bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Ligament Mapping from Different Magnetic Resonance Image Quality on Joint Stability in a Personalized Dynamic Model of the Human Ankle Complex
Authors: Campagnoli Elena , Siegler Sorin , Ruiz Maria , Leardini Alberto , Belvedere Claudio
Published: May 2022

Background. Mechanical models of the human ankle complex are used to study the stabilizing role of ligaments. Identification of ligament function may be improved via image-based personalized approach. The aim of this study is to compare the effect of the ligament origin and insertion site definitions obtained with different magnetic resonance imaging (MRI) modalities on the mechanical behaviour of a dynamic model of the ankle complex. Methods. MRI scans, both via 1.5 T and 3.0 T, were performed on a lower-limb specimen, free from anatomical defects, to obtain morphological information on ligament-to-bone attachment sites. This specimen was used previously to develop the dynamic model. A third ligament attachment site mapping scheme was based on anatomical dissection of the scanned specimen. Following morphological comparison of the ligament attachment sites, their effect on the mechanical behaviour of the ankle complex, expressed by three-dimensional load–displacement properties, was assessed through the model. Results. Large differences were observed in the subtalar ligament attachment sites between those obtained through the two MRI scanning modalities. The 3.0 T MRI mapping was more consistent with dissection than the 1.5 T MRI. Load–displacement curves showed similar mechanical behaviours between the three mappings in the frontal plane, but those obtained from the 3.0 T MRI mapping were closer to those obtained from dissection. Conclusions. The state-of-the-art 3.0 T MRI image analysis resulted in more realistic mapping of ligament fibre origin and insertion site definitions; corresponding load–displacement predictions from a subject-specific model of the ankle complex showed a mechanical behaviour more similar to that using direct ligament attachment observations.
Modelling Soil Temperature by Tree-Based Machine Learning Methods in Different Climatic Regions of China
Authors: Dong Jianhua , Huang Guomin , Wu Lifeng , Liu Fa , Li Sien , Cui Yaokui , Wang Yicheng , Leng Menghui , Wu Jie , Wu Shaofei
Published: May 2022

Accurate estimation of soil temperature (Ts) at a national scale under different climatic conditions is important for soil–plant–atmosphere interactions. This study estimated daily Ts at the 0 cm depth for 689 meteorological stations in seven different climate zones of China for the period 1966–2015 with the M5P model tree (M5P), random forests (RF), and the extreme gradient boosting (XGBoost). The results showed that the XGBoost model (averaged coefficient of determination (R2) = 0.964 and root mean square error (RMSE) = 2.066 °C) overall performed better than the RF (averaged R2 = 0.959 and RMSE = 2.130 °C) and M5P (averaged R2 = 0.954 and RMSE = 2.280 °C) models for estimating Ts with higher computational efficiency. With the combination of mean air temperature (Tmean) and global solar radiation (Rs) as inputs, the estimating accuracy of the models was considerably high (averaged R2 = 0.96–0.97 and RMSE = 1.73–1.99 °C). On the basis of Tmean, adding Rs to the model input had a greater degree of influence on model estimating accuracy than adding other climatic factors to the input. Principal component analysis indicated that soil organic matter, soil water content, Tmean, relative humidity (RH), Rs, and wind speed (U2) are the main factors that cause errors in estimating Ts, and the total error interpretation rate was 97.9%. Overall, XGBoost would be a suitable algorithm for estimating Ts in different climate zones of China, and the combination of Tmean and Rs as model inputs would be more practical than other input combinations.
Parametric Analyses of the Response of Masonry Walls with Reinforced Plaster
Authors: Scamardo Manuela , Cattaneo Sara , Biolzi Luigi , Vafa Navid
Published: May 2022

This paper presents the results of a parametric study on the response of unreinforced and retrofitted masonry specimens. The adopted strengthening technique is the steel-reinforced plaster, which is very commonly used but it is not supported by a proper theoretical and experimental characterization in the scientific literature. The aim was to investigate the main parameters that affect the structural performances of the walls. Several numerical models were implemented using the finite element method to analyze the influence of the bricks’ arrangements, the mechanical properties of the mortar joints, the number of connectors, and the mechanical properties and thickness of the plaster coating. A concrete damage plasticity model was adopted to describe the bricks, the mortar joints, and the plaster behaviors. For the unreinforced specimens, the outcomes confirmed that the mortar strength had a significant influence on the performance of the wall, together with the presence of potential weaknesses in the bricks, while the bond effect was negligible. For reinforced walls, the connectors do not have a significant influence on retrofitted wall capacity but may prevent instability if a proper number is considered. Furthermore, the strength of the plaster coating does not affect the collapse load significantly, while increasing the fracture energy, which can be produced, for instance, by using fiber-reinforced concrete, increases the capacity of retrofitted walls, with more limited damage. Finally, an increase in the plaster thickness may be beneficial in terms of collapse load, even though greater thickness may increase the seismic masses significantly.
Special Issue: Advancement in Biomonitoring and Remediation Treatments of Pollutants in Aquatic Environments
Authors: Ferri Elida Nora
Published: May 2022

A series of negative, attendant circumstances threaten the ecological equilibrium, the quality, and even the existence of the different aquatic ecosystems nowadays more than ever [...]
Fusing Local and Global Information for One-Step Multi-View Subspace Clustering
Authors: Duan Yiqiang , Yuan Haoliang , Lai Chun Sing , Lai Loi Lei
Published: May 2022

