bluuebunny/crossref_metadata_2025 huggingface dataset:
DeepOMe: A Web Server for the Prediction of 2′-O-Me Sites Based on the Hybrid CNN and BLSTM Architecture
Authors: Li Hongyu , Chen Li , Huang Zaoli , Luo Xiaotong , Li Huiqin , Ren Jian , Xie Yubin
Published: May 2021

2′-O-methylations (2′-O-Me or Nm) are one of the most important layers of regulatory control over gene expression. With increasing attentions focused on the characteristics, mechanisms and influences of 2′-O-Me, a revolutionary technique termed Nm-seq were established, allowing the identification of precise 2′-O-Me sites in RNA sequences with high sensitivity. However, as the costs and complexities involved with this new method, the large-scale detection and in-depth study of 2′-O-Me is still largely limited. Therefore, the development of a novel computational method to identify 2′-O-Me sites with adequate reliability is urgently needed at the current stage. To address the above issue, we proposed a hybrid deep-learning algorithm named DeepOMe that combined Convolutional Neural Networks (CNN) and Bidirectional Long Short-term Memory (BLSTM) to accurately predict 2′-O-Me sites in human transcriptome. Validating under 4-, 6-, 8-, and 10-fold cross-validation, we confirmed that our proposed model achieved a high performance (AUC close to 0.998 and AUPR close to 0.880). When testing in the independent data set, DeepOMe was substantially superior to NmSEER V2.0. To facilitate the usage of DeepOMe, a user-friendly web-server was constructed, which can be freely accessed at http://deepome.renlab.org.
Development and Characterization of PLGA Nanoparticles Containing 17-DMAG, an Hsp90 Inhibitor
Authors: Cruz Kercia P. , Patricio Beatriz F. C. , Pires Vinícius C. , Amorim Marina F. , Pinho Alan G. S. F. , Quadros Helenita C. , Dantas Diana A. S. , Chaves Marcelo H. C. , Formiga Fabio R. , Rocha Helvécio V. A. , Veras Patrícia S. T.
Published: May 2021

Leishmaniasis is a spectrum of neglected tropical diseases and its cutaneous form (CL) is characterized by papillary or ulcerated skin lesions that negatively impact patients' quality of life. Current CL treatments suffer limitations, such as severe side effects and high cost, making the search for new therapeutic alternatives an imperative. In this context, heat shock protein 90 (Hsp90) could present a novel therapeutic target, as evidence suggests that Hsp90 inhibitors, such as 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17-DMAG), may represent promising chemotherapeutic agents against CL. As innovative input for formulation development of 17-DMAG, nano-based drug delivery systems could provide controlled release, targeting properties, and reduced drug toxicity. In this work, a double emulsion method was used to develop poly (lactic-co-glycolic acid) (PLGA) nanoparticles containing 17-DMAG. The nanoparticle was developed using two distinct protocols: Protocol 1 (P1) and Protocol 2 (P2), which differed concerning the organic solvent (acetone or dichloromethane, respectively) and procedure used to form double-emulsions (Ultra-Turrax® homogenization or sonication, respectively). The nanoparticles produced by P2 were comparatively smaller (305.5 vs. 489.0 nm) and more homogeneous polydispersion index (PdI) (0.129 vs. 0.33) than the ones made by P1. Afterward, the P2 was optimized and the best composition consisted of 2 mg of 17-DMAG, 100 mg of PLGA, 5% of polyethylene glycol (PEG 8000), 1.5 mL of the internal aqueous phase, 1% of polyvinyl alcohol (PVA), and 4 mL of the organic phase. Optimized P2 nanoparticles had a particle size of 297.2 nm (288.6–304.1) and encapsulation efficacy of 19.35% (15.42–42.18) by the supernatant method and 31.60% (19.9–48.79) by the filter/column method. Release kinetics performed at 37°C indicated that ~16% of the encapsulated 17-DMAG was released about to 72 h. In a separate set of experiments, a cell uptake assay employing confocal fluorescence microscopy revealed the internalization by macrophages of P2-optimized rhodamine B labeled nanoparticles at 30 min, 1, 2, 4, 6, 24, 48, and 72 h. Collectively, our results indicate the superior performance of P2 concerning the parameters used to assess nanoparticle development. Therefore, these findings warrant further research to evaluate optimized 17-DMAG-loaded nanoparticles (NP2-17-DMAG) for toxicity and antileishmanial effects in vitro and in vivo.
The Potential Application of Magnetic Nanoparticles for Liver Fibrosis Theranostics
Authors: Eftekhari Aziz , Arjmand Allahveirdy , Asheghvatan Ayyub , Švajdlenková Helena , Šauša Ondrej , Abiyev Huseyn , Ahmadian Elham , Smutok Oleh , Khalilov Rovshan , Kavetskyy Taras , Cucchiarini Magali
Published: May 2021

Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic liver damage and leading to cirrhosis, liver cancer, and liver failure. To date, there is no effective and specific therapy for patients with hepatic fibrosis. As a result of their various advantages such as biocompatibility, imaging contrast ability, improved tissue penetration, and superparamagnetic properties, magnetic nanoparticles have a great potential for diagnosis and therapy in various liver diseases including fibrosis. In this review, we focus on the molecular mechanisms and important factors for hepatic fibrosis and on potential magnetic nanoparticles-based therapeutics. New strategies for the diagnosis of liver fibrosis are also discussed, with a summary of the challenges and perspectives in the translational application of magnetic nanoparticles from bench to bedside.
Requirements for a Dashboard to Support Quality Improvement Teams in Pain Management
Authors: Opie Jeremy , Bellio Maura , Williams Rachel , Sussman Maya , Voegele Petra , Welch John , Blandford Ann
Published: May 2021

