bluuebunny/crossref_metadata_2025_split huggingface dataset:
Axitinib in patients with advanced/metastatic soft tissue sarcoma (Axi-STS): an open-label, multicentre, phase II trial in four histological strata
Authors: Woll Penella J. , Gaunt Piers , Gaskell Charlotte , Young Robin , Benson Charlotte , Judson Ian R. , Seddon Beatrice M. , Marples Maria , Ali Nasim , Strauss Sandra J. , Lee Alexander , Hughes Ana , Kaur Baljit , Hughes David , Billingham Lucinda 
Published: September 2023

Abstract
Background
Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer.

Methods
Axi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon’s two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata.

Results
Between 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events.

Conclusions
Axitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials.

Clinical Trial Registration
ISRCTN 60791336
Activation of the integrated stress response by inhibitors of its kinases
Authors: Szaruga Maria , Janssen Dino A. , de Miguel Claudia , Hodgson George , Fatalska Agnieszka , Pitera Aleksandra P. , Andreeva Antonina , Bertolotti Anne 
Published: September 2023

AbstractPhosphorylation of the translation initiation factor eIF2α to initiate the integrated stress response (ISR) is a vital signalling event. Protein kinases activating the ISR, including PERK and GCN2, have attracted considerable attention for drug development. Here we find that the widely used ATP-competitive inhibitors of PERK, GSK2656157, GSK2606414 and AMG44, inhibit PERK in the nanomolar range, but surprisingly activate the ISR via GCN2 at micromolar concentrations. Similarly, a PKR inhibitor, C16, also activates GCN2. Conversely, GCN2 inhibitor A92 silences its target but induces the ISR via PERK. These findings are pivotal for understanding ISR biology and its therapeutic manipulations because most preclinical studies used these inhibitors at micromolar concentrations. Reconstitution of ISR activation with recombinant proteins demonstrates that PERK and PKR inhibitors directly activate dimeric GCN2, following a Gaussian activation-inhibition curve, with activation driven by allosterically increasing GCN2 affinity for ATP. The tyrosine kinase inhibitors Neratinib and Dovitinib also activate GCN2 by increasing affinity of GCN2 for ATP. Thus, the mechanism uncovered here might be broadly relevant to ATP-competitive inhibitors and perhaps to other kinases.
Sequential order dependent dark-exciton modulation in bi-layered TMD heterostructure
Authors: Sebait Riya , Rosati Roberto , Yun Seok Joon , Dhakal Krishna P. , Brem Samuel , Biswas Chandan , Puretzky Alexander , Malic Ermin , Lee Young Hee 
Published: September 2023

AbstractWe report the emergence of dark-excitons in transition-metal-dichalcogenide (TMD) heterostructures that strongly rely on the stacking sequence, i.e., momentum-dark K-Q exciton located exclusively at the top layer of the heterostructure. The feature stems from band renormalization and is distinct from those of typical neutral excitons or trions, regardless of materials, substrates, and even homogeneous bilayers, which is further confirmed by scanning tunneling spectroscopy. To understand the unusual stacking sequence, we introduce the excitonic Elliot formula by imposing strain exclusively on the top layer that could be a consequence of the stacking process. We further find that the intensity ratio of Q- to K-excitons in the same layer is inversely proportional to laser power, unlike for conventional K-K excitons. This can be a metric for engineering the intensity of dark K-Q excitons in TMD heterostructures, which could be useful for optical power switches in solar panels.
Fasting mimicking diet in mice delays cancer growth and reduces immunotherapy-associated cardiovascular and systemic side effects
Authors: Cortellino S. , Quagliariello V. , Delfanti G. , Blaževitš O. , Chiodoni C. , Maurea N. , Di Mauro A. , Tatangelo F. , Pisati F. , Shmahala A. , Lazzeri S. , Spagnolo V. , Visco E. , Tripodo C. , Casorati G. , Dellabona P. , Longo V. D. 
Published: September 2023

AbstractImmune checkpoint inhibitors cause side effects ranging from autoimmune endocrine disorders to severe cardiotoxicity. Periodic Fasting mimicking diet (FMD) cycles are emerging as promising enhancers of a wide range of cancer therapies including immunotherapy. Here, either FMD cycles alone or in combination with anti-OX40/anti-PD-L1 are much more effective than immune checkpoint inhibitors alone in delaying melanoma growth in mice. FMD cycles in combination with anti-OX40/anti-PD-L1 also show a trend for increased effects against a lung cancer model. As importantly, the cardiac fibrosis, necrosis and hypertrophy caused by immune checkpoint inhibitors are prevented/reversed by FMD treatment in both cancer models whereas immune infiltration of CD3+ and CD8+ cells in myocardial tissues and systemic and myocardial markers of oxidative stress and inflammation are reduced. These results indicate that FMD cycles in combination with immunotherapy can delay cancer growth while reducing side effects including cardiotoxicity.
Cyclic AMP induces reversible EPAC1 condensates that regulate histone transcription
Authors: Iannucci Liliana Felicia , D’Erchia Anna Maria , Picardi Ernesto , Bettio Daniela , Conca Filippo , Surdo Nicoletta Concetta , Di Benedetto Giulietta , Musso Deborah , Arrigoni Cristina , Lolicato Marco , Vismara Mauro , Grisan Francesca , Salviati Leonardo , Milanesi Luciano , Pesole Graziano , Lefkimmiatis Konstantinos 
Published: September 2023