Multi-view subspace clustering has drawn significant attention in the pattern recognition and machine learning research community. However, most of the existing multi-view subspace clustering methods are still limited in two aspects. (1) The subspace representation yielded by the self-expression reconstruction model ignores the local structure information of the data. (2) The construction of subspace representation and clustering are used as two individual procedures, which ignores their interactions. To address these problems, we propose a novel multi-view subspace clustering method fusing local and global information for one-step multi-view clustering. Our contribution lies in three aspects. First, we merge the graph learning into the self-expression model to explore the local structure information for constructing the specific subspace representations of different views. Second, we consider the multi-view information fusion by integrating these specific subspace representations into one common subspace representation. Third, we combine the subspace representation learning, multi-view information fusion, and clustering into a joint optimization model to realize the one-step clustering. We also develop an effective optimization algorithm to solve the proposed method. Comprehensive experimental results on nine popular multi-view data sets confirm the effectiveness and superiority of the proposed method by comparing it with many state-of-the-art multi-view clustering methods.
Feature Residual Analysis Network for Building Extraction from Remote Sensing Images
Authors: Miao Yuqi , Jiang Shanshan , Xu Yiming , Wang Dongjie
Published: May 2022

Building extraction of remote sensing images is very important for urban planning. In the field of deep learning, in order to extract more detailed building features, more complex convolution operations and larger network models are usually used to segment buildings, resulting in low efficiency of automatic extraction. The existing network is difficult to balance the extraction accuracy and extraction speed. Considering the segmentation accuracy and speed, a Feature Residual Analysis Network (FRA-Net) is proposed to realize fast and accurate building extraction. The whole network includes two stages: encoding and decoding. In the encoding stage, a Separable Residual Module (SRM) is designed to extract feature information and extract building features from remote sensing images, avoiding the use of large convolution kernels to reduce the complexity of the model. In the decoding stage, the SRM is used for information decoding, and a multi-feature attention module is constructed to enhance the effective information. The experimental results on the LandCover dataset and Massachusetts Buildings dataset show that the reasoning speed has been greatly improved without reducing the segmentation accuracy.
Life-Cycle Cost Analysis on Application of Asphalt and Concrete Pavement Overlay
Authors: Jung Haekook , Oli Topendra , Nam Jeonghee , Yun Kyongku , Kim Seungwon , Park Cheolwoo
Published: May 2022

Concrete pavement proportions are increasing in Korean expressways, resulting in increased maintenance cost. The length of degenerate concrete pavements that have exceeded the design life (20 years) was 1150 km in 2015 and 2605 km in 2020 and is expected to rapidly increase. To extend the service life of concrete pavements, life-cycle cost (LCC) analysis was conducted on asphalt and concrete overlays, based on the different maintenance methods. LCC analysis was performed when the shoulder was used and when it was not used between 6000 and 35,000 AADT traffic according to the two-lane and four-lane traffic. During overlay, one lane was completely blocked, and the value per vehicle was converted into the user cost using the Construction Analysis for Pavement Rehabilitation Strategies software, according to whether the shoulder was used to maintain the number of lanes. In addition, LCC analysis was conducted by examining the construction cost and life-cycle according to each overlay method. When the shoulder was used, the total construction cost decreased, owing to the reduction in user cost, indicating that the implementation of the traffic measure of using the road shoulder improves user satisfaction and cost. The asphalt overlay was observed to be more favorable than concrete overlay in terms of the initial total construction cost. However, under a 20-year cycle, the economic efficiency of concrete overlay was higher than that of asphalt overlay. After repairing the deteriorated target sections of concrete pavements, the overlay method (asphalt or concrete) ought to be selected according to the target service life for beneficial economic effect. Concrete overlay was to obtain about 20% or greater LCC effect compared to asphalt overlay, and at least 5% or more additional LCC effect obtained when the shoulder was used.
Analysis of Functional Layout in Emergency Departments (ED). Shedding Light on the Free Standing Emergency Department (FSED) Model
Authors: Brambilla Andrea , Mangili Silvia , Das Mohana , Lal Sanchit , Capolongo Stefano
Published: May 2022

The ever-increasing number of hospital Emergency Department (ED) visits pose a challenge to the effective running of health systems in many countries globally and multiple strategies have been adopted over the years to tackle the plight. According to a systematic review of the available literature, of the numerous models of healthcare systems used to address the issue in western countries, the FSED Model has the greatest potential for reducing hospital ED overcrowding as it can reduce the additional load by diverting minor cases, freeing up space for more urgent cases. The aim of the study is to shed light on the Free Standing Emergency Department (FSED) model and compare it with the traditional Hospital Based Emergency Department (HBED) in international contexts. In this study, 23 papers have been collected in a literature review and the main features have been highlighted; 12 case studies have been analyzed from a layout point of view and data have been collected in terms of surfaces, functions, and flow patterns. The percentages of floor areas devoted to each function have been compared to define evolution strategies in the development of emergency healthcare models and analyses. The use of FSED models is an interesting way to face the overcrowding problem and a specific range for functional area layout has been identified. Further studies on its application in different contexts are encouraged.
Approaches to Combat the Polysulfide Shuttle Phenomenon in Li–S Battery Technology
Authors: Suzanowicz Artur , Mei Cindy , Mandal Braja
Published: May 2022