Pain management is often considered lower priority than many other aspects of health management in hospitals. However, there is potential for Quality Improvement (QI) teams to improve pain management by visualising and exploring pain data sets. Although dashboards are already used by QI teams in hospitals, there is limited evidence of teams accessing visualisations to support their decision making. This study aims to identify the needs of the QI team in a UK Critical Care Unit (CCU) and develop dashboards that visualise longitudinal data on the efficacy of patient pain management to assist the team in making informed decisions to improve pain management within the CCU. This research is based on an analysis of transcripts of interviews with healthcare professionals with a variety of roles in the CCU and their evaluation of probes. We identified two key uses of pain data: direct patient care (focusing on individual patient data) and QI (aggregating data across the CCU and over time); in this paper, we focus on the QI role. We have identified how CCU staff currently interpret information and determine what supplementary information can better inform their decision making and support sensemaking. From these, a set of data visualisations has been proposed, for integration with the hospital electronic health record. These visualisations are being iteratively refined in collaboration with CCU staff and technical staff responsible for maintaining the electronic health record. The paper presents user requirements for QI in pain management and a set of visualisations, including the design rationale behind the various methods proposed for visualising and exploring pain data using dashboards.
Integrated Whole-Exome and Transcriptome Sequencing of Sporadic Parathyroid Adenoma
Authors: Hu Ya , Zhang Xiang , Wang Ou , Cui Ming , Li Xiaobin , Wang Mengyi , Hua Surong , Liao Quan
Published: May 2021

Purpose

Hyperparathyroidism is the third most common endocrine disease. Parathyroid adenoma (PA) accounts for approximately 85% of cases of primary hyperparathyroidism, but the molecular mechanism is not fully understood. Herein, we aimed to investigate the genetic and transcriptomic profiles of sporadic PA.

Methods

Whole-exome sequencing (WES) and transcriptome sequencing (RNA-seq) of 41 patients with PA and RNA-seq of 5 normal parathyroid tissues were performed. Gene mutations and characterized expression changes were identified. To elucidate the molecular mechanism underlying PA, unsupervised consensus clustering of RNA-seq data was performed. The correlations between the sequencing data and clinicopathological features of these patients were analyzed.

Results

Previously reported PA driver gene mutations, such as MEN1 (9/41), mTOR (4/41), ZFX (3/41), CASR (3/41), EZH2 (2/41) and FAT1 (2/41), were also identified in our cohort. Furthermore, somatic mutation of EZH1, which had not been reported in PA, was found in 4 samples. RNA-seq showed that the expression levels of 84 genes were upregulated and 646 were downregulated in PA samples compared with normal samples. Unsupervised clustering analysis of RNA-seq data clustered these patients into 10 subgroups related to mutation or abnormal expression of a group of potential pathogenic genes.

Conclusion

MEN1, EZH2, CASR, EZH1, ZFX, mTOR and FAT1 mutations in PA were revealed. According to the RNA-seq data clustering analysis, cyclin D1, β-catenin, VDR, CASR and GCM2 may be important factors contributing to the PA gene expression profile.
Multi-Objective Optimization and Dispatch of Distributed Energy Resources for Renewable Power Utilization Considering Time-of-Use Tariff
Authors: Xing Qinhao , Cheng Meng , Liu Shuran , Xiang Qianliang , Xie Hailian , Chen Tailai
Published: May 2021

The intermittency of wind and solar power generation brings risks to the safety and stability of the power system. In order to maximize the utilization of renewables, optimal control and dispatch methods of the Distributed Energy Resources including the generators, energy storage and flexible demand are necessary to be researched. This paper proposes an optimization and dispatch model of an aggregation of Distributed Energy Resources in order to facilitate the integration of renewables while considering the benefits for dispatchable resources under time-of-use tariff. The model achieves multi-objective optimization based on the constraints of day-ahead demand forecast, wind and solar generation forecast, electric vehicles charging routines, energy storage and DC power flow. The operating cost, the renewable energy utilization and the revenues of storages and electric vehicles are considered and optimized simultaneously through the min–max unification method to achieve the multi-objective optimization. The proposed model was then applied to a modified IEEE-30 bus case, demonstrating that the model is able to reconcile all participants in the system. Sensitivity analysis was undertaken to study the impact of initial states of the storages on the revenues to the resource owners.
Avian Use of Agricultural Areas as Migration Stopover Sites: A Review of Crop Management Practices and Ecological Correlates
Authors: Blount J. David , Horns Joshua J. , Kittelberger Kyle D. , Neate-Clegg Montague H. C. , Şekercioğlu Çağan Hakkı
Published: May 2021