AbstractThe second messenger cyclic AMP regulates many nuclear processes including transcription, pre-mRNA splicing and mitosis. While most functions are attributed to protein kinase A, accumulating evidence suggests that not all nuclear cyclic AMP-dependent effects are mediated by this kinase, implying that other effectors may be involved. Here we explore the nuclear roles of Exchange Protein Activated by cyclic AMP 1. We find that it enters the nucleus where forms reversible biomolecular condensates in response to cyclic AMP. This phenomenon depends on intrinsically disordered regions present at its amino-terminus and is independent of protein kinase A. Finally, we demonstrate that nuclear Exchange Protein Activated by cyclic AMP 1 condensates assemble at genomic loci on chromosome 6 in the proximity of Histone Locus Bodies and promote the transcription of a histone gene cluster. Collectively, our data reveal an unexpected mechanism through which cyclic AMP contributes to nuclear spatial compartmentalization and promotes the transcription of specific genes.
Global land and water limits to electrolytic hydrogen production using wind and solar resources
Authors: Tonelli Davide , Rosa Lorenzo , Gabrielli Paolo , Caldeira Ken , Parente Alessandro , Contino Francesco 
Published: September 2023

AbstractProposals for achieving net-zero emissions by 2050 include scaling-up electrolytic hydrogen production, however, this poses technical, economic, and environmental challenges. One such challenge is for policymakers to ensure a sustainable future for the environment including freshwater and land resources while facilitating low-carbon hydrogen production using renewable wind and solar energy. We establish a country-by-country reference scenario for hydrogen demand in 2050 and compare it with land and water availability. Our analysis highlights countries that will be constrained by domestic natural resources to achieve electrolytic hydrogen self-sufficiency in a net-zero target. Depending on land allocation for the installation of solar panels or wind turbines, less than 50% of hydrogen demand in 2050 could be met through a local production without land or water scarcity. Our findings identify potential importers and exporters of hydrogen or, conversely, exporters or importers of industries that would rely on electrolytic hydrogen. The abundance of land and water resources in Southern and Central-East Africa, West Africa, South America, Canada, and Australia make these countries potential leaders in hydrogen export.
Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids
Authors: Wu Hao , Huang Xing-Yao , Sun Meng-Xu , Wang Yue , Zhou Hang-Yu , Tian Ying , He Beijia , Li Kai , Li De-Yu , Wu Ai-Ping , Wang Hongmei , Qin Cheng-Feng 
Published: September 2023

AbstractZika virus (ZIKV) infection during pregnancy threatens pregnancy and fetal health. However, the infectivity and pathological effects of ZIKV on placental trophoblast progenitor cells in early human embryos remain largely unknown. Here, using human trophoblast stem cells (hTSCs), we demonstrated that hTSCs were permissive to ZIKV infection, and resistance to ZIKV increased with hTSC differentiation. Combining gene knockout and transcriptome analysis, we demonstrated that the intrinsic expression of AXL and TIM-1, and the absence of potent interferon (IFN)-stimulated genes (ISGs) and IFNs contributed to the high sensitivity of hTSCs to ZIKV. Furthermore, using our newly developed hTSC-derived trophoblast organoid (hTSC-organoid), we demonstrated that ZIKV infection disrupted the structure of mature hTSC-organoids and inhibited syncytialization. Single-cell RNA sequencing (scRNA-seq) further demonstrated that ZIKV infection of hTSC-organoids disrupted the stemness of hTSCs and the proliferation of cytotrophoblast cells (CTBs) and probably led to a preeclampsia (PE) phenotype. Overall, our results clearly demonstrate that hTSCs represent the major target cells of ZIKV, and a reduced syncytialization may result from ZIKV infection of early developing placenta. These findings deepen our understanding of the characteristics and consequences of ZIKV infection of hTSCs in early human embryos.
Serotonin signaling regulates actomyosin contractility during morphogenesis in evolutionarily divergent lineages
Authors: Karki Sanjay , Saadaoui Mehdi , Dunsing Valentin , Kerridge Stephen , Da Silva Elise , Philippe Jean-Marc , Maurange Cédric , Lecuit Thomas 
Published: September 2023