Lithium–sulfur battery (LSB) technology has tremendous prospects to substitute lithium-ion battery (LIB) technology due to its high energy density. However, the escaping of polysulfide intermediates (produced during the redox reaction process) from the cathode structure is the primary reason for rapid capacity fading. Suppressing the polysulfide shuttle (PSS) is a viable solution for this technology to move closer to commercialization and supersede the established LIB technology. In this review, we have analyzed the challenges faced by LSBs and outlined current methods and materials used to address these problems. We conclude that in order to further pioneer LSBs, it is necessary to address these essential features of the sulfur cathode: superior electrical conductivity to ensure faster redox reaction kinetics and high discharge capacity, high pore volume of the cathode host to maximize sulfur loading/utilization, and polar PSS-resistive materials to anchor and suppress the migration of polysulfides, which can be developed with the use of nanofabrication and combinations of the PSS-suppressive qualities of each component. With these factors addressed, our world will be able to forge ahead with the development of LSBs on a larger scale—for the efficiency of energy systems in technology advancement and potential benefits to outweigh the costs and performance decay.
Application of Sygen® in Diabetic Peripheral Neuropathies—A Review of Biological Interactions
Authors: Coelho Marcelo Amaral , Jeyaraman Madhan , Jeyaraman Naveen , Rajendran Ramya Lakshmi , Sugano André Atsushi , Mosaner Tomas , Santos Gabriel Silva , Bizinotto Lana João Vitor , Lana Anna Vitória Santos Duarte , da Fonseca Lucas Furtado , Domingues Rafael Barnabé , Gangadaran Prakash , Ahn Byeong-Cheol , Lana José Fábio Santos Duarte
Published: May 2022

This study investigates the role of Sygen® in diabetic peripheral neuropathy, a severe disease that affects the peripheral nervous system in diabetic individuals. This disorder often impacts the lower limbs, causing significant discomfort and, if left untreated, progresses into more serious conditions involving chronic ulcers and even amputation in many cases. Although there are management strategies available, peripheral neuropathies are difficult to treat as they often present multiple causes, especially due to metabolic dysfunction in diabetic individuals. Gangliosides, however, have long been studied and appreciated for their role in neurological diseases. The monosialotetrahexosylganglioside (GM1) ganglioside, popularly known as Sygen, provides beneficial effects such as enhanced neuritic sprouting, neurotrophism, neuroprotection, anti-apoptosis, and anti-excitotoxic activity, being particularly useful in the treatment of neurological complications that arise from diabetes. This product mimics the roles displayed by neurotrophins, improving neuronal function and immunomodulation by attenuating exacerbated inflammation in neurons. Furthermore, Sygen assists in axonal stabilization and keeps nodal and paranodal regions of myelin fibers organized. This maintains an adequate propagation of action potentials and restores standard peripheral nerve function. Given the multifactorial nature of this complicated disorder, medical practitioners must carefully screen the patient to avoid confusion and misdiagnosis. There are several studies analyzing the role of Sygen in neurological disorders. However, the medical literature still needs more robust investigations such as randomized clinical trials regarding the administration of this compound for diabetic peripheral neuropathies, specifically.
Adipose Tissue Extracellular Matrix Remodeling in Response to Dietary Patterns and Exercise: Molecular Landscape, Mechanistic Insights, and Therapeutic Approaches
Authors: de Sousa Neto Ivo Vieira , Durigan João Luiz Quagliotti , da Silva Adelino Sanchez Ramos , de Cássia Marqueti Rita
Published: May 2022

The extracellular matrix (ECM) is a 3-dimensional network of molecules that play a central role in differentiation, migration, and survival for maintaining normal homeostasis. It seems that ECM remodeling is required for adipose tissue expansion. Despite evidence indicating that ECM is an essential component of tissue physiology, adipose tissue ECM has received limited attention. Hence, there is great interest in approaches to neutralize the harmful effects of ECM enlargement. This review compiles and discusses the current literature on adipose tissue ECM remodeling in response to different dietary patterns and exercise training. High-calorie diets result in substantial adipose tissue ECM remodeling, which in turn could lead to fibrosis (excess deposition of collagens, elastin, and fibronectin), inflammation, and the onset of metabolic dysfunction. However, combining a nutritionally balanced diet with exercise is a remarkable potential strategy for lipolytic activity, preventing rapid ECM expansion in different adipose tissue depots. Despite the distinct exercise modalities (aerobic or resistance exercise) reversing adipose tissue fibrosis in animal models, the beneficial effect on humans remains controversial. Defining molecular pathways and specific mechanisms that mediate the positive effects on adipose tissue, ECM is essential in developing optimized interventions to improve health and clinical outcomes.
Characterization of Microbial Shifts during the Production and Ripening of Raw Ewe Milk-Derived Idiazabal Cheese by High-Throughput Sequencing
Authors: Santamarina-García Gorka , Hernández Igor , Amores Gustavo , Virto Mailo
Published: May 2022

In this study, we used high-throughput sequencing technologies (sequencing of V3–V4 hypervariable regions of 16S rRNA gene) to investigate for the first time the microbiota of Latxa ewe raw milk and the bacterial shifts that occur during the production and ripening of Idiazabal cheese. Results revealed several bacterial genera not reported previously in raw ewe milk and cheese, such as Buttiauxella and Obesumbacterium. Both the cheese making and ripening processes had a significant impact on bacterial communities. Overall, the growth of lactic acid bacteria (LAB) (Lactococcus, Lactobacillus, Leuconostoc, Enterococcus, Streptococcus and Carnobacterium) was promoted, whereas that of non-desirable and environmental bacteria was inhibited (such as Pseudomonas and Clostridium). However, considerable differences were observed among producers. It is noteworthy that the starter LAB (Lactococcus) predominated up to 30 or 60 days of ripening and then, the growth of non-starter LAB (Lactobacillus, Leuconostoc, Enterococcus and Streptococcus) was promoted. Moreover, in some cases, bacteria related to the production of volatile compounds (such as Hafnia, Brevibacterium and Psychrobacter) also showed notable abundance during the first few weeks of ripening. Overall, the results of this study enhance our understanding of microbial shifts that occur during the production and ripening of a raw ewe milk-derived cheese (Idiazabal), and could indicate that the practices adopted by producers have a great impact on the microbiota and final quality of this cheese.
Expression and Role of β3-Adrenergic Receptor during the Differentiation of 3T3-L1 Preadipocytes into Adipocytes
Authors: Roshanzadeh Amir , Yadav Anil Kumar , Pydi Sai-Prasad , Kimura Takefumi , Jang Byeong-Churl
Published: May 2022

