bluuebunny/crossref_metadata_2025 huggingface dataset:
VIoLET
Authors: Baheti Shrey , Badiger Shreyas , Simmhan Yogesh
Published: July 2021

Internet of Things (IoT) deployments have been growing manifold, encompassing sensors, networks, edge, fog, and cloud resources. Despite the intense interest from researchers and practitioners, most do not have access to large-scale IoT testbeds for validation. Simulation environments that allow analytical modeling are a poor substitute for evaluating software platforms or application workloads in realistic computing environments. Here, we propose a virtual environment for validating Internet of Things at large scales (VIoLET), an
emulator
for defining and launching large-scale IoT deployments within cloud VMs. It allows users to declaratively specify container-based compute resources that match the performance of native IoT compute devices using Docker. These can be inter-connected by complex topologies on which bandwidth and latency rules are enforced. Users can configure synthetic sensors for data generation as well. We also incorporate models for CPU resource dynamism, and for failure and recovery of the underlying devices. We offer a detailed comparison of VIoLET’s compute and network performance between the virtual and physical deployments, evaluate its scaling with deployments with up to 1, 000 devices and 4, 000 device-cores, and validate its ability to model resource dynamism. Our extensive experiments show that the performance of the virtual IoT environment
accurately
matches the expected behavior, with deviations levels within what is seen in actual physical devices. It also
scales
to 1, 000s of devices and at a modest cloud computing costs of under 0.15% of the actual hardware cost, per hour of use, with minimal management effort. This IoT emulation environment fills an essential gap between IoT simulators and real deployments.
Categorical Semantics of Cyber-Physical Systems Theory
Authors: Bakirtzis Georgios , Fleming Cody H. , Vasilakopoulou Christina
Published: July 2021

Cyber-physical systems require the construction and management of various models to assure their correct, safe, and secure operation. These various models are necessary because of the coupled physical and computational dynamics present in cyber-physical systems. However, to date the different model views of cyber-physical systems are largely related informally, which raises issues with the degree of formal consistency between those various models of requirements, system behavior, and system architecture. We present a category-theoretic framework to make different types of composition explicit in the modeling and analysis of cyber-physical systems, which could assist in verifying the system as a whole. This compositional framework for cyber-physical systems gives rise to unified system models, where system behavior is hierarchically decomposed and related to a system architecture using the systems-as-algebras paradigm. As part of this paradigm, we show that an algebra of (safety) contracts generalizes over the state of the art, providing more uniform mathematical tools for constraining the behavior over a richer set of composite cyber-physical system models, which has the potential of minimizing or eliminating hazardous behavior.
Ultrabright plasmonic fluor nanolabel-enabled detection of a urinary ER stress biomarker in autosomal dominant tubulointerstitial kidney disease
Authors: Kim Yeawon , Wang Zheyu , Li Chuang , Kidd Kendrah , Wang Yixuan , Johnson Bryce G. , Kmoch Stanislav , Morrissey Jeremiah J. , Bleyer Anthony J. , Duffield Jeremy S. , Singamaneni Srikanth , Chen Ying Maggie
Published: July 2021

Autosomal dominant tubulointerstitial kidney disease (ADTKD)-uromodulin ( UMOD) is an underdiagnosed cause of chronic kidney disease (CKD). Lack of ultrasensitive bioanalytical tools has hindered the discovery of low abundant urinary biomarkers in ADTKD. Here, we developed an ultrasensitive plasmon-enhanced fluorescence-linked immunosorbent assay (p-FLISA). p-FLISA demonstrated that secreted immunoglobulin heavy chain-binding protein is an early urinary endoplasmic reticulum stress biomarker in ADTKD- UMOD, which will be valuable in monitoring disease progression and the treatment response in ADTKD.
On the Investigation of Effective Factors on Higher Heating Value of Biodiesel: Robust Modeling and Data Assessments
Authors: Wang Shicheng , Li Wei , Alruyemi Issam
Published: July 2021

