechnology. However, the requirement of refractive index contrast and high laser power results in potential photon and thermal damage to the trapped objects, such as nanoparticles and biological cells. Optothermal tweezers have been developed to trap particles and biological cells via opto-thermophoresis with much lower laser powers. However, the intense laser heating and stringent requirement of the solution environment prevent their use for general biological applications. Here, we propose hypothermal opto-thermophoretic tweezers (HOTTs) to achieve low-power trapping of diverse colloids and biological cells in their native fluids. HOTTs exploit an environmental cooling strategy to simultaneously enhance the thermophoretic trapping force at sub-ambient temperatures and suppress the thermal damage to target objects. We further apply HOTTs to demonstrate the three-dimensional manipulation of functional plasmonic vesicles for controlled cargo delivery. With their noninvasiveness and versatile capabilities, HOTTs present a promising tool for fundamental studies and practical applications in materials science and biotechnology.
Stable trapping of multiple proteins at physiological conditions using nanoscale chambers with macromolecular gates
Authors: Svirelis Justas , Adali Zeynep , Emilsson Gustav , Medin Jesper , Andersson John , Vattikunta Radhika , Hulander Mats , Järlebark Julia , Kolman Krzysztof , Olsson Oliver , Sakiyama Yusuke , Lim Roderick Y. H. , Dahlin Andreas 
Published: August 2023

AbstractThe possibility to detect and analyze single or few biological molecules is very important for understanding interactions and reaction mechanisms. Ideally, the molecules should be confined to a nanoscale volume so that the observation time by optical methods can be extended. However, it has proven difficult to develop reliable, non-invasive trapping techniques for biomolecules under physiological conditions. Here we present a platform for long-term tether-free (solution phase) trapping of proteins without exposing them to any field gradient forces. We show that a responsive polymer brush can make solid state nanopores switch between a fully open and a fully closed state with respect to proteins, while always allowing the passage of solvent, ions and small molecules. This makes it possible to trap a very high number of proteins (500-1000) inside nanoscale chambers as small as one attoliter, reaching concentrations up to 60 gL−1. Our method is fully compatible with parallelization by imaging arrays of nanochambers. Additionally, we show that enzymatic cascade reactions can be performed with multiple native enzymes under full nanoscale confinement and steady supply of reactants. This platform will greatly extend the possibilities to optically analyze interactions involving multiple proteins, such as the dynamics of oligomerization events.
Biology-guided deep learning predicts prognosis and cancer immunotherapy response
Authors: Jiang Yuming , Zhang Zhicheng , Wang Wei , Huang Weicai , Chen Chuanli , Xi Sujuan , Ahmad M. Usman , Ren Yulan , Sang Shengtian , Xie Jingjing , Wang Jen-Yeu , Xiong Wenjun , Li Tuanjie , Han Zhen , Yuan Qingyu , Xu Yikai , Xing Lei , Poultsides George A. , Li Guoxin , Li Ruijiang 
Published: August 2023

AbstractSubstantial progress has been made in using deep learning for cancer detection and diagnosis in medical images. Yet, there is limited success on prediction of treatment response and outcomes, which has important implications for personalized treatment strategies. A significant hurdle for clinical translation of current data-driven deep learning models is lack of interpretability, often attributable to a disconnect from the underlying pathobiology. Here, we present a biology-guided deep learning approach that enables simultaneous prediction of the tumor immune and stromal microenvironment status as well as treatment outcomes from medical images. We validate the model for predicting prognosis of gastric cancer and the benefit from adjuvant chemotherapy in a multi-center international study. Further, the model predicts response to immune checkpoint inhibitors and complements clinically approved biomarkers. Importantly, our model identifies a subset of mismatch repair-deficient tumors that are non-responsive to immunotherapy and may inform the selection of patients for combination treatments.
Mimicking reductive dehalogenases for efficient electrocatalytic water dechlorination
Authors: Min Yuan , Mei Shu-Chuan , Pan Xiao-Qiang , Chen Jie-Jie , Yu Han-Qing , Xiong Yujie 
Published: August 2023