β3-adrenergic receptor (β3-AR) is expressed predominantly in mature white and brown/beige adipocytes. Although the lipolytic and thermogenic role of β3-AR in brown/beige adipocytes is well defined, the adipogenic role of β3-AR in white adipocytes remains unclear at present. In this study, we investigated the expression and function of β3-AR in differentiating 3T3-L1 cells, murine white preadipocytes. Of note, the expression of β3-AR at the protein and mRNA levels was highly induced in a time-dependent manner during 3T3-L1 preadipocyte differentiation. Interestingly, the results of the pharmacological inhibition study demonstrated the roles of p38 MAPK and PKC in the induction of β3-AR expression in differentiating 3T3-L1 cells. Knockdown of β3-AR led to less lipid accumulation and triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. Furthermore, knockdown of β3-AR resulted in a decrease in not only expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FASN), perilipin A, and leptin but also phosphorylation levels of signal transducer and activator of transcription-5 (STAT-5) during 3T3-L1 preadipocyte differentiation. In summary, these results demonstrate firstly that β3-AR expression is highly up-regulated in p38 MAPK and PKC-dependent manners, and the up-regulated β3-AR plays a crucial role in lipid accumulation in differentiating 3T3-L1 cells, which is mediated through control of expression and phosphorylation levels of C/EBP-α, PPAR-γ, STAT-5, FASN, and perilipin A.
Metabolic Engineering and Regulation of Diol Biosynthesis from Renewable Biomass in Escherichia coli
Authors: Wu Tong , Liu Yumei , Liu Jinsheng , Chen Zhenya , Huo Yi-Xin
Published: May 2022

As bulk chemicals, diols have wide applications in many fields, such as clothing, biofuels, food, surfactant and cosmetics. The traditional chemical synthesis of diols consumes numerous non-renewable energy resources and leads to environmental pollution. Green biosynthesis has emerged as an alternative method to produce diols. Escherichia coli as an ideal microbial factory has been engineered to biosynthesize diols from carbon sources. Here, we comprehensively summarized the biosynthetic pathways of diols from renewable biomass in E. coli and discussed the metabolic-engineering strategies that could enhance the production of diols, including the optimization of biosynthetic pathways, improvement of cofactor supplementation, and reprogramming of the metabolic network. We then investigated the dynamic regulation by multiple control modules to balance the growth and production, so as to direct carbon sources for diol production. Finally, we proposed the challenges in the diol-biosynthesis process and suggested some potential methods to improve the diol-producing ability of the host.
Effect of Locally Delivered Minocycline on the Profile of Subgingival Bacterial Genera in Patients with Periodontitis: A Prospective Pilot Study
Authors: Morozumi Toshiya , Nakayama Yohei , Shirakawa Satoshi , Imamura Kentaro , Nohno Kaname , Nagano Takatoshi , Miyazawa Haruna , Hokari Takahiro , Takuma Ryo , Sugihara Shuntaro , Gomi Kazuhiro , Saito Atsushi , Ogata Yorimasa , Komaki Motohiro
Published: May 2022

This prospective pilot study aimed to evaluate the effect of minocycline-HCl ointment (MO), locally delivered as an adjunct to scaling and root planing (SRP), on subgingival microflora. A total of 59 periodontitis patients received SRP as an initial periodontal therapy. In the selected periodontal pockets with probing depths (PD) of 6–9 mm, the sites that exhibited a positive reaction following a bacterial test using an immunochromatographic device were subsequently treated with MO (SRP + MO group, n = 25). No additional treatment was performed at sites showing a negative reaction (SRP group, n = 34). In addition to subgingival plaque sampling, measurement of clinical parameters including PD, clinical attachment level (CAL), bleeding on probing (BOP), plaque index and gingival index (GI) were performed at baseline and 4 weeks after the initial periodontal therapy. The subgingival microflora were assessed by terminal restriction fragment-length polymorphism analysis. Relative to baseline values, the mean scores for PD-, CAL-, BOP-, and GI-sampled sites were significantly decreased post treatment in both groups (p < 0.01). The intra-comparisons showed a significant decrease in the counts of the genera Eubacterium, Parvimonas, Filifactor, Veillonella, Fusobacterium, Porphyromonas, Prevotella, and unknown species in the SRP + MO group (p < 0.05). Inter-comparisons indicated a significant decrease in the genera Veillonella in the SRP + MO group (p = 0.01). Combination therapy of SRP and local MO induced a change in the subgingival microbial community: particularly, the number of Veillonella spp. was markedly reduced.
Perspective: Chicken Models for Studying the Ontogenetic Origin of Neuropsychiatric Disorders
Authors: Huang Xiaohong , Cheng Heng-wei
Published: May 2022

