bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional crosstalk between myeloid Foxo1–β-catenin axis and Hedgehog/Gli1 signaling in oxidative stress response
Authors: Li Changyong , Sheng Mingwei , Lin Yuanbang , Xu Dongwei , Tian Yizhu , Zhan Yongqiang , Jiang Longfeng , Coito Ana J. , Busuttil Ronald W. , Farmer Douglas G. , Kupiec-Weglinski Jerzy W. , Ke Bibo
Published: December 2020

Foxo1 transcription factor is an evolutionarily conserved regulator of cell metabolism, oxidative stress, inflammation, and apoptosis. Activation of Hedgehog/Gli signaling is known to regulate cell growth, differentiation, and immune function. However, the molecular mechanisms by which interactive cell signaling networks restrain oxidative stress response and necroptosis are still poorly understood. Here, we report that myeloid-specific Foxo1 knockout (Foxo1M-KO) mice were resistant to oxidative stress-induced hepatocellular damage with reduced macrophage/neutrophil infiltration, and proinflammatory mediators in liver ischemia/reperfusion injury (IRI). Foxo1M-KO enhanced β-catenin-mediated Gli1/Snail activity, and reduced receptor-interacting protein kinase 3 (RIPK3) and NIMA-related kinase 7 (NEK7)/NLRP3 expression in IR-stressed livers. Disruption of Gli1 in Foxo1M-KO livers deteriorated liver function, diminished Snail, and augmented RIPK3 and NEK7/NLRP3. Mechanistically, macrophage Foxo1 and β-catenin colocalized in the nucleus, whereby the Foxo1 competed with T-cell factor (TCF) for interaction with β-catenin under inflammatory conditions. Disruption of the Foxo1–β-catenin axis by Foxo1 deletion enhanced β-catenin/TCF binding, activated Gli1/Snail signaling, leading to inhibited RIPK3 and NEK7/NLRP3. Furthermore, macrophage Gli1 or Snail knockout activated RIPK3 and increased hepatocyte necroptosis, while macrophage RIPK3 ablation diminished NEK7/NLRP3-driven inflammatory response. Our findings underscore a novel molecular mechanism of the myeloid Foxo1–β-catenin axis in regulating Hedgehog/Gli1 function that is key in oxidative stress-induced liver inflammation and necroptosis.
Calculating the economic burden of presumed microbial keratitis admissions at a tertiary referral centre in the UK
Authors: Moussa George , Hodson James , Gooch Nick , Virdee Jasvir , Penaloza Cristina , Kigozi Jesse , Rauz Saaeha
Published: December 2020

Purpose

Microbial keratitis (MK) is the most common non-surgical ophthalmic emergency admission in the UK. However, few prospective health-economic studies of MK have been performed, and no specific healthcare resources group (HRG) code exists. This study is designed to determine the feasibility of a data collection tool derived from the microbiology ophthalmology group (MOG) clinical record form, to enable quantification of direct costs of inpatient care, as well as prospective capture of epidemiological data relating to outcomes of MK.

Methods

Clinical, demographic and economic data were collected retrospectively between January and December 2013 for 101 consecutive patients admitted with MK, using an adaption of the MOG toolset. The direct cost of admission (COA) was calculated using national reference costs and compared to actual income to generate profit/deficit profiles for individual patients. Indices of multiple deprivation were used to assess effect of deprivation on the COA.

Results

The total income generated through discharge coding was £252,116, compared to a COA of £357,075, yielding a deficit of £104,960 (median: £754 per patient). The cost deficit increased significantly with length of stay (LOS, p < 0.001), whilst patients with short LOS were income generators; cost neutrality occurred at 4.8 days. Greater socioeconomic deprivation was also associated with a significantly higher cost deficit.

Conclusion

LOS is the key driver for COA of care for MK admissions. Protocols should encourage discharge of patients who are able to self-administer treatment after the sterilisation phase. The MOG-derived data collection toolset captures pertinent clinical data for quantification of COA. Further development into a multiuser and multisite platform is required for robust prospective testing, together with expansion to capture indirect costs of disease burden, including impact of treatment, visual morbidity and quality of life.
Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death
Authors: Hayashi K. , Nikolos F. , Lee Y. C. , Jain A. , Tsouko E. , Gao H. , Kasabyan A. , Leung H. E. , Osipov A. , Jung S. Y. , Kurtova A. V. , Chan K. S.
Published: December 2020

Induction of tumor cell death is the therapeutic goal for most anticancer drugs. Yet, a mode of drug-induced cell death, known as immunogenic cell death (ICD), can propagate antitumoral immunity to augment therapeutic efficacy. Currently, the molecular hallmark of ICD features the release of damage-associated molecular patterns (DAMPs) by dying cancer cells. Here, we show that gemcitabine, a standard chemotherapy for various solid tumors, triggers hallmark immunostimualtory DAMP release (e.g., calreticulin, HSP70, and HMGB1); however, is unable to induce ICD. Mechanistic studies reveal gemcitabine concurrently triggers prostaglandin E2 release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs. Pharmacological blockade of prostaglandin E2 biosythesis favors CD103+ dendritic cell activation that primes a Tc1-polarized CD8+ T cell response to bolster tumor rejection. Herein, we postulate that an intricate balance between immunostimulatory and inhibitory DAMPs could determine the outcome of drug-induced ICD and pose COX-2/prostaglandin E2 blockade as a strategy to harness ICD.
Segment-specific optogenetic stimulation in Drosophila melanogaster with linear arrays of organic light-emitting diodes
Authors: Murawski Caroline , Pulver Stefan R. , Gather Malte C.
Published: December 2020