An estimated 17% of migratory bird species are threatened or near threatened with extinction. This represents an enormous potential loss of biodiversity and cost to human societies due to the economic benefits that birds provide through ecosystem services and ecotourism. Conservation of migratory bird species presents many unique challenges, as these birds rely on multiple geographically distinct habitats, including breeding grounds, non-breeding grounds, and stopover sites during migration. In particular, stopover habitats are seldom studied relative to breeding and non-breeding habitats, despite their importance as refueling stations for migratory birds. In this study, we summarize the current research on the use of temporary primary crops by birds during migration and we assess the species characteristics and agricultural practices most often associated with the use of cropland as stopover habitat. First, we conducted a systematic review of the literature to document the effects various farming practices and crop types have on the abundance and diversity of migratory birds using agricultural areas for stopovers. Second, we analyzed the ecological correlates of bird species in the Northern Hemisphere that predict which species may use these areas while migrating. We ran a GLMM to test whether primary diet, diet breadth, primary habitat, habitat breadth, or realm predicted stopover use of agricultural areas. Our review suggests that particular crop types (principally rice, corn, and sunflower), as well as farming practices that result in higher non-cultivated plant diversity, encourage the use of agricultural areas by migrating birds. We found that cropland is used as stopover habitat by bird species that can utilize a large breadth of habitats, as well as species with preferences for habitat similar in structure to agricultural areas.
Promotion of Anti-Tuberculosis Macrophage Activity by L-Arginine in the Absence of Nitric Oxide
Authors: McKell Melanie C. , Crowther Rebecca R. , Schmidt Stephanie M. , Robillard Michelle C. , Cantrell Rachel , Lehn Maria A. , Janssen Edith M. , Qualls Joseph E.
Published: May 2021

Macrophages are indispensable immune cells tasked at eliminating intracellular pathogens.Mycobacterium tuberculosis(Mtb), one of the most virulent intracellular bacterial pathogens known to man, infects and resides within macrophages. While macrophages can be provoked by extracellular stimuli to inhibit and killMtbbacilli, these host defense mechanisms can be blocked by limiting nutritional metabolites, such as amino acids. The amino acid L-arginine has been well described to enhance immune function, especially in the context of driving macrophage nitric oxide (NO) production in mice. In this study, we aimed to establish the necessity of L-arginine on anti-Mtbmacrophage functionindependentof NO. Utilizing anin vitrosystem, we identified that macrophages relied on NO for only half of their L-arginine-mediated host defenses and this L-arginine-mediated defense in the absence of NO was associated with enhanced macrophage numbers and viability. Additionally, we observed macrophage glycolysis to be driven by both L-arginine and mechanistic target of rapamycin (mTOR), and inhibition of glycolysis or mTOR reduced macrophage control ofMtbas well as macrophage number and viability in the presence of L-arginine. Our data underscore L-arginine as an essential nutrient for macrophage function, not only by fueling anti-mycobacterial NO production, but also as a central regulator of macrophage metabolism and additional host defense mechanisms.
2,4-Dimethoxy-6-Methylbenzene-1,3-diol, a Benzenoid From Antrodia cinnamomea, Mitigates Psoriasiform Inflammation by Suppressing MAPK/NF-κB Phosphorylation and GDAP1L1/Drp1 Translocation
Authors: Chuang Shih-Yi , Chen Chi-Yuan , Yang Shih-Chun , Alalaiwe Ahmed , Lin Chih-Hung , Fang Jia-You
Published: May 2021

Antrodia cinnamomea exhibits anti-inflammatory, antioxidant, and immunomodulatory activities. We aimed to explore the antipsoriatic potential of 2,4-dimethoxy-6-methylbenzene-1,3-diol (DMD) derived from A. cinnamomea. The macrophages activated by imiquimod (IMQ) were used as the cell model for examining the anti-inflammatory effect of DMD in vitro. A significantly high inhibition of IL-23 and IL-6 by DMD was observed in THP-1 macrophages and bone marrow-derived mouse macrophages. The conditioned medium of DMD-treated macrophages could reduce neutrophil migration and keratinocyte overproliferation. DMD could downregulate cytokine/chemokine by suppressing the phosphorylation of mitogen-activated protein kinases (MAPKs) and NF-κB. We also observed inhibition of GDAP1L1/Drp1 translocation from the cytoplasm to mitochondria by DMD intervention. Thus, mitochondrial fission could be a novel target for treating psoriatic inflammation. A psoriasiform mouse model treated by IMQ showed reduced scaling, erythema, and skin thickening after topical application of DMD. Compared to the IMQ stimulation only, the active compound decreased epidermal thickness by about 2-fold. DMD diminished the number of infiltrating macrophages and neutrophils and their related cytokine/chemokine production in the lesional skin. Immunostaining of the IMQ-treated skin demonstrated the inhibition of GDAP1LI and phosphorylated Drp1 by DMD. The present study provides insight regarding the potential use of DMD as an effective treatment modality for psoriatic inflammation.
Patients With Common Variable Immunodeficiency (CVID) Show Higher Gut Bacterial Diversity and Levels of Low-Abundance Genes Than the Healthy Housemates
Authors: Bosák Juraj , Lexa Matej , Fiedorová Kristýna , Gadara Darshak C. , Micenková Lenka , Spacil Zdenek , Litzman Jiří , Freiberger Tomáš , Šmajs David
Published: May 2021

Common variable immunodeficiency (CVID) is a clinically and genetically heterogeneous disorder with inadequate antibody responses and low levels of immunoglobulins including IgA that is involved in the maintenance of the intestinal homeostasis. In this study, we analyzed the taxonomical and functional metagenome of the fecal microbiota and stool metabolome in a cohort of six CVID patients without gastroenterological symptomatology and their healthy housemates. The fecal microbiome of CVID patients contained higher numbers of bacterial species and altered abundance of thirty-four species. Hungatella hathewayi was frequent in CVID microbiome and absent in controls. Moreover, the CVID metagenome was enriched for low-abundance genes likely encoding nonessential functions, such as bacterial motility and metabolism of aromatic compounds. Metabolomics revealed dysregulation in several metabolic pathways, mostly associated with decreased levels of adenosine in CVID patients. Identified features have been consistently associated with CVID diagnosis across the patients with various immunological characteristics, length of treatment, and age. Taken together, this initial study revealed expansion of bacterial diversity in the host immunodeficient conditions and suggested several bacterial species and metabolites, which have potential to be diagnostic and/or prognostic CVID markers in the future.
Association of Dynamic Changes in Peripheral Blood Indexes With Response to PD-1 Inhibitor-Based Combination Therapy and Survival Among Patients With Advanced Non-Small Cell Lung Cancer
Authors: Chen Yuzhong , Wen Shaodi , Xia Jingwei , Du Xiaoyue , Wu Yuan , Pan Banzhou , Zhu Wei , Shen Bo
Published: May 2021

