bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncolytic adenoviruses synergistically enhance anti-PD-L1 and anti-CTLA-4 immunotherapy by modulating the tumour microenvironment in a 4T1 orthotopic mouse model
Authors: Zhang Huan , Xie Weimin , Zhang Yuning , Dong Xiwen , Liu Chao , Yi Jing , Zhang Shun , Wen Chunkai , Zheng Li , Wang Hua 
Published: October 2021

AbstractEffective therapeutic strategies for triple-negative breast cancer (TNBC) are still lacking. Clinical data suggest that a large number of TNBC patients cannot benefit from single immune checkpoint inhibitor (ICI) treatment due to the immunosuppressive tumour microenvironment (TME). Therefore, combination immunotherapy is an alternative approach to overcome this limitation. In this article, we combined two kinds of oncolytic adenoviruses with ICIs to treat TNBC in an orthotopic mouse model. Histopathological analysis and immunohistochemistry as well as multiplex immunofluorescence were used to analyse the TME. The immunophenotype of the peripheral blood and spleen was detected by using flow cytometry. Oncolytic adenovirus-mediated immune activity in a coculture system of lytic supernatant and splenocytes supported the study of the mechanism of combination therapy in vitro. Our results showed that the combination of oncolytic adenoviruses with anti-programmed cell death-ligand 1 (anti-PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (anti-CTLA-4) (aPC) can significantly inhibit tumour growth and prolong survival in a TNBC model. The combination therapy synergistically enhanced the antitumour effect by recruiting CD8+T and T memory cells, reducing the number of regulatory T cells and tumour-associated macrophages, and promoting the polarization of macrophages from the M2 to the M1 phenotype to regulate the TME. The rAd.GM regimen performed better than the rAd.Null treatment. Furthermore, aPC efficiently blocked oncolytic virus-induced upregulation of PD-L1 and CTLA-4. These findings indicate that oncolytic adenoviruses can reprogramme the immunosuppressive TME, while ICIs can prevent immune escape after oncolytic virus therapy by reducing the expression of immune checkpoint molecules. Our results provide a mutually reinforcing strategy for clinical combination immunotherapy.
Genomic comparison between cerebrospinal fluid and primary tumor revealed the genetic events associated with brain metastasis in lung adenocarcinoma
Authors: Deng Zhiyong , Cui Liang , Li Pansong , Ren Nianjun , Zhong Zhe , Tang Zhi , Wang Lei , Gong Jianwu , Cheng Haofeng , Guan Yanfang , Yi Xin , Xia Xuefeng , Zhou Rongrong , He Zhengwen 
Published: October 2021

AbstractLung adenocarcinoma (LUAD) is most common pathological type of lung cancer. LUAD with brain metastases (BMs) usually have poor prognosis. To identify the potential genetic factors associated with BM, a genomic comparison for BM cerebrospinal fluid (CSF) and primary lung tumor samples obtained from 1082 early- and late-stage LUAD patients was performed. We found that single nucleotide variation (SNV) of EGFR was highly enriched in CSF (87% of samples). Compared with the other primary lung tissues, copy number gain of EGFR (27%), CDK4 (11%), PMS2 (11%), MET (10%), IL7R (8%), RICTOR (7%), FLT4 (5%), and FGFR4 (4%), and copy number loss of CDKN2A (28%) and CDKN2B (18%) were remarkably more frequent in CSF samples. CSF had significantly lower tumor mutation burden (TMB) level but more abundant copy number variant. It was also found that the relationships among co-occurrent and mutually exclusive genes were dynamically changing with LUAD development. Additionally, CSF (97% of samples) harbored more abundant targeted drugs related driver and fusion genes. The signature 15 associated with defective DNA mismatch repair (dMMR) was only identified in the CSF group. Cancer associated pathway analysis further revealed that ErbB (95%) and cell cycle (84%) were unique pathways in CSF samples. The tumor evolution analysis showed that CSF carried significantly fewer clusters, but subclonal proportion of EGFR was remarkably increased with tumor progression. Collectively, CSF sequencing showed unique genomic characteristics and the intense copy number instability associated with cell cycle disorder and dMMR might be the crucial genetic factors in BM of LUAD.
Pyrvinium pamoate regulates MGMT expression through suppressing the Wnt/β-catenin signaling pathway to enhance the glioblastoma sensitivity to temozolomide
Authors: Li Haisong , Liu Shuhan , Jin Rihua , Xu Haiyang , Li Yunqian , Chen Yong , Zhao Gang 
Published: October 2021