Nutrients and xenobiotics cross the blood–placenta barrier, potentially depositing in the fetal brain. The prenatal exposure affects the neuroendocrine and microbial development. The mechanism underlying maternal risk factors reprograming the microbiota–gut–brain axis with long-term effects on psychosocial behaviors in offspring is not clear. In humans, it is not possible to assess the nutrient or xenobiotic deposition in the fetal brain and gastrointestinal system for ethical reasons. Moreover, the maternal–fetal microbe transfer during gestation, natural labor, and breast-feeding constitutes the initial gut microbiome in the progeny, which is inevitable in the most widely utilized rodent models. The social predisposition in precocial birds, including chickens, provides the possibility to test behavioral responses shortly after being hatched. Hence, chickens are advantageous in investigating the ontogenetic origin of behaviors. Chicken embryos are suitable for deposition assessment and mechanistic study due to the accessibility, self-contained development, uniform genetic background, robust microbiota, and easy in vivo experimental manipulation compared to humans and rodents. Therefore, chicken embryos can be used as an alternative to the rodent models in assessing the fetal exposure effect on neurogenesis and investigating the mechanism underlying the ontogenetic origin of neuropsychiatric disorders.
Extrahepatic Disease in Hepatocellular Carcinoma: Do We Always Need Whole-Body CT or Is Liver MRI Sufficient? A Subanalysis of the SORAMIC Trial
Authors: Geyer Thomas , Kazmierczak Philipp M. , Steffen Ingo G. , Malfertheiner Peter , Peynircioglu Bora , Loewe Christian , Delden Otto van , Vandecaveye Vincent , Gebauer Bernhard , Pech Maciej , Sengel Christian , Bargellini Irene , Iezzi Roberto , Benito Alberto , Zech Christoph J. , Gasbarrini Antonio , Schütte Kerstin , Ricke Jens , Seidensticker Max
Published: May 2022

Background: To investigate whole-body contrast-enhanced CT and hepatobiliary contrast liver MRI for the detection of extrahepatic disease (EHD) in hepatocellular carcinoma (HCC) and to quantify the impact of EHD on therapy decision. Methods: In this post-hoc analysis of the prospective phase II open-label, multicenter, randomized controlled SORAMIC trial, two blinded readers independently analyzed the whole-body contrast-enhanced CT and gadoxetic acid-enhanced liver MRI data sets of 538 HCC patients. EHD (defined as tumor manifestation outside the liver) detection rates of the two imaging modalities were compared using multiparametric statistical tests. In addition, the most appropriate treatment recommendation was determined by a truth panel. Results: EHD was detected significantly more frequently in patients with portal vein infiltration (21% vs. 10%, p < 0.001), macrovascular infiltration (22% vs. 9%, p < 0.001), and bilobar liver involvement (18% vs. 9%, p = 0.006). Further on, the maximum lesion diameter in patients with EHD was significantly higher (8.2 cm vs. 5.8 cm, p = 0.002). CT detected EHD in significantly more patients compared to MRI in both reader groups (p < 0.001). Higher detection rates of EHD in CT led to a change in management only in one patient since EHD was predominantly present in patients with locally advanced HCC, in whom palliative treatment is the standard of care. Conclusions: Whole-body contrast-enhanced CT shows significantly higher EHD detection rates compared to hepatobiliary contrast liver MRI. However, the higher detection rate did not yield a significant impact on patient management in advanced HCC.
The Use of Machine Learning Algorithms and the Mass Spectrometry Lipidomic Profile of Serum for the Evaluation of Tacrolimus Exposure and Toxicity in Kidney Transplant Recipients
Authors: Burghelea Dan , Moisoiu Tudor , Ivan Cristina , Elec Alina , Munteanu Adriana , Iancu Ștefania D. , Truta Anamaria , Kacso Teodor Paul , Antal Oana , Socaciu Carmen , Elec Florin Ioan , Kacso Ina Maria
Published: May 2022

Tacrolimus has a narrow therapeutic window; a whole-blood trough target concentration of between 5 and 8 ng/mL is considered a safe level for stable kidney transplant recipients. Tacrolimus serum levels must be closely monitored to obtain a balance between maximizing efficacy and minimizing dose-related toxic effects. Currently, there is no specific tacrolimus toxicity biomarker except a graft biopsy. Our study aimed to identify specific serum metabolites correlated with tacrolinemia levels using serum high-precision liquid chromatography–mass spectrometry and standard laboratory evaluation. Three machine learning algorithms were used (Naïve Bayes, logistic regression, and Random Forest) in 19 patients with high tacrolinemia (8 ng/mL) and 23 patients with low tacrolinemia (5 ng/mL). Using a selected panel of five lipid metabolites (phosphatidylserine, phosphatidylglycerol, phosphatidylethanolamine, arachidyl palmitoleate, and ceramide), Mg2+, and uric acid, all three machine learning algorithms yielded excellent classification accuracies between the two groups. The highest classification accuracy was obtained by Naïve Bayes, with an area under the curve of 0.799 and a classification accuracy of 0.756. Our results show that using our identified five lipid metabolites combined with Mg2+ and uric acid serum levels may provide a novel tool for diagnosing tacrolimus toxicity in kidney transplant recipients. Further validation with targeted MS and biopsy-proven TAC toxicity is needed.
Combination of Elacridar with Imatinib Modulates Resistance Associated with Drug Efflux Transporters in Chronic Myeloid Leukemia
Authors: Alves Raquel , Gonçalves Ana Cristina , Jorge Joana , Almeida António M. , Sarmento-Ribeiro Ana Bela
Published: May 2022