Higher heating value (HHV) is one of the properties of biomass fuels which is essential in investigating their special characteristics and potentialities. In this paper, various techniques based on Gaussian process regression (GPR) were utilized to assess this value for biomass fuels, including several kernel functions, i.e., exponential, Matern, rational quadratic, and squared exponential. An extensive databank was collected from literature. The findings were compared, and the results indicated that Exponential‐based model was more accurate, with the coefficient of regression (R2) of 0.961 and the mean relative error (% MRE) of 3.11 for total data. Compared to former models presented by previous researchers, the model proposed in this study showed a higher ability to predict output values. With various analyses, it can be concluded that the proposed method has a high rate of efficiency in assessing the HHV of various biomass.
Solving Poisson Equation by Distributional HK-Integral: Prospects and Limitations
Authors: Maldeniya Amila J. , Ganegoda Naleen C. , De Silva Kaushika , Boralugoda Sanath K.
Published: July 2021

In this paper, we present some properties of integrable distributions which are continuous linear functional on the space of test functionDℝ2. Here, it uses two-dimensional Henstock–Kurzweil integral. We discuss integrable distributional solution for Poisson’s equation in the upper half spaceℝ+3with Dirichlet boundary condition.
Nobiletin Decreases Inflammatory Mediator Expression in Tumor Necrosis Factor-Stimulated Human Periodontal Ligament Cells
Authors: Hosokawa Yoshitaka , Hosokawa Ikuko , Ozaki Kazumi
Published: July 2021

Nobiletin, a biologically active substance in the skin of citrus fruits, has been reported to be an effective anti-inflammatory, anticancer, and antimicrobial agent. In this study, we aimed to examine the anti-inflammatory effects of nobiletin on tumor necrosis factor- (TNF-) stimulated human periodontal ligament cells (HPDLCs). Our results demonstrated that nobiletin treatment could decrease the expressions of inflammatory cytokines (C-X-C motif chemokine ligand (CXCL)10, C-C motif chemokine ligand (CCL)2, and interleukin- (IL-) 8), matrix metalloproteinases (MMPs) (MMP1 and MMP3), and prostaglandin-endoperoxide synthase 2 (PTGS2) in TNF-stimulated HPDLCs. Moreover, we revealed that nobiletin could inhibit the activation of nuclear factor- (NF-) κB and protein kinase B (AKT1) pathways in TNF-stimulated HPDLCs. Furthermore, nobiletin treatment enhanced nuclear factor, erythroid 2 like 2 (NFE2L2) and heme oxygenase 1 (HMOX1) expressions in TNF-stimulated HPDLCs. In conclusion, these findings suggest that nobiletin can inhibit inflammatory responses in TNF-stimulated HPDLCs by inhibiting NF-κB and AKT1 activations and upregulating the NFE2L2 and HMOX1 expression.
Elevated Serum Interleukin-23 Levels in Patients with Oral and Cutaneous Lichen Planus
Authors: Mardani Maryam , Mofidi Hossein , Dastgheib Ladan , Ranjbar Sara , Hamidizadeh Nasrin
Published: July 2021

Lichen planus is considered a chronic inflammatory disease which affects different sites, such as the skin, mucous membranes, hair, and nails. Based on the evidence, a complex cytokine network plays a crucial role in lichen planus pathogenesis. The study was aimed at assessing the serum IL-23 levels in the patients with cutaneous and oral lichen planus compared to healthy controls. Method. The study included 30 cutaneous lichen planus patients, 20 oral lichen planus patients, and 33 control subjects. Five milliliters of peripheral blood was obtained from each patient, and the serum was separated. IL-23 levels were determined using the ELISA kit, and the data were analyzed using the Mann–Whitney test. Results. IL-23 levels in the patient serum with oral lichen planus (

P

value ≤ 0.001) were significantly higher than in controls. Furthermore, there were significant differences in IL-23 serum levels in the patients with cutaneous lichen planus compared to the healthy controls (

P

value ≤ 0.001). Moreover, IL-23 serum levels were statistically different between patients with cutaneous lichen planus and patients with oral lichen planus (

P

value ≤ 0.001). Based on the mean concentration of interleukin-23, IL-23 levels were higher in the patients with oral lichen planus than in the patients with cutaneous lichen planus. Conclusions. Elevated serum IL-23 levels in the patients with oral lichen planus may indicate that IL-23 plays a crucial role in the pathogenesis of oral lichen planus. However, more research is needed with a larger sample size.
On the Generic Uniqueness of Pareto-Efficient Solutions of Vector Optimization Problems
Authors: Zhang Dejin , Xiang Shuwen , Yang Yanlong , Deng Xicai
Published: July 2021