Background

PD-1 inhibitors have been routinely used in the treatment of advanced non-small cell lung cancer (NSCLC), and have demonstrated to significantly improve survivorship when combining with other conventional therapies, such as chemotherapy and anti-angiogenesis therapy. PD-L1 is the most commonly used biomarker to select benefiting groups, while not all patients with high PD-L1 expression benefit from immunotherapy. Therefore, identifying other prognostic and predictive biomarkers, including peripheral blood indexes, is essential.

Methods

We retrospectively collected medical records and hematological data of 151 patients with advanced NSCLC treated with PD-1 inhibitor-based combination therapy in our hospital. The peripheral blood indexes of interest were NLR, PLR, PAR, Hb, LDH, CEA, and NSE. The association between peripheral blood indexes and treatment responses or survival outcomes was examined by multivariable logistic regression and Cox regression, respectively.

Results

The decreased CEA at week 6 (OR = 4.209, 95%CI: 1.287-13.758) or 12 (OR = 7.267, 95%CI: 1.508-35.006) post-treatment was related to a higher disease control rate. The decrease or NLR at week 6 (OR = 3.081, 95%CI: 1.464-6.483) or 12 (OR = 3.304, 95%CI: 1.560-7.001) post-treatment, or CEA at week 12 post-treatment (OR = 2.469, 95%CI: 1.134-5.375), was associated with a higher objective response rate. Patients whose NLR (HR = 0.610, 95%CI: 0.411-0.907) or CEA (HR = 0.477, 95%CI: 0.320-0.710) decreased at week 6 post-treatment tended to have longer progression-free survival, and similar results were found in those with decreased NLR (HR = 0.587, 95%CI: 0.388-0.886) or CEA (HR = 0.406, 95%CI: 0.270-0.609) at week 12 post-treatment. Patients whose CEA (HR = 0.543, 95%CI: 0.339-0.871) or NSE (HR = 0.619, 95%CI: 0.386-0.994) decreased after 6 weeks post-treatment appeared to have longer overall survival, and the same was found for those whoseCEA (HR = 0.620, 95%CI: 0.390-0.986) or NSE (HR = 0.578, 95%CI: 0.353-0.947) was decreased at 12 weeks after treatment.

Conclusion

Post-treatment NLR, CEA and NSE changes are suggestive indicators for the prognosis of NSCLC patients after immunotherapy.
Changes in Circadian Rhythms Dysregulate Inflammation in Ageing: Focus on Leukocyte Trafficking
Authors: Nathan Poppy , Gibbs Julie Elizabeth , Rainger G. Ed , Chimen Myriam
Published: May 2021

Leukocyte trafficking shows strong diurnal rhythmicity and is tightly regulated by circadian rhythms. As we age, leukocyte trafficking becomes dysregulated, contributing to the increased systemic, low-grade, chronic inflammation observed in older adults. Ageing is also associated with diminished circadian outputs and a dysregulation of the circadian rhythm. Despite this, there is little evidence to show the direct impact of age-associated dampening of circadian rhythms on the dysregulation of leukocyte trafficking. Here, we review the core mammalian circadian clock machinery and discuss the changes that occur in this biological system in ageing. In particular, we focus on the changes that occur to leukocyte trafficking rhythmicity with increasing age and consider how this impacts inflammation and the development of immune-mediated inflammatory disorders (IMIDs). We aim to encourage future ageing biology research to include a circadian approach in order to fully elucidate whether age-related circadian changes occur as a by-product of healthy ageing, or if they play a significant role in the development of IMIDs.
High Clonality and Geographically Separated Cryptic Lineages in the Threatened Temperate Coral, Acropora pruinosa
Authors: Pipithkul Supisara , Ishizu Sota , Shimura Akifumi , Yokochi Hiroyuki , Nagai Satoshi , Fukami Hironobu , Yasuda Nina
Published: May 2021

Acropora pruinosa is a threatened zooxanthellate scleractinian coral that is distributed in the temperate areas along the coastline of Japan and the northern area of the South China Sea. Since A. pruinosa propagates both asexually and sexually, assessing clonal diversity and genetic connectivity among populations is important for conservation. In addition, high morphological variations in the field create confusion during species identification. To examine the existence of hidden genetic lineages, clonality, and genetic connectivity of A. pruinosa for conservation, we applied microsatellite analysis. Clustering analysis indicated two distinct geographically separated genetic lineages: one is distributed in the west, and the other is distributed in the east. The two lineages co-existed in Nishidomari, Kochi. There was no obvious difference in morphological characteristics between the two lineages. Although the factors influencing the observed distribution patterns remain unknown, there is a possibility that the two lineages might have diverged somewhere in the north-western Kyushu and north-eastern Pacific coast habitats in the past, and then periodically colonized the current habitats. A low clonal diversity was observed in most of the populations, indicating a high rate of asexual reproduction associated with their branching morphologies. In addition, there are strong genetic structuring in this species, indicating weak connectivity among populations. These results indicated a low larval dispersal potential among populations and that populations are basically sustained by a high rate of clone propagation and self-seeding. The existence of cryptic lineages and genetically isolated populations with high clonality emphasized the importance of conservation of A. pruinosa.
Effects of Titanium Corrosion Products on In Vivo Biological Response: A Basis for the Understanding of Osseointegration Failures Mechanisms
Authors: Biguetti Claudia Cristina , Cavalla Franco , Fonseca Angélica Cristina , Tabanez Andre Petenucci , Siddiqui Danyal A. , Wheelis Sutton E. , Taga Rumio , Fakhouri Walid D. , Silva Renato Menezes , Rodrigues Danieli C. , Garlet Gustavo Pompermaier
Published: May 2021