Optogenetics allows light-driven, non-contact control of neural systems, but light delivery remains challenging, in particular when fine spatial control of light is required to achieve local specificity. Here, we employ organic light-emitting diodes (OLEDs) that are micropatterned into linear arrays to obtain precise optogenetic control in Drosophila melanogaster larvae expressing the light-gated activator CsChrimson and the inhibitor GtACR2 within their peripheral sensory system. Our method allows confinement of light stimuli to within individual abdominal segments, which facilitates the study of larval behaviour in response to local sensory input. We show controlled triggering of specific crawling modes and find that targeted neurostimulation in abdominal segments switches the direction of crawling. More broadly, our work demonstrates how OLEDs can provide tailored patterns of light for photo-stimulation of neuronal networks, with future implications ranging from mapping neuronal connectivity in cultures to targeted photo-stimulation with pixelated OLED implants in vivo.
Quantifying the influence of mutation detection on tumour subclonal reconstruction
Authors: Liu Lydia Y. , Bhandari Vinayak , Salcedo Adriana , Espiritu Shadrielle M. G. , Morris Quaid D. , Kislinger Thomas , Boutros Paul C.
Published: December 2020

Whole-genome sequencing can be used to estimate subclonal populations in tumours and this intra-tumoural heterogeneity is linked to clinical outcomes. Many algorithms have been developed for subclonal reconstruction, but their variabilities and consistencies are largely unknown. We evaluate sixteen pipelines for reconstructing the evolutionary histories of 293 localized prostate cancers from single samples, and eighteen pipelines for the reconstruction of 10 tumours with multi-region sampling. We show that predictions of subclonal architecture and timing of somatic mutations vary extensively across pipelines. Pipelines show consistent types of biases, with those incorporating SomaticSniper and Battenberg preferentially predicting homogenous cancer cell populations and those using MuTect tending to predict multiple populations of cancer cells. Subclonal reconstructions using multi-region sampling confirm that single-sample reconstructions systematically underestimate intra-tumoural heterogeneity, predicting on average fewer than half of the cancer cell populations identified by multi-region sequencing. Overall, these biases suggest caution in interpreting specific architectures and subclonal variants.
Thymic iNKT single cell analyses unmask the common developmental program of mouse innate T cells
Authors: Harsha Krovi S. , Zhang Jingjing , Michaels-Foster Mary Jessamine , Brunetti Tonya , Loh Liyen , Scott-Browne James , Gapin Laurent
Published: December 2020

Most T lymphocytes leave the thymus as naïve cells with limited functionality. However, unique populations of innate-like T cells differentiate into functionally distinct effector subsets during their development in the thymus. Here, we profiled >10,000 differentiating thymic invariant natural killer T (iNKT) cells using single-cell RNA sequencing to produce a comprehensive transcriptional landscape that highlights their maturation, function, and fate decisions at homeostasis. Our results reveal transcriptional profiles that are broadly shared between iNKT and mucosal-associated invariant T (MAIT) cells, illustrating a common core developmental program. We further unmask a mutual requirement for Hivep3, a zinc finger transcription factor and adapter protein. Hivep3 is expressed in early precursors and regulates the post-selection proliferative burst, differentiation and functions of iNKT cells. Altogether, our results highlight the common requirements for the development of innate-like T cells with a focus on how Hivep3 impacts the maturation of these lymphocytes.
Light-directed trapping of metastable intermediates in a self-assembly process
Authors: Seo Joonsik , Joung Joonyoung F. , Park Sungnam , Son Young Ji , Noh Jaegeun , Kim Jong-Man
Published: December 2020

Self-assembly is a dynamic process that often takes place through a stepwise pathway involving formation of kinetically favored metastable intermediates prior to generation of a thermodynamically preferred supramolecular framework. Although trapping intermediates in these pathways can provide significant information about both their nature and the overall self-assembly process, it is a challenging venture without altering temperature, concentrations, chemical compositions and morphologies. Herein, we report a highly efficient and potentially general method for “trapping” metastable intermediates in self-assembly processes that is based on a photopolymerization strategy. By employing a chiral perylene-diimide possessing a diacetylene containing an alkyl chain, we demonstrated that the metastable intermediates, including nanoribbons, nanocoils and nanohelices, can be effectively trapped by using UV promoted polymerization before they form thermodynamic tubular structures. The strategy developed in this study should be applicable to naturally and synthetically abundant alkyl chain containing self-assembling systems.
Fully phased human genome assembly without parental data using single-cell strand sequencing and long reads
Authors:   Human Genome Structural Variation Consortium, Porubsky David , Ebert Peter , Audano Peter A. , Vollger Mitchell R. , Harvey William T. , Marijon Pierre , Ebler Jana , Munson Katherine M. , Sorensen Melanie , Sulovari Arvis , Haukness Marina , Ghareghani Maryam , Lansdorp Peter M. , Paten Benedict , Devine Scott E. , Sanders Ashley D. , Lee Charles , Chaisson Mark J. P. , Korbel Jan O. , Eichler Evan E. , Marschall Tobias
Published: December 2020