AbstractTemozolomide (TMZ) is the mainstream chemotherapeutic drug for treating glioblastoma multiforme (GBM), but the intrinsic or acquired chemoresistance to TMZ has become the leading clinical concern, which is related to the repair of DNA alkylation sites by O6-methylguanine-DNA methyltransferase (MGMT). Pyrvinium pamoate (PP), the FDA-approved anthelminthic drug, has been reported to inhibit the Wnt/β-catenin pathway within numerous cancer types, and Wnt/β-catenin signaling pathway can modulate the expression of MGMT gene. However, whether PP affects the expression of MGMT and enhances TMZ sensitivity in GBM cells remains unclear. In the present study, we found that PP and TMZ had synergistic effect on inhibiting the viability of GBM cells, and PP induced inhibition of MGMT and enhanced the TMZ chemosensitivity of GBM cells through down-regulating Wnt/β-catenin pathway. Moreover, the overexpression of MGMT or β-catenin weakened the synergy between PP and TMZ. The mechanism of PP in inhibiting the Wnt pathway was indicated that PP resulted in the degradation of β-catenin via the AKT/GSK3β/β-catenin signaling axis. Moreover, Ser552 phosphorylation in β-catenin, which promotes its nuclear accumulation and transcriptional activity, is blocked by PP that also inhibits the Wnt pathway to some extent. The intracranial GBM mouse model also demonstrated that the synergy between PP and TMZ could be achieved through down-regulating β-catenin and MGMT, which prolonged the survival time of tumor-bearing mice. Taken together, our data suggest that PP may serve as the prospect medicine to improve the chemotherapeutic effect on GBM, especially for chemoresistant to TMZ induced by MGMT overexpression.
Identification of the suprachiasmatic nucleus venous portal system in the mammalian brain
Authors: Yao Yifan , Taub Alana B’nai , LeSauter Joseph , Silver Rae 
Published: October 2021

AbstractThere is only one known portal system in the mammalian brain - that of the pituitary gland, first identified in 1933 by Popa and Fielding. Here we describe a second portal pathway in the mouse linking the capillary vessels of the brain’s clock suprachiasmatic nucleus (SCN) to those of the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ. The localized blood vessels of portal pathways enable small amounts of important secretions to reach their specialized targets in high concentrations without dilution in the general circulatory system. These brain clock portal vessels point to an entirely new route and targets for secreted SCN signals, and potentially restructures our understanding of brain communication pathways.
Directed evolution of rRNA improves translation kinetics and recombinant protein yield
Authors: Liu Fan , Bratulić Siniša , Costello Alan , Miettinen Teemu P. , Badran Ahmed H. 
Published: October 2021

AbstractIn bacteria, ribosome kinetics are considered rate-limiting for protein synthesis and cell growth. Enhanced ribosome kinetics may augment bacterial growth and biomanufacturing through improvements to overall protein yield, but whether this can be achieved by ribosome-specific modifications remains unknown. Here, we evolve 16S ribosomal RNAs (rRNAs) from Escherichia coli, Pseudomonas aeruginosa, and Vibrio cholerae towards enhanced protein synthesis rates. We find that rRNA sequence origin significantly impacted evolutionary trajectory and generated rRNA mutants with augmented protein synthesis rates in both natural and engineered contexts, including the incorporation of noncanonical amino acids. Moreover, discovered consensus mutations can be ported onto phylogenetically divergent rRNAs, imparting improved translational activities. Finally, we show that increased translation rates in vivo coincide with only moderately reduced translational fidelity, but do not enhance bacterial population growth. Together, these findings provide a versatile platform for development of unnatural ribosomal functions in vivo.
Exceptional uranium(VI)-nitride triple bond covalency from 15N nuclear magnetic resonance spectroscopy and quantum chemical analysis
Authors: Du Jingzhen , Seed John A. , Berryman Victoria E. J. , Kaltsoyannis Nikolas , Adams Ralph W. , Lee Daniel , Liddle Stephen T. 
Published: October 2021