In this paper, the generic uniqueness of Pareto weakly efficient solutions, especially Pareto-efficient solutions, of vector optimization problems is studied by using the nonlinear and linear scalarization methods, and some further results on the generic uniqueness are proved. These results present that, for most of the vector optimization problems in the sense of the Baire category, the Pareto weakly efficient solution, especially the Pareto-efficient solution, is unique. Furthermore, based on these results, the generic Tykhonov well-posedness of vector optimization problems is given.
Ethnopharmacological Survey on Treatment of Hypertension by Traditional Healers in Bukavu City, DR Congo
Authors: Mushagalusa Kasali Félicien , Ahadi Irenge Christian , Murhula Hamuli Pacifique , Birindwa Mulashe Patient , Murhula Katabana Delphin , Mangambu Mokoso Jean De Dieu , Mpiana Pius Tshimankinda , Ntokamunda Kadima Justin
Published: July 2021

Background. Ethnopharmacological studies are relevant for sustaining and improving knowledge of traditional medicine within the framework of complementary/alternative therapeutic practices based solely on experience and observation across generations. Hypertension is a common cardiovascular disorder affecting more than 50% of older people in Africa (PLoS One. 2019; 14 (4): e0214934; published online on April 5, 2019, doi: 10.1371/journal.pone.0214934). Methods. We conducted a cross-sectional survey from October 2014 to August 2015 with 18 renowned traditional healers from the city of Bukavu to capture botanical plant species and remedies used by herbalists to manage hypertension in the Democratic Republic of Congo. Results. Respondents cited 41 plant species belonging to 25 botanical families. The ten most common plants are Allium sativum, Galinsoga ciliata, Moringa oleifera, Bidens pilosa, Persea americana, Piper capense, Catharanthus roseus, Rauvolfia vomitoria, Sida rhombifolia, and Vernonia amygdalina. The parts used are primary leaves (48.8%) formulated as oral decoctions (65.9%). Conclusion. The literature review validated the use of 73.2% of the plants listed. Plants of high local use-value not supported by other studies deserve in-depth chemical and pharmacological studies.
IOT-Based Cotton Whitefly Prediction Using Deep Learning
Authors: Saleem Rana Muhammad , Kazmi Rafaqat , Bajwa Imran Sarwar , Ashraf Amna , Ramzan Shabana , Anwar Waheed
Published: July 2021

Agriculture is suffering from the problem of low fertility and climate hazards such as increased pest attacks and diseases. Early prediction of pest attacks can be very helpful in improving productivity in agriculture. Insect pest (whitefly) attack has a high influence on cotton crop yield. Internet of Things solution is proposed to predict the whitefly attack to take prevention measures. An insect pest prediction system (IPPS) was developed with the help of the Internet of Things and a RBFN algorithm based on environmental parameters such as temperature, humidity, rainfall, and wind speed. Pest Warning and Quality Control of Pesticides proposed an economic threshold level for prediction of whitefly attack. The economic threshold level and RBFN algorithm are used to predict the whitefly attack using temperature, humidity, rainfall, and wind speed. The seven evaluation metrics accuracy, f-measures, precision, recall, Cohen’s kappa, ROC AUC, and confusion matrix are used to determine the performance of the RBFN algorithm. The proposed insect pest prediction system is deployed in the high influenced region of pest that provides pest prediction information to the farmer to take control measures.
Trehalose Augments Neuron Survival and Improves Recovery from Spinal Cord Injury via mTOR‐Independent Activation of Autophagy
Authors: Zhou Kailiang , Chen Huanwen , Xu Huazi , Jia Xiaofeng
Published: July 2021

