bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical utility of serial analysis of circulating tumour cells for detection of minimal residual disease of metastatic nasopharyngeal carcinoma
Authors: Ko Josephine Mun-Yee , Vardhanabhuti Vince , Ng Wai-Tong , Lam Ka-On , Ngan Roger Kai-Cheong , Kwong Dora Lai-Wan , Lee Victor Ho-fun , Lui Yun-Hoi , Yau Chun-Chung , Kwan Chung-Kong , Li Wing-Sum , Yau Stephen , Guo Chen , Choi Sheyne Sta Ana , Lei Lisa Chan , Chan Kenneth Chun-Ho , Lam Candy Chi-Shan , Chan Candy King-Chi , Dai Wei , Khong Pek-Lan , Lung Maria Li 
Published: May 2020

Abstract
Background
Nasopharyngeal carcinoma (NPC) is an important cancer in Hong Kong. We aim to utilise liquid biopsies for serial monitoring of disseminated NPC in patients to compare with PET-CT imaging in detection of minimal residual disease.

Method
Prospective serial monitoring of liquid biopsies was performed for 21 metastatic patients. Circulating tumour cell (CTC) enrichment and characterisation was performed using a sized-based microfluidics CTC chip, enumerating by immunofluorescence staining, and using target-capture sequencing to determine blood mutation load. PET-CT scans were used to monitor NPC patients throughout their treatment according to EORTC guidelines.

Results
The longitudinal molecular analysis of CTCs by enumeration or NGS mutational profiling findings provide supplementary information to the plasma EBV assay for disease progression for good responders. Strikingly, post-treatment CTC findings detected positive findings in 75% (6/8) of metastatic NPC patients showing complete response by imaging, thereby demonstrating more sensitive CTC detection of minimal residual disease. Positive baseline, post-treatment CTC, and longitudinal change of CTCs significantly associated with poorer progression-free survival by the Kaplan–Meier analysis.

Conclusions
We show the potential usefulness of application of serial analysis in metastatic NPC of liquid biopsy CTCs, as a novel more sensitive biomarker for minimal residual disease, when compared with imaging.
I-BET726 suppresses human skin squamous cell carcinoma cell growth in vitro and in vivo
Authors: Liu Zhengjun , Li Ping , Yang Yong-qiang , Cai Shang , Lin Xiangwei , Chen Min-bin , Guo Hailei 
Published: May 2020

AbstractBromodomain-containing protein 4 (BRD4) is a potential therapeutic target of skin squamous cell carcinoma (SCC). I-BET726 is a novel BRD4 inhibitor. Its potential effect in skin SCC cells was tested in the present study. We show that I-BET726 potently inhibited survival, proliferation, cell cycle progression, and migration in established (A431/SCC-9/SCC-12/SCC-13 lines) and primary human skin SCC cells. I-BET726 induced significant apoptosis activation in skin SCC cells. It was more efficient in inhibiting skin SCC cells than known BRD4 inhibitors (JQ1, CPI203, and AZD5153). I-BET726 not only downregulated BRD4-regulated proteins (c-Myc, Bcl-2, and cyclin D1), but also inhibited sphingosine kinase 1 (SphK1) and Akt signalings in SCC cells. Restoring Akt activation, by a constitutively active S473D mutant Akt1 (“caAkt1”), partially inhibited I-BET726-induced cytotoxicity in A431 cells. In vivo, I-BET726 oral administration potently inhibited A431 xenograft growth in severe combined immunodeficient mice. Downregulation of BRD4-regulated proteins and inhibition of the SphK1-Akt signaling were detected in I-BET726-treated A431 xenograft tumor tissues. Together, I-BET726 inhibits skin SCC cell growth in vitro and in vivo.
Exosomal miR-25-3p from mesenchymal stem cells alleviates myocardial infarction by targeting pro-apoptotic proteins and EZH2
Authors: Peng Yi , Zhao Ji-Ling , Peng Zhi-Yong , Xu Wei-Fang , Yu Guo-Long 
Published: May 2020