AbstractDetermining the nature and extent of covalency of early actinide chemical bonding is a fundamentally important challenge. Recently, X-ray absorption, electron paramagnetic, and nuclear magnetic resonance spectroscopic studies have probed actinide-ligand covalency, largely confirming the paradigm of early actinide bonding varying from ionic to polarised-covalent, with this range sitting on the continuum between ionic lanthanide and more covalent d transition metal analogues. Here, we report measurement of the covalency of a terminal uranium(VI)-nitride by 15N nuclear magnetic resonance spectroscopy, and find an exceptional nitride chemical shift and chemical shift anisotropy. This redefines the 15N nuclear magnetic resonance spectroscopy parameter space, and experimentally confirms a prior computational prediction that the uranium(VI)-nitride triple bond is not only highly covalent, but, more so than d transition metal analogues. These results enable construction of general, predictive metal-ligand 15N chemical shift-bond order correlations, and reframe our understanding of actinide chemical bonding to guide future studies.
An intermittent detachment faulting system with a large sulfide deposit revealed by multi-scale magnetic surveys
Authors: Wu Tao , Tivey Maurice A. , Tao Chunhui , Zhang Jinhui , Zhou Fei , Liu Yunlong 
Published: October 2021

AbstractMagmatic and tectonic processes can contribute to discontinuous crustal accretion and play an important role in hydrothermal circulation at ultraslow-spreading ridges, however, it is difficult to accurately describe the processes without an age framework to constrain crustal evolution. Here we report on a multi-scale magnetic survey that provides constraints on the fine-scale evolution of a detachment faulting system that hosts hydrothermal activity at 49.7°E on the Southwest Indian Ridge. Reconstruction of the multi-stage detachment faulting history shows a previous episode of detachment faulting took place 0.76~1.48 My BP, while the present fault has been active for the past ~0.33 My and is just in the prime of life. This fault sustains hydrothermal circulation that has the potential for developing a large sulfide deposit. High resolution multiscale magnetics allows us to constrain the relative balance between periods of detachment faulting and magmatism to better describe accretionary processes on an ultraslow spreading ridge.
Palladium-catalyzed regio- and enantioselective migratory allylic C(sp3)-H functionalization
Authors: Chen Ye-Wei , Liu Yang , Lu Han-Yu , Lin Guo-Qiang , He Zhi-Tao 
Published: October 2021

AbstractTransition metal-catalyzed asymmetric allylic substitution with a suitably pre-stored leaving group in the substrate is widely used in organic synthesis. In contrast, the enantioselective allylic C(sp3)-H functionalization is more straightforward but far less explored. Here we report a catalytic protocol for the long-standing challenging enantioselective allylic C(sp3)-H functionalization. Through palladium hydride-catalyzed chain-walking and allylic substitution, allylic C-H functionalization of a wide range of acyclic nonconjugated dienes is achieved in high yields (up to 93% yield), high enantioselectivities (up to 98:2 er), and with 100% atom efficiency. Exploring the reactivity of substrates with varying pKa values uncovers a reasonable scope of nucleophiles and potential factors controlling the reaction. A set of efficient downstream transformations to enantiopure skeletons showcase the practical value of the methodology. Mechanistic experiments corroborate the PdH-catalyzed asymmetric migratory allylic substitution process.
ENSO impacts child undernutrition in the global tropics
Authors: Anttila-Hughes Jesse K. , Jina Amir S. , McCord Gordon C. 
Published: October 2021

AbstractThe El Niño Southern Oscillation (ENSO) is a principal component of global climate variability known to influence a host of social and economic outcomes, but its systematic effects on human health remain poorly understood. We estimate ENSO’s association with child nutrition at global scale by combining variation in ENSO intensity from 1986-2018 with children’s height and weight from 186 surveys conducted in 51 teleconnected countries, containing 48% of the world’s under-5 population. Warmer El Niño conditions predict worse child undernutrition in most of the developing world, but better outcomes in the small number of areas where precipitation is positively affected by warmer ENSO. ENSO’s contemporaneous effects on child weight loss are detectable years later as decreases in height. This relationship looks similar at both global and regional scale, and has not appreciably weakened over the last four decades. Results imply that almost 6 million additional children were underweight during the 2015 El Niño compared to a counterfactual of neutral ENSO conditions in 2015. This demonstrates a pathway through which human well-being remains subject to predictable climatic processes.
Shape-programmable liquid crystal elastomer structures with arbitrary three-dimensional director fields and geometries
Authors: Guo Yubing , Zhang Jiachen , Hu Wenqi , Khan Muhammad Turab Ali , Sitti Metin 
Published: October 2021