Human genomes are typically assembled as consensus sequences that lack information on parental haplotypes. Here we describe a reference-free workflow for diploid de novo genome assembly that combines the chromosome-wide phasing and scaffolding capabilities of single-cell strand sequencing1,2 with continuous long-read or high-fidelity3 sequencing data. Employing this strategy, we produced a completely phased de novo genome assembly for each haplotype of an individual of Puerto Rican descent (HG00733) in the absence of parental data. The assemblies are accurate (quality value > 40) and highly contiguous (contig N50 > 23 Mbp) with low switch error rates (0.17%), providing fully phased single-nucleotide variants, indels and structural variants. A comparison of Oxford Nanopore Technologies and Pacific Biosciences phased assemblies identified 154 regions that are preferential sites of contig breaks, irrespective of sequencing technology or phasing algorithms.
Using phidelta diagrams to discover relevant patterns in multilayer perceptrons
Authors: Armano Giuliano
Published: December 2020

Understanding the inner behaviour of multilayer perceptrons during and after training is a goal of paramount importance for many researchers worldwide. This article experimentally shows that relevant patterns emerge upon training, which are typically related to the underlying problem difficulty. The occurrence of these patterns is highlighted by means of$$\langle \varphi ,\delta \rangle$$⟨φ,δ⟩diagrams, a 2D graphical tool originally devised to support the work of researchers on classifier performance evaluation and on feature assessment. The underlying assumption being that multilayer perceptrons are powerful engines for feature encoding, hidden layers have been inspected as they were in fact hosting new input features. Interestingly, there are problems that appear difficult if dealt with using a single hidden layer, whereas they turn out to be easier upon the addition of further layers. The experimental findings reported in this article give further support to the standpoint according to which implementing neural architectures with multiple layers may help to boost their generalisation ability. A generic training strategy inspired by some relevant recommendations of deep learning has also been devised. A basic implementation of this strategy has been thoroughly used during the experiments aimed at identifying relevant patterns inside multilayer perceptrons. Further experiments performed in a comparative setting have shown that it could be adopted as viable alternative to the classical backpropagation algorithm.
Targeting macrophage priming by polyphyllin VII triggers anti-tumor immunity via STING-governed cytotoxic T-cell infiltration in lung cancer
Authors: Yu Jinglu , Deng Haibin , Xu Zhenye
Published: December 2020

Stimulator of interferon genes (STING) controlled innate immune pathway is essential for host defense against pathogenic infection and effective anti-tumor adaptive immunity initiation. Although macrophages transformed across diverse phenotypes play crucial roles in anti-tumor immune response, events determining this transformation and the host-intrinsic role of STING in this process remain controversial. Here we report how STING signaling acts as a key switch to dominate the gene expression patterns of macrophage transformation for promoting priming and releasing immunosuppression. Furthermore, polyphyllin VII, a potential STING agonist, exerts anti-tumor efficacy upon macrophages priming and subsequent cytotoxic T lymphocytes intratumoral infiltration. Meanwhile, the simultaneous PD-L1 amplification on macrophages in response to PP VII is also ruled by STING, thus PP VII may benefit immune-checkpoint blockade therapy for combining. Moreover, PP VII suppresses carcinogenesis upon restraining the immunosuppressed macrophage transformation. This is due to the boosted STING that negatively regulates a STAT3 propagated crosstalk between immune cells and tumor cells. Overall, PP VII-stimulated STING in macrophages provides a paradigm for anti-tumor, and if possible, anti-infection immunotherapy.
Trends of low physical activity among Iranian adolescents across urban and rural areas during 2006–2011
Authors: Amiri Parisa , Naseri Parisa , Vahedi-Notash Golnaz , Jalali-Farahani Sara , Mehrabi Yadollah , Hamzavi-Zarghani Najmeh , Azizi Fereidoun , Hadaegh Farzad , Khalili Davood
Published: December 2020

It is well documented that physical inactivity is related to weight gain and a whole host of chronic diseases. This study investigated trends of low physical activity among Iranian adolescents in urban and rural areas between 2006–2011. A total of 12,178 adolescents, aged between 15 and 19 years, participated in National Surveys of Risk Factors for Non-Communicable Diseases. Data on physical activity was obtained using the global physical activity questionnaire. A complex sample survey and multinomial logistic regression were used to model physical activity levels. The percentage of adolescents who had low levels of physical activity increased from 2006 to 2011 in both urban and rural areas. Low and moderate levels of physical activity were lower in rural girls as compared with urban girls, with a prevalence ratio of 0.59 (95% CI 0.47–0.74) and 0.59 (95% CI 0.47–0.74), respectively. The corresponding values for boys residing in rural areas compared with boys in urban areas were 0.56 (95% CI 0.43–0.75) and 0.60 (95% CI 0.48–0.74), respectively. The adolescents' lifestyles showed an increasing trend for physical inactivity in both genders; however, in rural areas, only girls had a rising affinity for a sedentary lifestyle throughout the 2006–2011 years.
Linear infrastructure habitats increase landscape-scale diversity of plants but not of flower-visiting insects
Authors: Dániel-Ferreira Juliana , Bommarco Riccardo , Wissman Jörgen , Öckinger Erik
Published: December 2020