Corrosion resistance is a key feature of titanium biocompatibility. However, Ti surfaces exposed to critical environments (such as, chronic infection and inflammation) can undergo corrosion processes in vivo, leading to an unfavorable biological response and clinical failure, which remains poorly explored. In this study, we characterized an experimental model to replicate the surface features of Ti corrosion process observed within in vivo failures, and the cellular, tissue and molecular events associated with corroded Ti surface implantation into subcutaneous and bone tissue of C57Bl/6 mice. Prior to in vivo implantation, commercially pure Ti Commercially pure titanium and Ti–6Al–4V alloy (Ti64) specimens were exposed to electrochemical polarization in 30% citric acid, while being polarized at 9 V against a saturated calomel electrode for 20 min. The electrochemical attack induced accelerated corrosion on both Ti-based specimens, producing structural and chemical changes on the surface, comparable to changes observed in failed implants. Then, microscopy and molecular parameters for healing and inflammation were investigated following control and corroded Ti implantation in subcutaneous (cpTi disks) and oral osseointegration (Ti64 screws) models at 3, 7, 14 and 21 days. The host response was comparatively evaluated between control and corroded Ti groups by microCT (bone), histology (H&E, histomorphometry, immunostaining and picrosirius red), and real-time PCR array for inflammatory and healings markers. Corroded cpTi disks and Ti64 screws induced a strong foreign body response (FBR) from 3 to 21 days-post implantation, with unremitting chronic inflammatory reaction lasting up to 21 days in both subcutaneous and osseointegration models. In the subcutaneous model, FBR was accompanied by increased amount of blood vessels and their molecular markers, as well as increased TRAP+ foreign body giant cell count. In the osseointegration model, failures were identified by an osteolytic reaction/bone loss detected by microCT and histological analyses. The corroded devices were associated with a dominant M1-type response, while controls showed transient inflammation, an M2-type response, and suitable healing and osseointegration. In conclusion, corrosion of Ti-based biomaterials induced exacerbated inflammatory response in both connective tissue and bone, linked to the upregulation of fibrosis, pro-inflammatory and osteoclastic markers and resulted in unfavorable healing and osseointegration outcomes.
Influence of Bond Coat on Thermal Shock Resistance and Thermal Ablation Resistance for Polymer Matrix Composites
Authors: Zhou Jiahui , Jiang Jianing , Deng Longhui , Huang Jingqi , Yuan Jieyan , Cao Xueqiang
Published: May 2021

Polymer matrix composites (PMCs) have been widely used in aero industry because of its low density and high strength-to-weight ratio. However, the application of PMCs is still limited by poor abrasion resistance, weak oxidation resistance and low operation temperature. In this study, Cu (Al)/NiCrAlY/YSZ triple layer coating system was deposited on glass fiber reinforced polyimide matrix composites (FPM) by means of High Velocity Oxygen Fuel (HVOF) for metallic coatings and Atmospheric Plasma Spraying (APS) for YSZ coating. The influences of different bond coats and different thickness of the top coat on the thermal shock resistance and thermal ablation resistance of the coating system was investigated. Compared with Al particle, Cu particle has a high density and correspondingly a high kinetic energy during spraying by HVOF, resulting in a high bonding strength between the Cu coating and FPM substrate. In the thermal shock test, the coating Cu/NiCrAlY/YSZ has a much longer lifetime than the coating Al/NiCrAlY/YSZ. After high-speed impact on the substrate, there is a great compressive stress at the interface, which makes a plastic deformation to the substrate, and the particles are closely embedded into the substrate to form a strong mechanical interlock. The coating system consisting of 50 μm Cu, 50 μm NiCrAlY, and 200 μm 8YSZ exhibited the best thermal shock resistance, thermal ablation resistance and bonding strength. The increase of the top coat thickness will lead to the increase of residual stress and the decrease of bonding strength. The failure mechanism of the coating is mainly attributed to the residual stress in the deposition process and the thermal stress caused by thermal expansion mismatch.
Risk Factors and Prediction Model for Non-curative Resection of Early Gastric Cancer With Endoscopic Resection and the Evaluation
Authors: Ma Xiaoqian , Zhang Qian , Zhu Shengtao , Zhang Shutian , Sun Xiujing
Published: May 2021

Background and Study Aim: EGC, also known as Early Gastric Cancer is known to lack the lymph node metastasis and confined along the mucosa, which is treated through an endoscopic resection procedure that includes ESD (Endoscopic Submucosal dissection) and EMR (Endoscopic Mucosal Resection). However, some cases underwent residual disease, recurrence, or additional gastrectomy because of non-curative resection. The following research aims to delineate the threat factors causing the non-curative resection as well as develop a predictive model.