Multidrug resistance (MDR) development has emerged as a complication that compromises the success of several chemotherapeutic agents. In chronic myeloid leukemia (CML), imatinib resistance has been associated with changes in BCR-ABL1 and intracellular drug concentration, controlled by SLC and ABC transporters. We evaluate the therapeutic potential of a P-glycoprotein and BCRP inhibitor, elacridar, in sensitive (K562 and LAMA-84) and imatinib-resistant (K562-RC and K562-RD) CML cell lines as monotherapy and combined with imatinib. Cell viability was analyzed by resazurin assay. Drug transporter activity, cell death, cell proliferation rate, and cell cycle distribution were analyzed by flow cytometry. Both resistant models presented an increased activity of BCRP and P-gP compared to K562 cells. Elacridar as monotherapy did not reach IC50 in any CML models but activated apoptosis without cytostatic effect. Nevertheless, the association of elacridar (250 nM) with imatinib overcomes resistance, re-sensitizing K562-RC and K562-RD cells with five and ten times lower imatinib concentrations, respectively. Drug combination induced apoptosis with increased cleaved-caspases-3, cleaved-PARP and DNA damage, reduced cell proliferation rate, and arrested CML cells in the S phase. These data suggest that elacridar combined with imatinib might represent a new therapeutic option for overcoming TKI resistance involving efflux transporters.
Altered Ocular Surface Health Status and Tear Film Immune Profile Due to Prolonged Daily Mask Wear in Health Care Workers
Authors: D’Souza Sharon , Vaidya Tanuja , Nair Archana Padmanabhan , Shetty Rohit , Kumar Nimisha Rajiv , Bisht Anadi , Panigrahi Trailokyanath , J Tejal S. , Khamar Pooja , Dickman Mor M. , Agrawal Ruchika , Mahajan Sanjay , Sengupta Sneha , Nuijts Rudy M. M. A. , Sethu Swaminathan , Ghosh Arkasubhra
Published: May 2022

Prolonged daily face mask wearing over several months might affect health of the ocular surface and is reported to be associated with complaints of discomfort and dry-eye-like symptoms. We studied the ocular surface clinical parameters, tear soluble factors and immune cell proportions in ophthalmologists practicing within similar environmental conditions (n = 17) at two time points: pre-face-mask period (Pre-FM; end of 2019) and post-face-mask-wearing period (Post-FM; during 2020 COVID-19 pandemic), with continuous (~8 h/day) mask wear. A significant increase in ocular surface disease index (OSDI) scores without changes in tear breakup time (TBUT), Schirmer’s test 1 (ST1) and objective scatter index (OSI) was observed Post-FM. Tear soluble factors (increased—IL-1β, IL-33, IFNβ, NGF, BDNF, LIF and TSLP; decreased—IL-12, IL-13, HGF and VEGF-A) and mucins (MUC5AC) were significantly altered Post-FM. Ex vivo, human donor and corneoscleral explant cultures under elevated CO2 stress revealed that the molecular profile, particularly mucin expression, was similar to the Post-FM tear molecular profile, suggesting hypercapnia is a potential contributor to ocular surface discomfort. Among the immune cell subsets determined from ocular surface wash samples, significantly higher proportions of leukocytes and natural killer T cells were observed in Post-FM compared to Pre-FM. Therefore, it is important to note that the clinical parameters, tear film quality, tear molecular factors and immune cells profile observed in prolonged mask-wear-associated ocular surface discomfort were distinct from dry eye disease or other common ocular surface conditions. These observations are important for differential diagnosis as well as selection of appropriate ocular surface treatment in such subjects.
Sleep Disturbance Alters Cocaine-Induced Locomotor Activity: Involvement of Striatal Neuroimmune and Dopamine Signaling
Authors: Roodsari Soheil Kazemi , Cheng Yan , Reed Kirstin M. , Wellman Laurie L. , Sanford Larry D. , Kim Woong-Ki , Guo Ming-Lei
Published: May 2022

Sleep disorders have high comorbidity with drug addiction and function as major risk factors for developing drug addiction. Recent studies have indicated that both sleep disturbance (SD) and abused drugs could activate microglia, and that increased neuroinflammation plays a critical role in the pathogenesis of both diseases. Whether microglia are involved in the contribution of chronic SDs to drug addiction has never been explored. In this study, we employed a mouse model of sleep fragmentation (SF) with cocaine treatment and examined their locomotor activities, as well as neuroinflammation levels and dopamine signaling in the striatum, to assess their interaction. We also included mice with, or without, SF that underwent cocaine withdrawal and challenge. Our results showed that SF significantly blunted cocaine-induced locomotor stimulation while having marginal effects on locomotor activity of mice with saline injections. Meanwhile, SF modulated the effects of cocaine on neuroimmune signaling in the striatum and in ex vivo isolated microglia. We did not observe differences in dopamine signaling in the striatum among treatment groups. In mice exposed to cocaine and later withdrawal, SF reduced locomotor sensitivity and also modulated neuroimmune and dopamine signaling in the striatum. Taken together, our results suggested that SF was capable of blunting cocaine-induced psychoactive effects through modulating neuroimmune and dopamine signaling. We hypothesize that SF could affect neuroimmune and dopamine signaling in the brain reward circuitry, which might mediate the linkage between sleep disorders and drug addiction.
Multi-Level Analysis of Adipose Tissue Reveals the Relevance of Perivascular Subpopulations and an Increased Endothelial Permeability in Early-Stage Lipedema
Authors: Strohmeier Karin , Hofmann Martina , Jacak Jaroslaw , Narzt Marie-Sophie , Wahlmueller Marlene , Mairhofer Mario , Schaedl Barbara , Holnthoner Wolfgang , Barsch Martin , Sandhofer Matthias , Wolbank Susanne , Priglinger Eleni
Published: May 2022