Habitats along linear infrastructure, such as roads and electrical transmission lines, can have high local biodiversity. To determine whether these habitats also contribute to landscape-scale biodiversity, we estimated species richness, evenness and phylogenetic diversity of plant, butterfly and bumblebee communities in 32 4 km2 landscapes with or without power line corridors, and with contrasting areas of road verges. Landscapes with power line corridors had on average six more plant species than landscapes without power lines, but there was no such effect for butterflies and bumblebees. Plant communities displayed considerable evenness in species abundances both in landscapes with and without power lines and high and low road verge densities. We hypothesize that the higher number of plant species in landscapes with power line corridors is due to these landscapes having a higher extinction debt than the landscapes without power line corridors, such that plant diversity is declining slower in landscapes with power lines. This calls for targeted conservation actions in semi-natural grasslands within landscapes with power line corridors to maintain biodiversity and prevent imminent population extinctions.
Impedance analysis of adherent cells after in situ electroporation-mediated delivery of bioactive proteins, DNA and nanoparticles in µL-volumes
Authors: Stolwijk Judith A. , Wegener Joachim
Published: December 2020

Specific intracellular manipulation of animal cells is a persistent goal in experimental cell biology. Such manipulations allow precise and targeted interference with signaling cascades, metabolic pathways, or bi-molecular interactions for subsequent tracking of functional consequences. However, most biomolecules capable of molecular recognition are membrane impermeable. The ability to introduce these molecules into the cytoplasm and then to apply appropriate readouts to monitor the corresponding cell response could prove to be an important research tool. This study describes such an experimental approach combining in situ electroporation (ISE) as a means to efficiently deliver biomolecules to the cytoplasm with an impedance-based, time-resolved analysis of cell status using electric cell-substrate impedance sensing (ECIS). In this approach, gold-film electrodes, deposited on the bottom of regular culture dishes, are used for both electroporation and monitoring. The design of the electrode layout and measurement chamber allows working with sample volumes as small as 10 µL. A miniaturized setup for combined electroporation and impedance sensing (µISE-ECIS) was applied to load different adherent cells with bioactive macromolecules including enzymes, antibodies, nucleic acids and quantum dot nanoparticles. The cell response after loading the cytoplasm with RNase A or cytochrome c (in the presence or absence of caspase inhibitors) was tracked by non-invasive impedance readings in real-time.
Personalized quantification of facial normality: a machine learning approach
Authors: Boyaci Osman , Serpedin Erchin , Stotland Mitchell A.
Published: December 2020

What is a normal face? A fundamental task for the facial reconstructive surgeon is to answer that question as it pertains to any given individual. Accordingly, it would be important to be able to place the facial appearance of a patient with congenital or acquired deformity numerically along their own continuum of normality, and to measure any surgical changes against such a personalized benchmark. This has not previously been possible. We have solved this problem by designing a computerized model that produces realistic, normalized versions of any given facial image, and objectively measures the perceptual distance between the raw and normalized facial image pair. The model is able to faithfully predict human scoring of facial normality. We believe this work represents a paradigm shift in the assessment of the human face, holding great promise for development as an objective tool for surgical planning, patient education, and as a means for clinical outcome measurement.
Post-operative fracture risk assessment following tumor curettage in the distal femur: a hybrid in vitro and in silico biomechanical approach
Authors: Ghouchani Azadeh , Rouhi Gholamreza , Ebrahimzadeh Mohammad Hosein
Published: December 2020

The distal femur is the predominant site for benign bone tumours and a common site for fracture following tumour removal or cementation. However, the lack of conclusive assessment criterion for post-operative fracture risk and appropriate devices for cement augmentation are serious concerns. Hence, a validated biomechanical tool was developed to assess bone strength, depending on the size and location of artificially created tumorous defects in the distal femora. The mechanics of the bone–cement interface was investigated to determine the main causes of reconstruction failure. Based on quantitative-CT images, non-linear and heterogeneous finite element (FE) models of human cadaveric distal femora with simulated tumourous defects were created and validated using in vitro mechanical tests from 14 cadaveric samples. Statistical analyses demonstrated a strong linear relationship (R2 = 0.95, slope = 1.12) with no significant difference between bone strengths predicted by in silico analyses and in vitro tests (P = 0.174). FE analyses showed little reduction in bone strength until the defect was 35% or more of epiphyseal volume, and reduction in bone strength was less pronounced for laterally located defects than medial side defects. Moreover, the proximal end of the cortical window and the most interior wall of the bone–cement interface were the most vulnerable sites for reconstruction failure.
The effect of acute exercise on interleukin-6 and hypothalamic–pituitary–adrenal axis responses in patients with coronary artery disease
Authors: Mahmood Zeid , Davidsson Anette , Olsson Eva , Leanderson Per , Lundberg Anna K. , Jonasson Lena
Published: December 2020

Vulnerability to stress-induced inflammation has been linked to a dysfunctional hypothalamus–pituitary–adrenal (HPA) axis. In the present study, patients with known or suspected coronary artery disease (CAD) were assessed with respect to inflammatory and HPA axis response to acute physical exercise. An exercise stress test was combined with SPECT myocardial perfusion imaging. Plasma and saliva samples were collected before and 30 min after exercise. Interleukin (IL)-6 and adrenocorticotropic hormone (ACTH) were measured in plasma, while cortisol was measured in both plasma and saliva. In total, 124 patients were included of whom 29% had a prior history of CAD and/or a myocardial perfusion deficit. The levels of exercise intensity and duration were comparable in CAD and non-CAD patients. However, in CAD patients, IL-6 increased after exercise (p = 0.019) while no differences were seen in HPA axis variables. Conversely, patients without CAD exhibited increased levels of ACTH (p = 0.003) and cortisol (p = 0.004 in plasma, p = 0.006 in saliva), but no change in IL-6. We conclude that the IL-6 response to acute physical exercise is exaggerated in CAD patients and may be out of balance due to HPA axis hypoactivity. It remains to be further investigated whether this imbalance is a potential diagnostic and therapeutic target in CAD.
Optimization of one-parameter family of integration formulae for solving stiff chemical-kinetic ODEs
Authors: Morii Youhi , Shima Eiji
Published: December 2020