AbstractMesenchymal stem cell (MSC) therapy is a promising approach against myocardial infarction (MI). Studies have demonstrated that MSCs can communicate with other cells by secreting exosomes. In the present study, we aimed to identify exosomal microRNAs that might contribute to MSC-mediated cardioprotective effects. Primary cardiomyocytes were deprived of oxygen and glucose to mimic MI in vitro. For the animal model of MI, the left anterior descending artery was ligated for 1 h, followed by reperfusion for 12 h. MSC-derived exosomes were used to treat primary cardiomyocytes or mice. Cardioprotection-related microRNAs were determined, followed by target gene identification and functional studies with quantitative PCR, western blotting, MTT assay, flow cytometry assay, chromatin immunoprecipitation and dual-luciferase assay. We found that MSC co-culture reduced OGD-induced cardiomyocyte apoptosis and inflammatory responses. Cardioprotection was also observed upon treatment with MSC-derived exosomes in vitro and in vivo. In line with this, exosome uptake led to a significant increase in miR-25-3p in cardiomyocytes. Depletion of miR-25-3p in MSCs abolished the protective effects of exosomes. Mechanistically, miR-25-3p directly targeted the pro-apoptotic genes FASL and PTEN and reduced their protein levels. Moreover, miR-25-3p decreased the levels of EZH2 and H3K27me3, leading to derepression of the cardioprotective gene eNOS as well as the anti-inflammatory gene SOCS3. Inhibition of EZH2 or overexpression of miR-25-3p in cardiomyocytes was sufficient to confer cardioprotective effects in vitro and in vivo. We concluded that exosomal miR-25-3p from MSCs alleviated MI by targeting pro-apoptotic proteins and EZH2.
Nestin protects podocyte from injury in lupus nephritis by mitophagy and oxidative stress
Authors: Tian Yuexin , Guo Huifang , Miao Xinyan , Xu Jie , Yang Ran , Zhao Lu , Liu Jinxi , Yang Lin , Gao Fan , Zhang Wei , Liu Qingjuan , Sun Shaoguang , Tian Yu , Li Hongbo , Huang Jie , Gu Cunyang , Liu Shuxia , Feng Xiaojuan 
Published: May 2020

AbstractPodocyte injury is the main cause of proteinuria in lupus nephritis (LN). Nestin, an important cytoskeleton protein, is expressed stably in podocytes and is associated with podocyte injury. However, the role of nestin in the pathogenesis of proteinuria in LN remains unclear. The correlations among nestin, nephrin and proteinuria were analyzed in LN patients and MRL/lpr lupus-prone mice. The expression of nestin in mouse podocyte lines (MPCs) and MRL/lpr mice was knocked down to determine the role of nestin in podocyte injury. Inhibitors and RNAi method were used to explore the role of mitophagy and oxidative stress in nestin protection of podocyte from damage. There was a significantly negative correlation between nestin and proteinuria both in LN patients and MRL/lpr mice, whereas the expression of nephrin was positively correlated with nestin. Knockdown of nestin resulted in not only the decrease of nephrin, p-nephrin (Y1217) and mitophagy-associated proteins in cultured podocytes and the podocytes of MRL/lpr mice, but also mitochondrial dysfunction in podocytes stimulated with LN plasma. The expression and phosphorylation of nephrin was significantly decreased by reducing the level of mitophagy or production of reactive oxygen species (ROS) in cultured podocytes. Our findings suggested that nestin regulated the expression of nephrin through mitophagy and oxidative stress to protect the podocytes from injury in LN.
Economic motivation for raising coastal flood defenses in Europe
Authors: Vousdoukas Michalis I. , Mentaschi Lorenzo , Hinkel Jochen , Ward Philip J. , Mongelli Ignazio , Ciscar Juan-Carlos , Feyen Luc 
Published: May 2020

AbstractExtreme sea levels (ESLs) in Europe could rise by as much as one metre or more by the end of this century due to climate change. This poses significant challenges to safeguard coastal communities. Here we present a comprehensive analysis of economically efficient protection scenarios along Europe’s coastlines during the present century. We employ a probabilistic framework that integrates dynamic simulations of all ESL components and flood inundation, impact modelling and a cost-benefit analysis of raising dykes. We find that at least 83% of flood damages in Europe could be avoided by elevating dykes in an economically efficient way along 23.7%-32.1% of Europe’s coastline, specifically where high value conurbations exist. The European mean benefit to cost ratio of the investments varies from 8.3 to 14.9 while at country level this ranges between 1.6 and 34.3, with higher efficiencies for a scenario with high-end greenhouse gas emissions and strong socio-economic growth.
Multimodal determinants of phase-locked dynamics across deep-superficial hippocampal sublayers during theta oscillations
Authors: Navas-Olive Andrea , Valero Manuel , Jurado-Parras Teresa , de Salas-Quiroga Adan , Averkin Robert G. , Gambino Giuditta , Cid Elena , de la Prida Liset M. 
Published: May 2020