Lipedema is a chronic, progressive disease of adipose tissue with unknown etiology. Based on the relevance of the stromal vascular fraction (SVF) cell population in lipedema, we performed a thorough characterization of subcutaneous adipose tissue, SVF isolated thereof and the sorted populations of endothelial cells (EC), pericytes and cultured adipose-derived stromal/stem cells (ASC) of early-stage lipedema patients. We employed histological and gene expression analysis and investigated the endothelial barrier by immunofluorescence and analysis of endothelial permeability in vitro. Although there were no significant differences in histological stainings, we found altered gene expression of factors relevant for local estrogen metabolism (aromatase), preadipocyte commitment (ZNF423) and immune cell infiltration (CD11c) in lipedema on the tissue level, as well as in distinct cellular subpopulations. Machine learning analysis of immunofluorescence images of CD31 and ZO-1 revealed a morphological difference in the cellular junctions of EC cultures derived from healthy and lipedema individuals. Furthermore, the secretome of lipedema-derived SVF cells was sufficient to significantly increase leakiness of healthy human primary EC, which was also reflected by decreased mRNA expression of VE-cadherin. Here, we showed for the first time that the secretome of SVF cells creates an environment that triggers endothelial barrier dysfunction in early-stage lipedema. Moreover, since alterations in gene expression were detected on the cellular and/or tissue level, the choice of sample material is of high importance in elucidating this complex disease.
Meleagrin Isolated from the Red Sea Fungus Penicillium chrysogenum Protects against Bleomycin-Induced Pulmonary Fibrosis in Mice
Authors: Elhady Sameh S. , Goda Marwa S. , Mehanna Eman T. , Elfaky Mahmoud A. , Koshak Abdulrahman E. , Noor Ahmad O. , Bogari Hanin A. , Malatani Rania T. , Abdelhameed Reda F. A. , Wahba Alaa S.
Published: May 2022

The Red Sea marine fungus Penicillium chrysogenum (Family: Ascomycota) comprises a panel of chemically diverse natural metabolites. A meleagrin alkaloid was isolated from deep-sediment-derived P. chrysogenum Strain S003 and has been reported to exert antibacterial and cytotoxic activities. The present study aimed to explore the therapeutic potential of meleagrin on pulmonary fibrosis. Lung fibrosis was induced in mice by a single intratracheal instillation of 2.5 mg/kg bleomycin. Mice were given 5 mg/kg meleagrin daily either for 3 weeks after bleomycin administration in the treatment group or 2 weeks before and 3 weeks after bleomycin administration in the protection group. Bleomycin triggered excessive ROS production, inflammatory infiltration, collagen overproduction and fibrosis. Bleomycin-induced pulmonary fibrosis was attenuated by meleagrin. Meleagrin was noted to restore the oxidant–antioxidant balance, as evidenced by lower MDA contents and higher levels of SOD and catalase activities and GSH content compared to the bleomycin group. Meleagrin also activated the Nrf2/HO-1 antioxidant signaling pathway and inhibited TLR4 and NF-κB gene expression, with a subsequent decreased release of pro-inflammatory cytokines (TNF-α, IL-6 and IFN-γ). Additionally, meleagrin inhibited bleomycin-induced apoptosis by abating the activities of pro-apoptotic proteins Bax and caspase-3 while elevating Bcl2. Furthermore, it suppressed the gene expression of α-SMA, TGF-β1, Smad-2, type I collagen and MMP-9, with a concomitant decrease in the protein levels of TGF-β1, α-SMA, phosphorylated Smad-2, MMP-9, elastin and fibronectin. This study revealed that meleagrin’s protective effects against bleomycin-induced pulmonary fibrosis are attributed to its antioxidant, anti-inflammatory, anti-apoptotic and antifibrotic properties. Notably, the use of meleagrin as a protective agent against bleomycin-induced lung fibrosis was more efficient than its use as a treatment agent.
Long-Term Anxiety-like Behavior and Microbiota Changes Induced in Mice by Sublethal Doses of Acute Sarin Surrogate Exposure
Authors: François Sabine , Mondot Stanislas , Gerard Quentin , Bel Rosalie , Knoertzer Julie , Berriche Asma , Cavallero Sophie , Baati Rachid , Orset Cyrille , Dal Bo Gregory , Thibault Karine
Published: May 2022

Anxiety disorder is one of the most reported complications following organophosphorus (OP) nerve agent (NA) exposure. The goal of this study was to characterize the long-term behavioral impact of a single low dose exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. We chose two different sublethal doses of NIMP, each corresponding to a fraction of the median lethal dose (one mild and one convulsive), and evaluated behavioral changes over a 6-month period following exposure. Mice exposed to both doses showed anxious behavior which persisted for six-months post-exposure. A longitudinal magnetic resonance imaging examination did not reveal any anatomical changes in the amygdala throughout the 6-month period. While no cholinesterase activity change or neuroinflammation could be observed at the latest timepoint in the amygdala of NIMP-exposed mice, important modifications in white blood cell counts were noted, reflecting a perturbation of the systemic immune system. Furthermore, intestinal inflammation and microbiota changes were observed at 6-months in NIMP-exposed animals regardless of the dose received. This is the first study to identify long-term behavioral impairment, systemic homeostasis disorganization and gut microbiota alterations following OP sublethal exposure. Our findings highlight the importance of long-term care for victims of NA exposure, even in asymptomatic cases.
Inflammatory Mechanisms of Diabetes and Its Vascular Complications
Authors: Nedosugova Lyudmila V. , Markina Yuliya V. , Bochkareva Leyla A. , Kuzina Irina A. , Petunina Nina A. , Yudina Irina Y. , Kirichenko Tatiana V.
Published: May 2022