A fast and robust Jacobian-free time-integration method—called Minimum-error Adaptation of a Chemical-Kinetic ODE Solver (MACKS)—for solving stiff ODEs pertaining to chemical-kinetics is proposed herein. The MACKS formulation is based on optimization of the one-parameter family of integration formulae coupled with a dual time-stepping method to facilitate error minimization. The proposed method demonstrates higher accuracy compared to the method—Extended Robustness-enhanced numerical algorithm (ERENA)—previously proposed by the authors. Additionally, when this method is employed in homogeneous-ignition simulations, it facilitates realization of faster performance compared to CVODE.
Degree difference: a simple measure to characterize structural heterogeneity in complex networks
Authors: Farzam Amirhossein , Samal Areejit , Jost Jürgen
Published: December 2020

Despite the growing interest in characterizing the local geometry leading to the global topology of networks, our understanding of the local structure of complex networks, especially real-world networks, is still incomplete. Here, we analyze a simple, elegant yet underexplored measure, ‘degree difference’ (DD) between vertices of an edge, to understand the local network geometry. We describe the connection between DD and global assortativity of the network from both formal and conceptual perspective, and show that DD can reveal structural properties that are not obtained from other such measures in network science. Typically, edges with different DD play different structural roles and the DD distribution is an important network signature. Notably, DD is the basic unit of assortativity. We provide an explanation as to why DD can characterize structural heterogeneity in mixing patterns unlike global assortativity and local node assortativity. By analyzing synthetic and real networks, we show that DD distribution can be used to distinguish between different types of networks including those networks that cannot be easily distinguished using degree sequence and global assortativity. Moreover, we show DD to be an indicator for topological robustness of scale-free networks. Overall, DD is a local measure that is simple to define, easy to evaluate, and that reveals structural properties of networks not readily seen from other measures.
Metabolism and pharmacokinetics of a novel polyphenol fatty acid ester phloridzin docosahexaenoate in Balb/c female mice
Authors: Fernando Wasundara , Goralski Kerry B. , Hoskin David W. , Rupasinghe H. P. Vasantha
Published: December 2020

Flavonoids are known to undergo phase II metabolism and produce metabolites with similar or stronger biological effects compared to the parent flavonoids. However, the limited cellular uptake and bioavailability restrict their clinical use. We synthesized phloridzin docosahexaenoate (PZ-DHA), a novel fatty acid ester of polyphenol, through an acylation reaction with the aim of increasing the cellular availability and stability of the parent biomolecules, phloridzin (PZ) and docosahexaenoic acid (DHA). Here, we report metabolites and pharmacokinetic parameters of PZ-DHA, determined using ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. PZ-DHA was taken-up by human (MDA-MB-231, MDA-MB-468, and MCF-7) and mouse (4T1) mammary carcinoma and human non-malignant mammary epithelial cells (MCF-10A) in cellular uptake assays. Our results suggested that the acylation improves the cellular uptake of PZ and stability of DHA within cells. In mouse hepatic microsomal assays, two major glucuronides of PZ-DHA, PZ-DHA-4-O-glucuronide and PZ-DHA-4′-O-glucuronide (MW = 923.02 g/mol), were detected. One tri-methylated- (4,4′,6′-O-trimethyl-PZ-DHA) (MW = 788.88 g/mol) and one di-sulphated- (PZ-DHA-4,4′-O-disulphide) PZ-DHA metabolite (MW = 906.20 g/mol) were also identified. Intraperitoneal injections of PZ-DHA (100 mg/kg) into Balb/c female mice was rapidly absorbed with a serum Cmax and Tmax of 23.7 µM and 60 min, respectively, and rapidly eliminated (t1/2 = 28.7 min). PZ-DHA and its metabolites are readily distributed throughout the body (Vd = 57 mL) into many organs. We identified in vitro and in vivo metabolites of PZ-DHA, which could be tested for potential use to treat diseases such as cancer in multiple organ systems.
Impact of bleeding during dual antiplatelet therapy in patients with coronary artery disease
Authors: Tung Ying-Chang , See Lai-Chu , Chang Shu-Hao , Liu Jia-Rou , Kuo Chi-Tai , Chang Chi-Jen
Published: December 2020

This nationwide retrospective cohort study used the National Health Insurance Research Database of Taiwan to compare the impact of bleeding on clinical outcomes in patients with acute myocardial infarction (AMI) versus chronic coronary syndrome (CCS). Between July 2007 and December 2010, patients with AMI (n = 15,391) and CCS (n = 19,724) who received dual antiplatelet therapy after coronary stenting were identified from the database. AMI was associated with increased risks of MI (AMI vs. CCS: 0.38 vs. 0.16 per 100 patient-months; p < 0.01), all-cause death (0.49 vs. 0.32 per 100 patient-months; p < 0.01), and BARC type 3 bleeding (0.22 vs. 0.13 per 100 patient-months; p < 0.01) at 1 year compared with CCS, while the risk of BARC type 2 bleeding was marginally higher in the CCS patients than in the AMI patients (1.32 vs. 1.4 per 100 person-months; p = 0.06). Bleeding was an independent predictor of MI, stroke, and all-cause death in this East Asian population, regardless of the initial presentation. Among the patients with bleeding, AMI was associated with a higher risk of ischemic events at 1 year after bleeding compared with CCS (MI: 0.34 vs. 0.25 per 100 patient-months; p = 0.06; ischemic stroke: 0.22 vs. 0.13 per 100 patient-months; p = 0.02). The 1-year mortality after bleeding was comparable between the two groups after propensity score weighting. In conclusion, bleeding conferred an increased risk of adverse outcomes in East Asian patients with AMI and CCS.
The Habc domain of syntaxin 3 is a ubiquitin binding domain
Authors: Giovannone Adrian J. , Reales Elena , Bhattaram Pallavi , Nackeeran Sirpi , Monahan Adam B. , Syed Rashid , Weimbs Thomas
Published: December 2020