AbstractElectrochemical technology is a robust approach to removing toxic and persistent chlorinated organic pollutants from water; however, it remains a challenge to design electrocatalysts with high activity and selectivity as elaborately as natural reductive dehalogenases. Here we report the design of high-performance electrocatalysts toward water dechlorination by mimicking the binding pocket configuration and catalytic center of reductive dehalogenases. Specifically, our designed electrocatalyst is an assembled heterostructure by sandwiching a molecular catalyst into the interlayers of two-dimensional graphene oxide. The electrocatalyst exhibits excellent dechlorination performance, which enhances reduction of intermediate dichloroacetic acid by 7.8 folds against that without sandwich configuration and can selectively generate monochloro-groups from trichloro-groups. Molecular simulations suggest that the sandwiched inner space plays an essential role in tuning solvation shell, altering protonation state and facilitating carbon−chlorine bond cleavage. This work demonstrates the concept of mimicking natural reductive dehalogenases toward the sustainable treatment of organohalogen-contaminated water and wastewater.
Nano-metal diborides-supported anode catalyst with strongly coupled TaOx/IrO2 catalytic layer for low-iridium-loading proton exchange membrane electrolyzer
Authors: Wang Yuannan , Zhang Mingcheng , Kang Zhenye , Shi Lei , Shen Yucheng , Tian Boyuan , Zou Yongcun , Chen Hui , Zou Xiaoxin 
Published: August 2023

AbstractThe sluggish kinetics of oxygen evolution reaction (OER) and high iridium loading in catalyst coated membrane (CCM) are the key challenges for practical proton exchange membrane water electrolyzer (PEMWE). Herein, we demonstrate high-surface-area nano-metal diborides as promising supports of iridium-based OER nanocatalysts for realizing efficient, low-iridium-loading PEMWE. Nano-metal diborides are prepared by a novel disulphide-to-diboride transition route, in which the entropy contribution to the Gibbs free energy by generation of gaseous sulfur-containing products plays a crucial role. The nano-metal diborides, TaB2 in particular, are investigated as the support of IrO2 nanocatalysts, which finally forms a TaOx/IrO2 heterojunction catalytic layer on TaB2 surface. Multiple advantageous properties are achieved simultaneously by the resulting composite material (denoted as IrO2@TaB2), including high electrical conductivity, improved iridium mass activity and enhanced corrosion resistance. As a consequence, the IrO2@TaB2 can be used to fabricate the membrane electrode with a low iridium loading of 0.15 mg cm−2, and to give an excellent catalytic performance (3.06 A cm−2@2.0 V@80 oC) in PEMWE―the one that is usually inaccessible by unsupported Ir-based nanocatalysts and the vast majority of existing supported Ir-based catalysts at such a low iridium loading.
Self-triggered thermoelectric nanoheterojunction for cancer catalytic and immunotherapy
Authors: Yuan Xue , Kang Yong , Dong Jinrui , Li Ruiyan , Ye Jiamin , Fan Yueyue , Han Jingwen , Yu Junhui , Ni Guangjian , Ji Xiaoyuan , Ming Dong 
Published: August 2023

AbstractThe exogenous excitation requirement and electron-hole recombination are the key elements limiting the application of catalytic therapies. Here a tumor microenvironment (TME)-specific self-triggered thermoelectric nanoheterojunction (Bi0.5Sb1.5Te3/CaO2 nanosheets, BST/CaO2 NSs) with self-built-in electric field facilitated charge separation is fabricated. Upon exposure to TME, the CaO2 coating undergoes rapid hydrolysis, releasing Ca2+, H2O2, and heat. The resulting temperature difference on the BST NSs initiates a thermoelectric effect, driving reactive oxygen species production. H2O2 not only serves as a substrate supplement for ROS generation but also dysregulates Ca2+ channels, preventing Ca2+ efflux. This further exacerbates calcium overload-mediated therapy. Additionally, Ca2+ promotes DC maturation and tumor antigen presentation, facilitating immunotherapy. It is worth noting that the CaO2 NP coating hydrolyzes very slowly in normal cells, releasing Ca2+ and O2 without causing any adverse effects. Tumor-specific self-triggered thermoelectric nanoheterojunction combined catalytic therapy, ion interference therapy, and immunotherapy exhibit excellent antitumor performance in female mice.