AbstractTheta oscillations play a major role in temporarily defining the hippocampal rate code by translating behavioral sequences into neuronal representations. However, mechanisms constraining phase timing and cell-type-specific phase preference are unknown. Here, we employ computational models tuned with evolutionary algorithms to evaluate phase preference of individual CA1 pyramidal cells recorded in mice and rats not engaged in any particular memory task. We applied unbiased and hypothesis-free approaches to identify effects of intrinsic and synaptic factors, as well as cell morphology, in determining phase preference. We found that perisomatic inhibition delivered by complementary populations of basket cells interacts with input pathways to shape phase-locked specificity of deep and superficial pyramidal cells. Somatodendritic integration of fluctuating glutamatergic inputs defined cycle-by-cycle by unsupervised methods demonstrated that firing selection is tuneable across sublayers. Our data identify different mechanisms of phase-locking selectivity that are instrumental for flexible dynamical representations of theta sequences.
A high-resolution description of β1-adrenergic receptor functional dynamics and allosteric coupling from backbone NMR
Authors: Grahl Anne , Abiko Layara Akemi , Isogai Shin , Sharpe Timothy , Grzesiek Stephan 
Published: May 2020

AbstractSignal transmission and regulation of G-protein-coupled receptors (GPCRs) by extra- and intracellular ligands occurs via modulation of complex conformational equilibria, but their exact kinetic details and underlying atomic mechanisms are unknown. Here we quantified these dynamic equilibria in the β1-adrenergic receptor in its apo form and seven ligand complexes using 1H/15N NMR spectroscopy. We observe three major exchanging conformations: an inactive conformation (Ci), a preactive conformation (Cp) and an active conformation (Ca), which becomes fully populated in a ternary complex with a G protein mimicking nanobody. The Ci ↔ Cp exchange occurs on the microsecond scale, the Cp ↔ Ca exchange is slower than ~5 ms and only occurs in the presence of two highly conserved tyrosines (Y5.58, Y7.53), which stabilize the active conformation of TM6. The Cp→Ca chemical shift changes indicate a pivoting motion of the entire TM6 that couples the effector site to the orthosteric ligand pocket.
Segregation of an MSH1 RNAi transgene produces heritable non-genetic memory in association with methylome reprogramming
Authors: Yang Xiaodong , Sanchez Robersy , Kundariya Hardik , Maher Tom , Dopp Isaac , Schwegel Rosemary , Virdi Kamaldeep , Axtell Michael J. , Mackenzie Sally A. 
Published: May 2020

AbstractMSH1 is a plant-specific protein. RNAi suppression of MSH1 results in phenotype variability for developmental and stress response pathways. Segregation of the RNAi transgene produces non-genetic msh1 ‘memory’ with multi-generational inheritance. First-generation memory versus non-memory comparison, and six-generation inheritance studies, identifies gene-associated, heritable methylation repatterning. Genome-wide methylome analysis integrated with RNAseq and network-based enrichment studies identifies altered circadian clock networks, and phytohormone and stress response pathways that intersect with circadian control. A total of 373 differentially methylated loci comprising these networks are sufficient to discriminate memory from nonmemory full sibs. Methylation inhibitor 5-azacytidine diminishes the differences between memory and wild type for growth, gene expression and methylation patterning. The msh1 reprogramming is dependent on functional HISTONE DEACETYLASE 6 and methyltransferase MET1, and transition to memory requires the RNA-directed DNA methylation pathway. This system of phenotypic plasticity may serve as a potent model for defining accelerated plant adaptation during environmental change.
Mutualist and pathogen traits interact to affect plant community structure in a spatially explicit model
Authors: Schroeder John W. , Dobson Andrew , Mangan Scott A. , Petticord Daniel F. , Herre Edward Allen 
Published: May 2020