Syntaxins are a family of membrane-anchored SNARE proteins that are essential components required for membrane fusion in eukaryotic intracellular membrane trafficking pathways. Syntaxins contain an N-terminal regulatory domain, termed the Habc domain that is not highly conserved at the primary sequence level but folds into a three-helix bundle that is structurally conserved among family members. The syntaxin Habc domain has previously been found to be structurally very similar to the GAT domain present in GGA family members and related proteins that are otherwise completely unrelated to syntaxins. Because the GAT domain has been found to be a ubiquitin binding domain we hypothesized that the Habc domain of syntaxins may also bind to ubiquitin. Here, we report that the Habc domain of syntaxin 3 (Stx3) indeed binds to monomeric ubiquitin with low affinity. This domain binds efficiently to K63-linked poly-ubiquitin chains within a narrow range of chain lengths but not to K48-linked poly-ubiquitin chains. Other syntaxin family members also bind to K63-linked poly-ubiquitin chains but with different chain length specificities. Molecular modeling suggests that residues of the GGA3-GAT domain known to be important for ionic and hydrophobic interactions with ubiquitin may have equivalent, conserved residues within the Habc domain of Stx3. We conclude that the syntaxin Habc domain and the GAT domain are both structurally and functionally related, and likely share a common ancestry despite sequence divergence. Binding of Ubiquitin to the Habc domain may regulate the function of syntaxins in membrane fusion or may suggest additional functions of this protein family.
Menstrual blood-derived stromal cells modulate functional properties of mouse and human macrophages
Authors: Martínez-Aguilar Rocío , Romero-Pinedo Salvador , Ruiz-Magaña M. José , Olivares Enrique G. , Ruiz-Ruiz Carmen , Abadía-Molina Ana C.
Published: December 2020

Menstrual blood-derived stromal cells (MenSCs) are emerging as a strong candidate for cell-based therapies due to their immunomodulatory properties. However, their direct impact on innate immune populations remains elusive. Since macrophages play a key role in the onset and development of inflammation, understanding MenSCs implication in the functional properties of these cells is required to refine their clinical effects during the treatment of inflammatory disorders. In this study, we assessed the effects that MenSCs had on the recruitment of macrophages and other innate immune cells in two mouse models of acute inflammation, a thioglycollate (TGC)-elicited peritonitis model and a monobacterial sepsis model. We found that, in the TGC model, MenSCs injection reduced the percentage of macrophages recruited to the peritoneum and promoted the generation of peritoneal immune cell aggregates. In the sepsis model, MenSCs exacerbated infection by diminishing the recruitment of macrophages and neutrophils to the site of infection and inducing defective bacterial clearance. Additional in vitro studies confirmed that co-culture with MenSCs impaired macrophage bactericidal properties, affecting bacterial killing and the production of reactive oxygen intermediates. Our findings suggest that MenSCs modulate the macrophage population and that this modulation must be taken into consideration when it comes to future clinical applications.
The impact of aspirin on Klebsiella pneumoniae liver abscess in diabetic patients
Authors: Tai Chien-Hsiang , Hsu Chien-Ning , Yang Shih-Cheng , Wu Cheng-Kun , Liang Chih-Ming , Tai Wei-Chen , Chuah Seng-Kee , Lee Chen-Hsiang
Published: December 2020

In this study, we aimed to investigate the impact of aspirin on the risk of pyogenic liver abscess caused by Klebsiella pneumoniae (KP-PLA) and invasive KP-PLA syndrome (IKPS) in diabetic patients. Diabetic patients who were propensity-score matched were retrospectively included from hospital-based database. Kaplan–Meier approach with a log-rank test was used to compare the cumulative incidences of KP-PLA including IKPS between aspirin users and non-users. Totally, 63,500 patients were analyzed after propensity-score matching (1:1). Compared with that of non-users, the incidence of KP-PLA was significantly reduced in aspirin users (0.31% vs. 0.50%, p < 0.01), but not for that of IKPS (0.02% vs. 0.03%, p = 0.29). Patients taking aspirin for ≥ 90 days had a significantly lower risk for KP-PLA (hazard ratio, 0.67; 95%CI, 0.50–0.90). Females, taking clopidogrel or metformin for ≥ 90 days, and taking H2-blockers or proton pump inhibitors (PPIs) for ≥ 5 days were also associated with a lower risk of KP-PLA. However, cholangitis and a glycated hemoglobin ≥ 8.5% were associated with an increased risk of KP-PLA.
Prediction of nodal-line semimetals in two-dimensional black phosphorous films
Authors: Liu Xiaojuan , Bao Hairui , Li Yue , Yang Zhongqin
Published: December 2020