Patient and Methods: Effort was taken to collect all the records about the health history of pathologically diagnosed EGC who experienced endoscopic treatment in the Department of Endoscopy, the Capital Medical University, and Beijing Friendship Hospital from January 2012 to January 2020. Patients were grouped into two categories primarily; a curative resection group and finally a non-curative resection group based on the outcomes of the postoperative pathological and immunohistochemical examination results. The statistical methods used included single factor analysis, a multivariate logistic regression analysis and a chi-square test. A nomogram for the prediction of non-curative resection was constructed, which included information on age, gender, resection method, postoperative pathology, tumor size, ulcer, treatment, and infiltration depth. Receiver operating characteristic (ROC) curve analysis and calibration were performed to present the predictive accuracy of the nomogram.

Results: Of 443 patients with 478 lesions who had undergone ESD or EMR for EGCs, 127 were identified as being treated non-curative resection. Older patients (>60 years), a large tumor size (>30 mm), submucosal lesion, piecemeal resection, EMR for treatment and undifferentiated tumor histology were associated with non-curative resection group. Our risk nomogram showed good discriminated performance in internal validation (bootstrap-corrected area under the receiver-operating characteristic curve, 0.881; P < 0.001).

Conclusions: A validated prediction model was developed to identify people who were subject to undergoing a non-curative resection for ESD. The predictive model that we formulated is essential in providing reliable information to guide the decision-making process on the treatment for EGC before undertaking an endoscopic resection.
Surfactin Facilitates Horizontal Gene Transfer in Bacillus subtilis
Authors: Danevčič Tjaša , Dragoš Anna , Spacapan Mihael , Stefanic Polonca , Dogsa Iztok , Mandic-Mulec Ines
Published: May 2021

Genetic competence for the uptake and integration of extracellular DNA is a key process in horizontal gene transfer (HGT), one of the most powerful forces driving the evolution of bacteria. In several species, development of genetic competence is coupled with cell lysis. Using Bacillus subtilis as a model bacterium, we studied the role of surfactin, a powerful biosurfactant and antimicrobial lipopeptide, in genetic transformation. We showed that surfactin itself promotes cell lysis and DNA release, thereby promoting HGT. These results, therefore, provide evidence for a fundamental mechanism involved in HGT and significantly increase our understanding of the spreading of antibiotic resistance genes and diversification of microbial communities in the environment.
Circulation of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli of Pandemic Sequence Types 131, 648, and 410 Among Hospitalized Patients, Caregivers, and the Community in Rwanda
Authors: Eger Elias , Heiden Stefan E. , Korolew Katja , Bayingana Claude , Ndoli Jules M. , Sendegeya Augustin , Gahutu Jean Bosco , Kurz Mathis S. E. , Mockenhaupt Frank P. , Müller Julia , Simm Stefan , Schaufler Katharina
Published: May 2021

Multi-drug resistant (MDR), gram-negative Enterobacteriaceae, such as Escherichia coli (E. coli) limit therapeutic options and increase morbidity, mortality, and treatment costs worldwide. They pose a serious burden on healthcare systems, especially in developing countries like Rwanda. Several studies have shown the effects caused by the global spread of extended-spectrum beta-lactamase (ESBL)-producing E. coli. However, limited data is available on transmission dynamics of these pathogens and the mobile elements they carry in the context of clinical and community locations in Sub-Saharan Africa. Here, we examined 120 ESBL-producing E. coli strains from patients hospitalized in the University Teaching Hospital of Butare (Rwanda), their attending caregivers as well as associated community members and livestock. Based on whole-genome analysis, the genetic diversification and phylogenetics were assessed. Moreover, the content of carried plasmids was characterized and investigated for putative transmission among strains, and for their potential role as drivers for the spread of antibiotic resistance. We show that among the 30 different sequence types (ST) detected were the pandemic clonal lineages ST131, ST648 and ST410, which combine high-level antimicrobial resistance with virulence. In addition to the frequently found resistance genes blaCTX–M–15, tet(34), and aph(6)-Id, we identified csg genes, which are required for curli fiber synthesis and thus biofilm formation. Numerous strains harbored multiple virulence-associated genes (VAGs) including pap (P fimbriae adhesion cluster), fim (type I fimbriae) and chu (Chu heme uptake system). Furthermore, we found phylogenetic relationships among strains from patients and their caregivers or related community members and animals, which indicates transmission of pathogens. Also, we demonstrated the presence and potential transfer of identical/similar ESBL-plasmids in different strains from the Rwandan setting and when compared to an external plasmid. This study highlights the circulation of clinically relevant, pathogenic ESBL-producing E. coli among patients, caregivers and the community in Rwanda. Combining antimicrobial resistance with virulence in addition to the putative exchange of mobile genetic elements among bacterial pathogens poses a significant risk around the world.
In vitro Activity of Antimicrobial Wound Dressings on P. aeruginosa Wound Biofilm
Authors: Stuermer Ewa Klara , Plattfaut Isabell , Dietrich Michael , Brill Florian , Kampe Andreas , Wiencke Vanessa , Ulatowski Anna , Geffken Maria , Rembe Julian-Dario , Naumova Ella Alexandrovna , Debus Sebastian Eike , Smeets Ralf
Published: May 2021