AbstractEmpirical studies show that plant-soil feedbacks (PSF) can generate negative density dependent (NDD) recruitment capable of maintaining plant community diversity at landscape scales. However, the observation that common plants often exhibit relatively weaker NDD than rare plants at local scales is difficult to reconcile with the maintenance of overall plant diversity. We develop a spatially explicit simulation model that tracks the community dynamics of microbial mutualists, pathogens, and their plant hosts. We find that net PSF effects vary as a function of both host abundance and key microbial traits (e.g., host affinity) in ways that are compatible with both common plants exhibiting relatively weaker local NDD, while promoting overall species diversity. The model generates a series of testable predictions linking key microbial traits and the relative abundance of host species, to the strength and scale of PSF and overall plant community diversity.
Zika virus noncoding RNA suppresses apoptosis and is required for virus transmission by mosquitoes
Authors: Slonchak Andrii , Hugo Leon E. , Freney Morgan E. , Hall-Mendelin Sonja , Amarilla Alberto A. , Torres Francisco J. , Setoh Yin Xiang , Peng Nias Y. G. , Sng Julian D. J. , Hall Roy A. , van den Hurk Andrew F. , Devine Gregor J. , Khromykh Alexander A. 
Published: May 2020

AbstractFlaviviruses, including Zika virus (ZIKV), utilise host mRNA degradation machinery to produce subgenomic flaviviral RNA (sfRNA). In mammalian hosts, this noncoding RNA facilitates replication and pathogenesis of flaviviruses by inhibiting IFN-signalling, whereas the function of sfRNA in mosquitoes remains largely elusive. Herein, we conduct a series of in vitro and in vivo experiments to define the role of ZIKV sfRNA in infected Aedes aegypti employing viruses deficient in production of sfRNA. We show that sfRNA-deficient viruses have reduced ability to disseminate and reach saliva, thus implicating the role for sfRNA in productive infection and transmission. We also demonstrate that production of sfRNA alters the expression of mosquito genes related to cell death pathways, and prevents apoptosis in mosquito tissues. Inhibition of apoptosis restored replication and transmission of sfRNA-deficient mutants. Hence, we propose anti-apoptotic activity of sfRNA as the mechanism defining its role in ZIKV transmission.
Predicting synthesizable multi-functional edge reconstructions in two-dimensional transition metal dichalcogenides
Authors: Hu Guoxiang , Fung Victor , Sang Xiahan , Unocic Raymond R. , Ganesh P. 
Published: May 2020

AbstractTwo-dimensional (2D) transition metal dichalcogenides (TMDCs) have attracted tremendous interest as functional materials due to their exceptionally diverse and tunable properties, especially in their edges. In addition to the conventional armchair and zigzag edges common to hexagonal 2D materials, more complex edge reconstructions can be realized through careful control over the synthesis conditions. However, the whole family of synthesizable, reconstructed edges remains poorly studied. Here, we develop a computational approach integrating ensemble-generation, force-relaxation, and electronic-structure calculations to systematically and efficiently discover additional reconstructed edges and screen their functional properties. Using MoS2 as a model system, we screened hundreds of edge-reconstruction to discover over 160 reconstructed edges to be more stable than the conventional ones. More excitingly, we discovered nine new synthesizable reconstructred edges with record thermodynamic stability, in addition to successfully reproducing three recently synthesized edges. We also find our predicted reconstructed edges to have multi-functional properties—they show near optimal hydrogen evolution activity over the conventional edges, ideal for catalyzing hydrogen-evolution reaction (HER) and also exhibit half-metallicity with a broad variation in magnetic moments, making them uniquely suitable for nanospintronic applications. Our work reveals the existence of a wide family of synthesizable, reconstructed edges in 2D TMDCs and opens a new materials-by-design paradigm of ‘intrinsic’ edge engineering multifunctionality in 2D materials.
Towards clinically actionable digital phenotyping targets in schizophrenia
Authors: Henson Philip , Barnett Ian , Keshavan Matcheri , Torous John 
Published: May 2020