Semimetals are a new kind of quantum materials, in which the conduction and valence bands cross each other near the Fermi level. Based on density-functional theory calculations and symmetry analysis, we propose nodal-line semimetals in layered stacked black phosphorus (BP) films which are designed to have a mirror symmetry lying in the BP layer plane and thus rendering them different from the BP film systems previously studied. A closed nodal-line degenerate band can appear around the Fermi level in the BP films after a biaxial compressive strain is applied. The calculated Z2 number of Z2 =  − 1 indicates the robustness of the nodal-line semimetals obtained in the BP films, protected by the in-plane mirror symmetry. Intriguingly, with the increase of the film thickness, a smaller biaxial compressive strain is required to produce the nodal-line semimetals, more accessible in experiments. Our results provide a promising route to carrying out the nodal-line semimetals based on various two-dimensional materials.
Simultaneous photoadhesion and photopatterning technique for passivation of flexible neural electrodes based on fluoropolymers
Authors: Kim Yong Hee , Jung Sang-Don
Published: December 2020

Herein, we introduce a method to simultaneously photoadhere a photocrosslinkable polymer to a plasma-treated fluoropolymer while photopatterning the photocrosslinkable polymer via a single-photo-exposure as a new electrode passivation technique. Photoadhesion was determined to result from plasma-generated radicals of the plasma-treated fluoropolymer. Crystallinity of the fluoropolymer was analysed to determine the photoadhesion strength through its effects on both the formation of radicals and the etching of fluoropolymers. Passivation feasibility of simultaneous photoadhesion and photopatterning (P&P) technique were demonstrated by fabricating an Au electrocorticography electrode array and modifying the electrode with electro-deposited metallic nanoparticles. Adhesion of sputter-deposited Au to the fluoropolymer was dependent on mechanical interlocking, indicated by the formation of Au clusters which are typically influenced by the surface temperature during the sputter-deposition and the glass transition temperature of the fluoropolymer. The adhesion of Au to the fluoropolymer without an additional adhesion promotor and the proposed P&P passivation technique would help prevent detachment of the electrode and the delamination of the passivation layer in fluoropolymer-based neural electrode.
Failure mechanism of TRSS mode in landslides induced by earthquake
Authors: Liu Renli , Han Yanhui , Xiao Jun , Wang Tao
Published: December 2020

Investigation of the slopes in the Wenchuan earthquake shows that tension failures appear in the upper part in many landslides. The typical failure mode can be generalized as “tensile-rupture and sheared-sliding” (TRSS). In this paper, the distinct element method (DEM) is employed to simulate the gradual failure process of the Tangjiashan landslide under the excitation of the Wenchuan earthquake. It is found that the first failure is the appearance of deep tension cracks on the top, and then shearing slip along the bottom. The posterior fracture is deep, steep, and rough, and the bottom shear slip surface has a relatively gently dip. The simulation shows the failure mode of TRSS in the slope can be well reproduced, and the geological and mechanical mechanisms can be revealed in the DEM model.
Comparative proteomic analysis of the sweetpotato provides insights into response mechanisms to Fusarium oxysporum f. sp. batatas
Authors: Lin ShiQiang , Yang ZhiJian , Huang BiFang , Bi ChuYun , Huang XiaoFang , Chen GuoTai , Nijiati Nuerla , Chen XuanYang
Published: December 2020

The Fusarium wilt disease caused byFusarium oxysporumf. sp.batatas(Fob) is one of the devastating diseases of sweetpotato. However, the molecular mechanisms of sweetpotato response to Fob is poorly understood. In the present study, comparative quantitative proteomic analysis was conducted to investigate the defense mechanisms involved. Two sweetpotato cultivars with differential Fob infection responses were inoculated with Fob spore suspensions and quantitatively analyzed by Tandem Mass Tags (TMT). 2267 proteins were identified and 1897 of them were quantified. There were 817 proteins with quantitative ratios of 1.2-fold change between Fob-inoculated and mock-treated samples. Further, nine differentially expressed proteins were validated by Parallel Reaction Monitoring (PRM). According to Gene Ontology (GO) annotation information, the proteins functioned in molecular metabolism, cellular component formation, and biological processes. Interestingly, the results showed that sweetpotato resistant response to Fob infection included many proteins associated with signaling transduction, plant resistance, chitinase and subtilisin-like protease. The functions and possible roles of those proteins were discussed. The results provides first insight into molecular mechanisms involved in sweetpotato defense responses to Fob.
Author Correction: Alternating Differentiation and Dedifferentiation between Mature Osteoblasts and Osteocytes
Authors: Sawa Naruhiko , Fujimoto Hiroki , Sawa Yoshihiko , Yamashita Junro
Published: December 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Essential role of submandibular lymph node dendritic cells in protective sublingual immunotherapy against murine allergy
Authors: Miyanaga Noriaki , Takagi Hideaki , Uto Tomofumi , Fukaya Tomohiro , Nasu Junta , Fukui Takehito , Nishikawa Yotaro , Sparwasser Tim , Choijookhuu Narantsog , Hishikawa Yoshitaka , Nakamura Takeshi , Tono Tetsuya , Sato Katsuaki
Published: December 2020