AbstractLiquid crystal elastomers exhibit large reversible strain and programmable shape transformations, enabling various applications in soft robotics, dynamic optics, and programmable origami and kirigami. The morphing modes of these materials depend on both their geometries and director fields. In two dimensions, a pixel-by-pixel design has been accomplished to attain more flexibility over the spatial resolution of the liquid crystal response. Here we generalize this idea in two steps. First, we create independent, cubic light-responsive voxels, each with a predefined director field orientation. Second, these voxels are in turn assembled to form lines, grids, or skeletal structures that would be rather difficult to obtain from an initially connected material sample. In this way, the orientation of the director fields can be made to vary at voxel resolution to allow for programmable optically- or thermally-triggered anisotropic or heterogeneous material responses and morphology changes in three dimensions that would be impossible or hard to implement otherwise.
Joint single-cell multiomic analysis in Wnt3a induced asymmetric stem cell division
Authors: Sun Zhongxing , Tang Yin , Zhang Yanjun , Fang Yuan , Jia Junqi , Zeng Weiwu , Fang Dong 
Published: October 2021

AbstractWnt signaling usually functions through a spatial gradient. Localized Wnt3a signaling can induce the asymmetric division of mouse embryonic stem cells, where proximal daughter cells maintain self-renewal and distal daughter cells acquire hallmarks of differentiation. Here, we develop an approach, same cell epigenome and transcriptome sequencing, to jointly profile the epigenome and transcriptome in the same single cell. Utilizing this method, we profiled H3K27me3 and H3K4me3 levels along with gene expression in mouse embryonic stem cells with localized Wnt3a signaling, revealing the cell type-specific maps of the epigenome and transcriptome in divided daughter cells. H3K27me3, but not H3K4me3, is correlated with gene expression changes during asymmetric cell division. Furthermore, cell clusters identified by H3K27me3 recapitulate the corresponding clusters defined by gene expression. Our study provides a convenient method to jointly profile the epigenome and transcriptome in the same cell and reveals mechanistic insights into the gene regulatory programs that maintain and reset stem cell fate during differentiation.
Predicting temperature-dependent ultimate strengths of body-centered-cubic (BCC) high-entropy alloys
Authors: Steingrimsson B. , Fan X. , Yang X. , Gao M. C. , Zhang Y. , Liaw P. K. 
Published: October 2021

AbstractThis paper presents a bilinear log model, for predicting temperature-dependent ultimate strength of high-entropy alloys (HEAs) based on 21 HEA compositions. We consider the break temperature, Tbreak, introduced in the model, an important parameter for design of materials with attractive high-temperature properties, one warranting inclusion in alloy specifications. For reliable operation, the operating temperature of alloys may need to stay below Tbreak. We introduce a technique of global optimization, one enabling concurrent optimization of model parameters over low-temperature and high-temperature regimes. Furthermore, we suggest a general framework for joint optimization of alloy properties, capable of accounting for physics-based dependencies, and show how a special case can be formulated to address the identification of HEAs offering attractive ultimate strength. We advocate for the selection of an optimization technique suitable for the problem at hand and the data available, and for properly accounting for the underlying sources of variations.
Different types of spin currents in the comprehensive materials database of nonmagnetic spin Hall effect
Authors: Zhang Yang , Xu Qiunan , Koepernik Klaus , Rezaev Roman , Janson Oleg , Železný Jakub , Jungwirth Tomáš , Felser Claudia , van den Brink Jeroen , Sun Yan 
Published: October 2021