The main cause of death in patients with type 2 DM is cardiovascular complications resulting from the progression of atherosclerosis. The pathophysiology of the association between diabetes and its vascular complications is complex and multifactorial and closely related to the toxic effects of hyperglycemia that causes increased generation of reactive oxygen species and promotes the secretion of pro-inflammatory cytokines. Subsequent oxidative stress and inflammation are major factors of the progression of type 2 DM and its vascular complications. Data on the pathogenesis of the development of type 2 DM and associated cardiovascular diseases, in particular atherosclerosis, open up broad prospects for the further development of new diagnostic and therapeutic approaches.
Anti-Quorum Sensing Activities of Gliptins against Pseudomonas aeruginosa and Staphylococcus aureus
Authors: Khayat Maan T. , Abbas Hisham A. , Ibrahim Tarek S. , Khayyat Ahdab N. , Alharbi Majed , Darwish Khaled M. , Elhady Sameh S. , Khafagy El-Sayed , Safo Martin K. , Hegazy Wael A. H.
Published: May 2022

The development of bacterial resistance to traditional antibiotics constitutes an emerging public health issue. Promising approaches have been innovated to conquer bacterial resistance, and targeting bacterial virulence is one of these approaches. Bacterial virulence mitigation offers several merits, as antivirulence agents do not affect the growth of bacteria and hence do not induce bacteria to develop resistance. In this direction, numerous drugs have been repurposed as antivirulence agents prior to their clinical use alone or in combination with traditional antibiotics. Quorum sensing (QS) plays a key role in controlling bacterial virulence. In the current study, dipeptidase inhibitor-4 (DPI-4) antidiabetic gliptins were screened for their antivirulence and anti-quorum sensing (anti-QS) activities against Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus. Upon assessing their antibiofilm activities, the ten tested gliptins significantly diminished biofilm formation. In particular, sitagliptin exhibited the most efficient antibiofilm activity, so it was chosen as a representative of all gliptins to further investigate its antivirulence activity. Sitagliptin significantly protected mice from P. aeruginosa and S. aureus pathogenesis. Furthermore, sitagliptin downregulated QS-encoding genes in P. aeruginosa and S. aureus. To test the anti-QS activities of gliptins, a detailed molecular docking study was conducted to evaluate the gliptins’ binding affinities to P. aeruginosa and S. aureus QS receptors, which helped explain the anti-QS activities of gliptins, particularly sitagliptin and omarigliptin. In conclusion, this study evaluates the possible antivirulence and anti-QS activities of gliptins that could be promising novel candidates for the treatment of aggressive Gram-negative or -positive bacterial infections either alone or as adjuvants to other antibiotics.
Natural Polyphenols, 1,2,3,4,6-O-Pentagalloyglucose and Proanthocyanidins, as Broad-Spectrum Anticoronaviral Inhibitors Targeting Mpro and RdRp of SARS-CoV-2
Authors: Jin Young-Hee , Lee Jihye , Jeon Sangeun , Kim Seungtaek , Min Jung Sun , Kwon Sunoh
Published: May 2022

The natural plant dietary polyphenols 1,2,3,4,6-O-Pentagalloylglucose (PGG) and proanthocyanidin (PAC) have potent antioxidant activity and a variety of pharmacological activities, including antiviral activity. In this study, we examined the inhibitory effect of PGG and PAC on SARS-CoV-2 virus infection, and elucidated its mode of action. PGG and PAC have dose-dependent inhibitory activity against SARS-CoV-2 infection in Vero cells. PGG has a lower IC50 (15.02 ± 0.75 μM) than PAC (25.90 ± 0.81 μM), suggesting that PGG has better inhibitory activity against SARS-CoV-2 than PAC. The PGG and PAC inhibit similar Mpro activities in a protease activity assay, with IC50 values of 25–26 μM. The effects of PGG and PAC on the activity of the other essential SARS-CoV-2 viral protein, RdRp, were analyzed using a cell-based activity assay system. The activity of RdRp is inhibited by PGG and PAC, and PGG has a lower IC50 (5.098 ± 1.089 μM) than PAC (21.022 ± 1.202 μM), which is consistent with their inhibitory capacity of SARS-CoV-2 infection. PGG and PAC also inhibit infection by SARS-CoV and MERS-CoV. These data indicate that PGG and PAC may be candidate broad-spectrum anticoronaviral therapeutic agents, simultaneously targeting the Mpro and RdRp proteins of SARS-CoV-2.
An Aptamer-Functionalised Schottky-Field Effect Transistor for the Detection of Proteins
Authors: Farrow Thomas , Laumier Siriny , Sandall Ian , van Zalinge Harm
Published: May 2022

The outbreak of the coronavirus disease 2019 (COVID-19) in December 2019 has highlighted the need for a flexible sensing system that can quickly and accurately determine the presence of biomarkers associated with the disease. This sensing system also needs to be easily adaptable to incorporate both novel diseases as well as changes in the existing ones. Here we report the feasibility of using a simple, low-cost silicon field-effect transistor functionalised with aptamers and designed to attach to the spike protein of SARS-CoV2. It is shown that a linear response can be obtained in a concentration range of 100 fM to 10 pM. Furthermore, by using a larger range of source-drain potentials compared with other FET based sensors, it is possible to look at a wider range of device parameters to optimise the response.