AbstractSerotonin is a neurotransmitter that signals through 5-HT receptors to control key functions in the nervous system. Serotonin receptors are also ubiquitously expressed in various organs and have been detected in embryos of different organisms. Potential morphogenetic functions of serotonin signaling have been proposed based on pharmacological studies but a mechanistic understanding is still lacking. Here, we uncover a role of serotonin signaling in axis extension ofDrosophilaembryos by regulating Myosin II (MyoII) activation, cell contractility and cell intercalation. We find that serotonin and serotonin receptors 5HT2A and 5HT2B form a signaling module that quantitatively regulates the amplitude of planar polarized MyoII contractility specified by Toll receptors and the GPCR Cirl. Remarkably, serotonin signaling also regulates actomyosin contractility at cell junctions, cellular flows and epiblast morphogenesis during chicken gastrulation. This phylogenetically conserved mechanical function of serotonin signaling in regulating actomyosin contractility and tissue flow reveals an ancestral role in morphogenesis of multicellular organisms.
Structural convergence endows nuclear transport receptor Kap114p with a transcriptional repressor function toward TATA-binding protein
Authors: Liao Chung-Chi , Wang Yi-Sen , Pi Wen-Chieh , Wang Chun-Hsiung , Wu Yi-Min , Chen Wei-Yi , Hsia Kuo-Chiang 
Published: September 2023

AbstractThe transcription factor TATA-box binding protein (TBP) modulates gene expression in nuclei. This process requires the involvement of nuclear transport receptors, collectively termed karyopherin-β (Kap-β) in yeast, and various regulatory factors. In previous studies we showed that Kap114p, a Kap-β that mediates nuclear import of yeast TBP (yTBP), modulates yTBP-dependent transcription. However, how Kap114p associates with yTBP to exert its multifaceted functions has remained elusive. Here, we employ single-particle cryo-electron microscopy to determine the structure of Kap114p in complex with the core domain of yTBP (yTBPC). Remarkably, Kap114p wraps around the yTBPC N-terminal lobe, revealing a structure resembling transcriptional regulators in complex with TBP, suggesting convergent evolution of the two protein groups for a common function. We further demonstrate that Kap114p sequesters yTBP away from promoters, preventing a collapse of yTBP dynamics required for yeast responses to environmental stress. Hence, we demonstrate that nuclear transport receptors represent critical elements of the transcriptional regulatory network.
Panoramic analysis of coronaviruses carried by representative bat species in Southern China to better understand the coronavirus sphere
Authors: Han Yelin , Xu Panpan , Wang Yuyang , Zhao Wenliang , Zhang Junpeng , Zhang Shuyi , Wang Jianwei , Jin Qi , Wu Zhiqiang 
Published: September 2023

AbstractBats, recognized as considerable reservoirs for coronaviruses (CoVs), serve as natural hosts for several highly pathogenic CoVs, including SARS-CoV and SARS-CoV-2. Investigating the bat CoV community provides insights into the origin for highly pathogenic CoVs and highlights bat CoVs with potential spillover risks. This study probes the evolution, recombination, host range, geographical distribution, and cross-species transmission characteristics of bat CoVs across China and its associated CoVs in other regions. Through detailed research on 13,064 bat samples from 14 provinces of China, 1141 CoV strains are found across 10 subgenera and one unclassified Alpha-CoV, generating 399 complete genome sequences. Within bat CoVs, 11 new CoV species are identified and 425 recombination events are detected. Bats in southern China, particularly in Yunnan province, exhibit a pronounced diversity of CoVs. Limited sampling and low detection rates exist for CoVs in Myotacovirus, Nyctacovirus, Hibecovirus, Nobecovirus in China. The genus Myotis is highlighted as a potential ancestral host for Alpha-CoV, with the genus Hipposideros suggested as a likely progenitor host for bat-associated Beta-CoV, indicating the complexity of cross-species transmission dynamics. Through the comprehensive analysis, this study enriches the understanding of bat CoVs and offers a valuable resource for future research.
Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis
Authors: Xu Yidan , Li Tingting , Zhou Zixuan , Hong Jingjing , Chao Yulin , Zhu Zhini , Zhang Ying , Qu Qianhui , Li Dianfan 
Published: September 2023