AbstractSpin Hall effect (SHE) has its special position in spintronics. To gain new insight into SHE and to identify materials with substantial spin Hall conductivity (SHC), we performed high-precision high-throughput ab initio calculations of the intrinsic SHC for over 20,000 nonmagnetic crystals. The calculations revealed a strong relationship between the magnitude of the SHC and the crystalline symmetry, where a large SHC is typically associated with mirror symmetry-protected nodal line band structures. This database includes 11 materials with an SHC comparable to or even larger than that of Pt. Materials with different types of spin currents were additionally identified. Furthermore, we found that different types of spin current can be obtained by rotating applied electrical fields. This improves our understanding and is expected to facilitate the design of new types of spin-orbitronic devices.
Long-read sequencing reveals the structural complexity of genomic integration of HBV DNA in hepatocellular carcinoma
Authors: Zhuo Zhongling , Rong Weiqi , Li Hexin , Li Ying , Luo Xuanmei , Liu Ye , Tang Xiaokun , Zhang Lili , Su Fei , Cui Hongyuan , Xiao Fei 
Published: October 2021

AbstractThe integration of HBV DNA into the human genome can disrupt its structure in hepatocellular carcinoma (HCC), but the complexity of HBV genomic integration remains elusive. Here we applied long-read sequencing to precisely elucidate the HBV integration pattern in the human hepatocellular genome. The DNA library was sequenced using the long-read sequencing on GridION and PacBio Sequel II, respectively. The DNA and mRNA were sequenced using next-generation sequencing on Illumina NextSeq. BLAST (Basic Local Alignment Search Tool) and local scripts were used to analyze HBV integration patterns. We established an analytical strategy based on the long-read sequences, and analyzed the complexity of HBV DNA integration into the hepatocellular genome. A total of 88 integrated breakpoints were identified. HBV DNA integration into human genomic DNA was mainly fragmented with different orientations, rarely with a complete genome. The same HBV integration breakpoints were identified among the three platforms. Most breakpoints were observed at P, X, and S genes in the HBV genome, and observed at introns, intergenic sequences, and exons in the human genome. Tumor tissue harbored a much higher integrated number than the adjacent tissue, and the distribution of HBV integrated into human chromosomes was more concentrated. HBV integration shows different patterns between cancer cells and adjacent normal cells. We for the first time obtained the entire HBV integration pattern through long-read sequencing and demonstrated the value of long-read sequencing in detecting the genomic integration structures of viruses in host cells.
Parkinson’s disease patients benefit from bicycling - a systematic review and meta-analysis
Authors: Tiihonen Marianne , Westner Britta U. , Butz Markus , Dalal Sarang S. 
Published: October 2021

AbstractMany Parkinson’s disease (PD) patients are able to ride a bicycle despite being severely compromised by gait disturbances up to freezing of gait. This review [PROSPERO CRD 42019137386] aimed to find out, which PD-related symptoms improve from bicycling, and which type of bicycling exercise would be most beneficial. Following a systematic database literature search, peer-reviewed studies with randomized control trials (RCT) and with non-randomized trials (NRCT) investigating the interventional effects of bicycling on PD patients were included. A quality analysis addressing reporting, design and possible bias of the studies, as well as a publication bias test was done. Out of 202 references, 22 eligible studies with 505 patients were analysed. An inverse variance-based analysis revealed that primary measures, defined as motor outcomes, benefitted from bicycling significantly more than cognitive measures. Additionally, secondary measures of balance, walking speed and capacity, and the PDQ-39 ratings improved with bicycling. The interventions varied in durations, intensities and target cadences. Conclusively, bicycling is particularly beneficial for the motor performance of PD patients, improving crucial features of gait. Furthermore, our findings suggest that bicycling improves the overall quality-of-life of PD patients.
Non-Markovian memory strength bounds quantum process recoverability
Authors: Taranto Philip , Pollock Felix A. , Modi Kavan 
Published: October 2021

AbstractGeneric non-Markovian quantum processes have infinitely long memory, implying an exact description that grows exponentially in complexity with observation time. Here, we present a finite memory ansatz that approximates (or recovers) the true process with errors bounded by the strength of the non-Markovian memory. The introduced memory strength is an operational quantity and depends on the way the process is probed. Remarkably, the recovery error is bounded by the smallest memory strength over all possible probing methods. This allows for an unambiguous and efficient description of non-Markovian phenomena, enabling compression and recovery techniques pivotal to near-term technologies. We highlight the implications of our results by analyzing an exactly solvable model to show that memory truncation is possible even in a highly non-Markovian regime.