While sublingual immunotherapy (SLIT) is known as an allergen-specific treatment for type-1 allergies, how it controls allergic pathogenesis remains unclear. Here, we show the prerequisite role of conventional dendritic cells in submandibular lymph nodes (ManLNs) in the effectiveness of SLIT for the treatment of allergic disorders in mice. Deficiency of conventional dendritic cells or CD4+Foxp3+regulatory T (Treg) cells abrogates the protective effect of SLIT against allergic disorders. Furthermore, sublingual antigenic application primarily induces antigen-specific CD4+Foxp3+Tregcells in draining ManLNs, in which it is severely impaired in the absence of cDCs. In ManLNs, migratory CD11b+cDCs are superior to other conventional dendritic cell subsets for the generation of antigen-specific CD4+Foxp3+Tregcells, which is reflected by their dominancy in the tolerogenic features to favor this program. Thus, ManLNs are privileged sites in triggering mucosal tolerance mediating protect effect of SLIT on allergic disorders that requires a tolerogenesis of migratory CD11b+conventional dendritic cells.
Detection of RNA viruses from influenza and HIV to Ebola and SARS-CoV-2: a review
Authors: Bukasov Rostislav , Dossym Dina , Filchakova Olena
Published: December 2020

RNA-based viruses likely make up the highest pandemic threat among all known pathogens in about the last 100 years, since the Spanish Flu of 1918 with 50 M deaths up to COVID-19.
Bulk ionic screening lengths from extremely large-scale molecular dynamics simulations
Authors: Zeman Johannes , Kondrat Svyatoslav , Holm Christian
Published: December 2020

Large-scale molecular simulations reveal two screening lengths satisfying distinct scaling relations but with unprecedented accuracy no underscreening is detected for concentrated ionic bulk systems.
Luminescence tuning and sensing properties of stable 2D lanthanide metal–organic frameworks built with symmetrical flexible tricarboxylic acid ligands containing ether oxygen bonds
Authors: Wang Jiao-Min , Zhang Peng-Feng , Cheng Jian-Guo , Wang Yao , Ma Lu-Lu , Yang Guo-Ping , Wang Yao-Yu
Published: December 2020

New Ln-MOFs were yielded by a flexible ligand and lanthanide ions. The colors can be regulated by adjusting the molar ratios of Eu3+/Tb3+, showing promising applications in NB sensing, tunable photoluminescence and pH sensing.
Multifunctional metal–organic framework heterostructures for enhanced cancer therapy
Authors: Liu Jintong , Huang Jing , Zhang Lei , Lei Jianping
Published: December 2020

We review the general principle of the design and functional modulation of nanoscaled MOF heterostructures, and biomedical applications in enhanced therapy.
Covalent organic frameworks: an ideal platform for designing ordered materials and advanced applications
Authors: Liu Ruoyang , Tan Ke Tian , Gong Yifan , Chen Yongzhi , Li Zhuoer , Xie Shuailei , He Ting , Lu Zhen , Yang Hao , Jiang Donglin
Published: December 2020

Covalent organic frameworks offer a molecular platform for integrating organic units into periodically ordered yet extended 2D and 3D polymers to create topologically well-defined polygonal lattices and built-in discrete micropores and/or mesopores.
Asymmetric desymmetrization of alkene-, alkyne- and allene-tethered cyclohexadienones using transition metal catalysis
Authors: Shu Tao , Cossy Janine
Published: December 2020

This review is covering the recent development of catalytic asymmetric domino reactions for the desymmetrization of alkene-, alkyne- and allene-tethered cyclohexadienones using transition metals and chiral ligands.
Integrated microfluidic platform with electrohydrodynamic focusing and a carbon-nanotube-based field-effect transistor immunosensor for continuous, selective, and label-free quantification of bacteria
Authors: Han Chang-Ho , Jang Jaesung
Published: December 2020

A microfluidic carbon-nanotube-based field-effect transistor immunosensor equipped with electrohydrodynamic focusing for continuous and label-free detection of flowing Staphylococcus aureus particles.
Design of biodegradable bi-compartmental microneedles for the stabilization and the controlled release of the labile molecule collagenase for skin healthcare
Authors: Di Natale Concetta , De Rosa Domenico , Profeta Martina , Jamaledin Rezvan , Attanasio Alessandro , Lagreca Elena , Scognamiglio Pasqualina Liana , Netti Paolo Antonio , Vecchione Raffaele
Published: December 2020

Polymeric microneedles (MNs) have emerged as a novel class of drug delivery system thanks to their ability in penetrating the skin with no pain, encapsulate active proteins and in particular, proposed bicompartimental MNs can tune protein release.
Energy limit of oil‐immersed transformers: A concept and its application in different climate conditions
Authors: Daminov Ildar , Prokhorov Anton , Caire Raphael , Alvarez‐Herault Marie‐Cécile
Published: December 2020

The reality of modern power grids requires the use of flexibilities from generation, load and storage. These flexibilities allow system operators to modify a transformer loading in a smart way. Therefore, power constraints of transformers can be overcome by using the appropriate flexibility. However, transformers have a physical limit of energy transfer which cannot be overpassed. This energy limit represents the unique transformer's loading profile, ensuring the highest energy transfer under a given ambient temperature profile.

The paper explains how the energy limit can be calculated. Typical characteristics of an energy limit are estimated in cold continental climate of Russia and warm temperate climate in France. Maximal, minimal and mean loadings are identified for each month. Loading durations of energy limit are determined for each cooling system. It is found that winding temperatures of transformers, operating at energy limits, remain in the vicinity of design winding temperature. Therefore, transformer operation at energy limit avoids a high temperature stress and simultaneously maximizes the energy transfer.

The application of energy limits for power system problems is briefly explained along the paper. Energy limit application can reduce an energy cost, maximize a renewable generation and increase a hosting capacity of distribution network.