AbstractMany eukaryotic receptors and enzymes rely on glycosylphosphatidylinositol (GPI) anchors for membrane localization and function. The transmembrane complex GPI-T recognizes diverse proproteins at a signal peptide region that lacks consensus sequence and replaces it with GPI via a transamidation reaction. How GPI-T maintains broad specificity while preventing unintentional cleavage is unclear. Here, substrates- and products-bound human GPI-T structures identify subsite features that enable broad proprotein specificity, inform catalytic mechanism, and reveal a multilevel safeguard mechanism against its promiscuity. In the absence of proproteins, the catalytic site is invaded by a locally stabilized loop. Activation requires energetically unfavorable rearrangements that transform the autoinhibitory loop into crucial catalytic cleft elements. Enzyme-proprotein binding in the transmembrane and luminal domains respectively powers the conformational rearrangement and induces a competent cleft. GPI-T thus integrates various weak specificity regions to form strong selectivity and prevent accidental activation. These findings provide important mechanistic insights into GPI-anchored protein biogenesis.
Shared and distinct genetic etiologies for different types of clonal hematopoiesis
Authors: Brown Derek W. , Cato Liam D. , Zhao Yajie , Nandakumar Satish K. , Bao Erik L. , Gardner Eugene J. , Hubbard Aubrey K. , DePaulis Alexander , Rehling Thomas , Song Lei , Yu Kai , Chanock Stephen J. , Perry John R. B. , Sankaran Vijay G. , Machiela Mitchell J. 
Published: September 2023

AbstractClonal hematopoiesis (CH)—age-related expansion of mutated hematopoietic clones—can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk.
A strategy for Cas13 miniaturization based on the structure and AlphaFold
Authors: Zhao Feiyu , Zhang Tao , Sun Xiaodi , Zhang Xiyun , Chen Letong , Wang Hejun , Li Jinze , Fan Peng , Lai Liangxue , Sui Tingting , Li Zhanjun 
Published: September 2023

AbstractThe small size of the Cas nuclease fused with various effector domains enables a broad range of function. Although there are several ways of reducing the size of the Cas nuclease complex, no efficient or generalizable method has been demonstrated to achieve protein miniaturization. In this study, we establish an Interaction, Dynamics and Conservation (IDC) strategy for protein miniaturization and generate five compact variants of Cas13 with full RNA binding and cleavage activity comparable the wild-type enzymes based on a combination of IDC strategy and AlphaFold2. In addition, we construct an RNA base editor, mini-Vx, and a single AAV (adeno-associated virus) carrying a mini-RfxCas13d and crRNA expression cassette, which individually shows efficient conversion rate and RNA-knockdown activity. In summary, these findings highlight a feasible strategy for generating downsized CRISPR/Cas13 systems based on structure predicted by AlphaFold2, enabling targeted degradation of RNAs and RNA editing for basic research and therapeutic applications.
CD44 connects autophagy decline and ageing in the vascular endothelium
Authors: Zhang Lu , Yang Peichang , Chen Jingxuan , Chen Zhiqiang , Liu Zhihui , Feng Gaoqing , Sha Fangfang , Li Zirui , Xu Zaoyi , Huang Yating , Shi Xiaotong , Li Xuebiao , Cui Jiatian , Zhang Chenyi , Fan Pei , Cui Liuqing , Shen Yunpeng , Zhou Guangzhou , Jing Hongjuan , Ma Shiwei 
Published: September 2023

AbstractThe decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and ageing in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in ageing vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and ageing phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature ageing characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature ageing of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and ageing.
Laser nanoprinting of 3D nonlinear holograms beyond 25000 pixels-per-inch for inter-wavelength-band information processing
Authors: Chen Pengcheng , Xu Xiaoyi , Wang Tianxin , Zhou Chao , Wei Dunzhao , Ma Jianan , Guo Junjie , Cui Xuejing , Cheng Xiaoyan , Xie Chenzhu , Zhang Shuang , Zhu Shining , Xiao Min , Zhang Yong 
Published: September 2023

AbstractNonlinear optics provides a means to bridge between different electromagnetic frequencies, enabling communication between visible, infrared, and terahertz bands through χ(2) and higher-order nonlinear optical processes. However, precisely modulating nonlinear optical waves in 3D space remains a significant challenge, severely limiting the ability to directly manipulate optical information across different wavelength bands. Here, we propose and experimentally demonstrate a three-dimensional (3D) χ(2)-super-pixel hologram with nanometer resolution in lithium niobate crystals, capable of performing advanced processing tasks. In our design, each pixel consists of properly arranged nanodomain structures capable of completely and dynamically manipulating the complex-amplitude of nonlinear waves. Fabricated by femtosecond laser writing, the nonlinear hologram features a pixel diameter of 500 nm and a pixel density of approximately 25000 pixels-per-inch (PPI), reaching far beyond the state of the art. In our experiments, we successfully demonstrate the novel functions of the hologram to process near-infrared (NIR) information at visible wavelengths, including dynamic 3D nonlinear holographic imaging and frequency-up-converted image recognition. Our scheme provides a promising nano-optic platform for high-capacity optical storage and multi-functional information processing across different wavelength ranges.