The treatment of acute and chronic infected wounds with residing biofilm still poses a major challenge in medical care. Interactions of antimicrobial dressings with bacterial load, biofilm matrix and the overall protein-rich wound microenvironment remain insufficiently studied. This analysis aimed to extend the investigation on the efficacy of a variety of antimicrobial dressings using an in vitro biofilm model (lhBIOM) mimicking the specific biofilm-environment in human wounds. Four wound dressings containing polyhexanide (PHMB), octendine di-hydrochloride (OCT), cadexomer-iodine (C-IOD) or ionic silver (AG) were compared regarding their antimicrobial efficacy. Quantitative analysis was performed using a quantitative suspension method, separately assessing remaining microbial counts within the solid biofilm as well as the dressing eluate (representing the absorbed wound exudate). Dressing performance was tested against P. aeruginosa biofilms over the course of 6 days. Scanning electron microscopy (SEM) was used to obtain qualitative visualization on changes in biofilm structure. C-IOD demonstrated superior bacterial reduction. In comparison it was the only dressing achieving a significant reduction of more than 7 log10 steps within 3 days. Neither the OCT- nor the AG-containing dressing exerted a distinct and sustained antimicrobial effect. PHMB achieved a non-significant microbicidal effect (1.71 ± 0.31 log10 steps) at day 1. Over the remaining course (6 days) it demonstrated a significant microbistatic effect compared to OCT, AG and the control. Quantitative results in the dressing eluate correlate with those of the solid biofilm model. Overall, AG- and OCT-containing dressings did not achieve the expected anti-biofilm efficacy, while C-IOD performed best. Chemical interaction with the biofilms extrapolymeric substance (EPS), visualized in the SEM, and dressing configuration (agent concentration and release pattern) are suspected to be responsible. The unexpected low and diverse results of the tested antimicrobial dressings indicate a necessity to rethink non-debridement anti-biofilm therapy. Focussing on the combination of biofilm-disruptive (for EPS structure) and antimicrobial (for residing microorganisms) features, as with C-IOD, using dehydration and iodine, appears reasonably complementary and an optimal solution, as suggested by the here presented in vitro data.
A Combined Acceptor Photobleaching and Donor Fluorescence Lifetime Imaging Microscopy Approach to Analyze Multi-Protein Interactions in Living Cells
Authors: Eckenstaler Robert , Benndorf Ralf A.
Published: May 2021

Protein–protein interaction studies often provide new insights, i.e., into the formation of protein complexes relevant for structural oligomerization, regulation of enzymatic activity or information transfer within signal transduction pathways. Mostly, biochemical approaches have been used to study such interactions, but their results are limited to observations from lysed cells. A powerful tool for the non-invasive investigation of protein–protein interactions in the context of living cells is the microscopic analysis of Förster Resonance Energy Transfer (FRET) among fluorescent proteins. Normally, FRET is used to monitor the interaction state of two proteins, but in addition, FRET studies have been used to investigate three or more interacting proteins at the same time. Here we describe a fluorescence microscopy-based method which applies a novel 2-step acceptor photobleaching protocol to discriminate between non-interacting, dimeric interacting and trimeric interacting states within a three-fluorophore setup. For this purpose, intensity- and fluorescence lifetime-related FRET effects were analyzed on representative fluorescent dimeric and trimeric FRET-constructs expressed in the cytosol of HEK293 cells. In particular, by combining FLIM- and intensity-based FRET data acquisition and interpretation, our method allows to distinguish trimeric from different types of dimeric (single-, double- or triple-dimeric) protein–protein interactions of three potential interaction partners in the physiological setting of living cells.
Understanding Systemic and Local Inflammation Induced by Nasal Polyposis: Role of the Allergic Phenotype
Authors: Delgado-Dolset María Isabel , Obeso David , Sánchez-Solares Javier , Mera-Berriatua Leticia , Fernández Paloma , Barbas Coral , Fresnillo Miguel , Chivato Tomás , Barber Domingo , Escribese María M. , Villaseñor Alma
Published: May 2021

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by persistent symptoms associated to the development of nasal polyps. To this day, the molecular mechanisms involved are still not well defined. However, it has been suggested that a sustained inflammation as allergy is involved in its onset. In this exploratory study, the aim was to investigate the effect of the allergic status in the development of CRSwNP. To achieve this, we recruited 22 patients with CRSwNP and classified them in non-allergic and allergic using ImmunoCAP ISAC molecular diagnosis. Plasma samples were analyzed using liquid chromatography coupled to mass spectrometry (LC-MS). Subsequently, significant metabolites from plasma that were commercially available were then analyzed by targeted analysis in some nasal polyps. Additionally, nasal polyp and nasal mucosa samples were examined for eosinophils, neutrophils, CD3+ and CD11c+ cells, as well as collagen deposition and goblet cell hyperplasia. We found that 9 out of the 22 patients were sensitized to some aeroallergens (named as allergic CRSwNP). The other 13 patients had no sensitizations (non-allergic CRSwNP). Regarding metabolomics, bilirubin, cortisol, lysophosphatidylcholines (LPCs) 16:0, 18:0 and 20:4 and lysophosphatidylinositol (LPI) 20:4, which are usually related to a sustained allergic inflammation, were unexpectedly increased in plasma of non-allergic CRSwNP compared to allergic CRSwNP. LPC 16:0, LPC 18:0 and LPI 20:4 followed the same trend in nasal polyp as they did in plasma. Comparison of nasal polyps with nasal mucosa showed a significant increase in eosinophils (p < 0.001) and neutrophils (p < 0.01) in allergic CRSwNP. There were more eosinophils in polyps of non-allergic CRSwNP than in their nasal mucosa (p < 0.01). Polyps from non-allergic CRSwNP had less eosinophils than the polyps of allergic CRSwNP (p < 0.05) and reduced amounts of collagen compared to their nasal mucosa (p < 0.001). Our data suggests that there is a systemic inflammatory response associated to CRSwNP in the absence of allergy, which could be accountable for the nasal polyp development. Allergic CRSwNP presented a higher number of eosinophils in nasal polyps, suggesting that eosinophilia might be connected to the development of nasal polyps in this phenotype.
The Functional Role of Sphingosine Kinase 2
Authors: Diaz Escarcega Rocio , McCullough Louise D. , Tsvetkov Andrey S.
Published: May 2021

Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule that is present in all eukaryotic cells and plays key roles in various extracellular, cytosolic, and nuclear signaling pathways. Two sphingosine kinase isoforms, sphingosine kinase 1 (SPHK1) and sphingosine kinase 2 (SPHK2), synthesize S1P by phosphorylating sphingosine. While SPHK1 is a cytoplasmic kinase, SPHK2 is localized to the nucleus, endoplasmic reticulum, and mitochondria. The SPHK2/S1P pathway regulates transcription, telomere maintenance, mitochondrial respiration, among many other processes. SPHK2 is under investigation as a target for treating many age-associated conditions, such as cancer, stroke, and neurodegeneration. In this review, we will focus on the role of SPHK2 in health and disease.
Systematic Review and Methodological Considerations for the Use of Single Prolonged Stress and Fear Extinction Retention in Rodents
Authors: Ferland-Beckham Chantelle , Chaby Lauren E. , Daskalakis Nikolaos P. , Knox Dayan , Liberzon Israel , Lim Miranda M. , McIntyre Christa , Perrine Shane A. , Risbrough Victoria B. , Sabban Esther L. , Jeromin Andreas , Haas Magali
Published: May 2021

Posttraumatic stress disorder (PTSD) is a mental health condition triggered by experiencing or witnessing a terrifying event that can lead to lifelong burden that increases mortality and adverse health outcomes. Yet, no new treatments have reached the market in two decades. Thus, screening potential interventions for PTSD is of high priority. Animal models often serve as a critical translational tool to bring new therapeutics from bench to bedside. However, the lack of concordance of some human clinical trial outcomes with preclinical animal efficacy findings has led to a questioning of the methods of how animal studies are conducted and translational validity established. Thus, we conducted a systematic review to determine methodological variability in studies that applied a prominent animal model of trauma-like stress, single prolonged stress (SPS). The SPS model has been utilized to evaluate a myriad of PTSD-relevant outcomes including extinction retention. Rodents exposed to SPS express an extinction retention deficit, a phenotype identified in humans with PTSD, in which fear memory is aberrantly retained after fear memory extinction. The current systematic review examines methodological variation across all phases of the SPS paradigm, as well as strategies for behavioral coding, data processing, statistical approach, and the depiction of data. Solutions for key challenges and sources of variation within these domains are discussed. In response to methodological variation in SPS studies, an expert panel was convened to generate methodological considerations to guide researchers in the application of SPS and the evaluation of extinction retention as a test for a PTSD-like phenotype. Many of these guidelines are applicable to all rodent paradigms developed to model trauma effects or learned fear processes relevant to PTSD, and not limited to SPS. Efforts toward optimizing preclinical model application are essential for enhancing the reproducibility and translational validity of preclinical findings, and should be conducted for all preclinical psychiatric research models.
Silencing of Long Noncoding RNA Growth Arrest–Specific 5 Alleviates Neuronal Cell Apoptosis and Inflammatory Responses Through Sponging microRNA-93 to Repress PTEN Expression in Spinal Cord Injury
Authors: Cao Yuanwu , Jiang Chang , Lin Haodong , Chen Zixian
Published: May 2021

A secondary injury induced by a spinal cord injury (SCI) remains the main cause of devastating neural dysfunction; therefore, it has been the subject of focused research for many years. Long noncoding RNA (lncRNA) has been found to participate in the SCI process, and this finding presents a high potential for diagnosis and treatment; however, the role of lncRNA in a secondary injury induced by SCI remains unclear. The aim of this study was to investigate the regulatory effect of lncRNA growth arrest–specific transcript 5 (GAS5) in secondary injury during SCI. The SCI mice model and hypoxic cellular model were established to research the roles of lncRNA GAS5 during SCI. Reverse transcription quantitative polymerase chain reaction (qRT-PCR) was conducted to determine the expression levels of microR-93 (miR-93) and lncRNA GAS5. Western blot analysis of the apoptosis regulator protein and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was conducted to evaluate neuron cell apoptosis. Basso, Beattie, and Bresnahan (BBB) scores were calculated to assess neurological function. Flow cytometry was used to determine neuron cell apoptosis. The associations among GAS5, miR-93, and the phosphatase and tensin homolog (PTEN) were disclosed using RNA immunoprecipitation (RIP) assay, RNA pulldown assay, and dual-luciferase reporter assay. QRT-PCR demonstrated that GAS5 was significantly upregulated in both the SCI mice and hypoxic cellular models. GAS5 knockdown suppressed neuron cell apoptosis and inflammatory response in the SCI mice model. Further studies have indicated that GAS5 functions as a competing endogenous RNA (ceRNA) by sponging miR-93 in neuronal cells. In addition, PTEN was a target of miR-93, and GAS5 knockdown exhibited its anti-apoptotic and anti-inflammatory effects through the miR-93/PTEN axis. These findings suggest that the GAS5/miR-93/PTEN axis may be a promising therapeutic target for SCI.