AbstractDigital phenotyping has potential to quantify the lived experience of mental illness and generate real-time, actionable results related to recovery, such as the case of social rhythms in individuals with bipolar disorder. However, passive data features for social rhythm clinical targets in individuals with schizophrenia have yet to be studied. In this paper, we explore the relationship between active and passive data by focusing on temporal stability and variance at an individual level as well as large-scale associations on a population level to gain clinically actionable information regarding social rhythms. From individual data clustering, we found a 19% cluster overlap between specific active and passive data features for participants with schizophrenia. In the same clinical population, two passive data features in particular associated with social rhythms, “Circadian Routine” and “Weekend Day Routine,” and were negatively associated with symptoms of anxiety, depression, psychosis, and poor sleep (Spearman ρ ranged from −0.23 to −0.30, p < 0.001). Conversely, in healthy controls, more stable social rhythms were positively correlated with symptomatology (Spearman ρ ranged from 0.20 to 0.44, p < 0.05). Our results suggest that digital phenotyping in schizophrenia may offer clinically relevant information for understanding how daily routines affect symptomatology. Specifically, negative correlations between smartphone reported anxiety, depression, psychosis, and poor sleep in individuals with schizophrenia, but not in healthy controls, offer an actionable clinical target and area for further investigation.
Genome sequence analysis of multidrug-resistant Mycobacterium tuberculosis from Malaysia
Authors: Tan Joon Liang , Simbun Alfred , Chan Kok-Gan , Ngeow Yun Fong 
Published: May 2020

AbstractMycobacterium tuberculosis (MTB) is commonly used as a model to study pathogenicity and multiple drug resistance in bacteria. These MTB characteristics are highly dependent on the evolution and phylogeography of the bacterium. In this paper, we describe 15 new genomes of multidrug-resistant MTB (MDRTB) from Malaysia. The assessments and annotations on the genome assemblies suggest that strain differences are due to lineages and horizontal gene transfer during the course of evolution. The genomes show mutations listed in current drug resistance databases and global MTB collections. This genome data will augment existing information available for comparative genomic studies to understand MTB drug resistance mechanisms and evolution.
Atypical responses of a large catchment river to the Holocene sea-level highstand: The Murray River, Australia
Authors: Helfensdorfer Anna M. , Power Hannah E. , Hubble Thomas C. T. 
Published: May 2020

AbstractThree-dimensional numerical modelling of the marine and fluvial dynamics of the lower Murray River demonstrate that the mid-Holocene sea-level highstand generated an extensive central basin environment extending at least 140 kilometres upstream from the river mouth and occupying the entire one to three kilometre width of the Murray Gorge. This unusually extensive, extremely low-gradient backwater environment generated by the two metre sea-level highstand captured most, if not all, of the fine-grained sediment discharged from the 1.06 million square kilometre Murray-Darling catchment. This material was sequestered within a >60 kilometre long, >10 metre thick valley-wide deposit of finely laminated mud. This previously unrecognised sediment trap persisted from 8,518 to 5,067 cal yr BP preventing sediment delivery to the marine environment. Its identification requires that mid-Holocene climate reconstructions for southeastern Australia based on fluctuations in the delivery of fine-grained sediment to the ocean offshore the lower Murray River’s mouth must be re-evaluated.
Computational Assessment of Thermokinetics and Associated Microstructural Evolution in Laser Powder Bed Fusion Manufacturing of Ti6Al4V Alloy
Authors: Pantawane Mangesh V. , Ho Yee-Hsien , Joshi Sameehan S. , Dahotre Narendra B. 
Published: May 2020

AbstractAlthough most of the near non-equilibrium microstructures of alloys produced by laser powder bed fusion (LPBF) additive manufacturing (AM) are being reported at a rapid rate, the accountable thermokinetics of the entire process have rarely been studied. In order to exploit the versatility of this AM process for the desired properties of built material, it is crucial to understand the thermokinetics associated with the process. In light of this, a three-dimensional thermokinetic model based on the finite element method was developed to correlate with the microstructure evolved in additively manufactured Ti6Al4V alloy. The computational model yielded the thermal patterns experienced at given location while building a single layer through multiple laser scans and a whole part through multiple layers above it. X-ray analysis of the resultant microstructure confirmed the presence of acicular martensitic (α′) phase of (002) texture within the build-plane. Computationally predicted magnitude of the thermal gradients within the additively manufactured Ti6Al4V alloy in different directions (X, Y, and Z) facilitated the understanding about the evolution of grain morphology and orientation of acicular martensite in prior β grains. The scanning electron microscopy observations of the alloy revealed the distinct morphology of phase precipitated within the martensitic phase, whose existence was, in turn, understood through predicted thermal history.