Spinal cord injury (SCI) is a major cause of irreversible nerve injury and leads to serious tissue loss and neurological dysfunction. Thorough investigation of cellular mechanisms, such as autophagy, is crucial for developing novel and effective therapeutics. We administered trehalose, an mTOR‐independent autophagy agonist, in SCI rats suffering from moderate compression injury to elucidate the relationship between autophagy and SCI and evaluate trehalose’s therapeutic potential. 60 rats were divided into 4 groups and were treated with either control vehicle, trehalose, chloroquine, or trehalose + chloroquine 2 weeks prior to administration of moderate spinal cord crush injury. 20 additional sham rats were treated with control vehicle. H&E staining, Nissl staining, western blot, and immunofluorescence studies were conducted to examine nerve morphology and quantify autophagy and mitochondrial‐dependent apoptosis at various time points after surgery. Functional recovery was assessed over a period of 4 weeks after surgery. Trehalose promotes autophagosome recruitment via an mTOR‐independent pathway, enhances autophagy flux in neurons, inhibits apoptosis via the intrinsic mitochondria‐dependent pathway, reduces lesion cavity expansion, decreases neuron loss, and ultimately improves functional recovery following SCI (all p < 0.05). Furthermore, these effects were diminished upon administration of chloroquine, an autophagy flux inhibitor, indicating that trehalose’s beneficial effects were due largely to activation of autophagy. This study presents new evidence that autophagy plays a critical neuroprotective and neuroregenerative role in SCI, and that mTOR‐independent activation of autophagy with trehalose leads to improved outcomes. Thus, trehalose has great translational potential as a novel therapeutic agent after SCI.
An Intelligent Heartbeat Classification System Based on Attributable Features with AdaBoost+Random Forest Algorithm
Authors: Li Runchuan , Zhang Wenzhi , Shen Shengya , Yao Jinliang , Li Bicao , Zhou Bing , Chen Gang , Wang Zongmin
Published: July 2021

Arrhythmia is a common cardiovascular disease that can threaten human life. In order to assist doctors in accurately diagnosing arrhythmia, an intelligent heartbeat classification system based on the selected optimal feature sets and AdaBoost + Random Forest model is developed. This system can acquire ECG signals through the Holter and transmit them to the cloud platform for preprocessing and feature extraction, and the features are input into AdaBoost + Random Forest for heartbeat classification. The analysis results are output in the form of reports. In this system, by comparing and analyzing the classification accuracy of different feature sets and classifiers, the optimal classification algorithm is obtained and applied to the system. The algorithm accuracy of the system is tested based on the MIT-BIH data set. The result shows that AdaBoost + Random Forest achieved 99.11% accuracy with optimal feature sets. The intelligent heartbeat classification system based on this algorithm has also achieved good results on clinical data.
Gaussian Perturbation Specular Reflection Learning and Golden‐Sine‐Mechanism‐Based Elephant Herding Optimization for Global Optimization Problems
Authors: Duan Yuxian , Liu Changyun , Li Song , Guo Xiangke , Yang Chunlin
Published: July 2021

Elephant herding optimization (EHO) has received widespread attention due to its few control parameters and simple operation but still suffers from slow convergence and low solution accuracy. In this paper, an improved algorithm to solve the above shortcomings, called Gaussian perturbation specular reflection learning and golden‐sine‐mechanism‐based EHO (SRGS‐EHO), is proposed. First, specular reflection learning is introduced into the algorithm to enhance the diversity and ergodicity of the initial population and improve the convergence speed. Meanwhile, Gaussian perturbation is used to further increase the diversity of the initial population. Second, the golden sine mechanism is introduced to improve the way of updating the position of the patriarch in each clan, which can make the best‐positioned individual in each generation move toward the global optimum and enhance the global exploration and local exploitation ability of the algorithm. To evaluate the effectiveness of the proposed algorithm, tests are performed on 23 benchmark functions. In addition, Wilcoxon rank‐sum tests and Friedman tests with 5% are invoked to compare it with other eight metaheuristic algorithms. In addition, sensitivity analysis to parameters and experiments of the different modifications are set up. To further validate the effectiveness of the enhanced algorithm, SRGS‐EHO is also applied to solve two classic engineering problems with a constrained search space (pressure‐vessel design problem and tension‐/compression‐string design problem). The results show that the algorithm can be applied to solve the problems encountered in real production.
The Chemical Composition and Biological Activities of Essential Oils from Zanthoxylum rhetsa Grown in Son La, Northwest Vietnam
Authors: Pham Cao Bach , Cam Thi Inh , Tran Thi Tuyen , Quan Pham Minh , Toan Tran Quoc , Do Huu Nghi , Thu Thuy Dinh Thi , Nguyen Thi Thuy , Trinh Anh Vien , Pham Thi Hong Minh , Pham Quoc Long , Hien Tran Thien , Pham Dung Thuy Nguyen , Nguyen Thi Hong Van
Published: July 2021

Essential oils (EOs) from the stem barks, leaf petioles, fruit petioles, fresh leaves, and fresh and dried fruits of Zanthoxylum rhetsa were extracted by hydrodistillation. The volatile compounds of the products were analyzed by gas chromatography (GC-FID) and gas chromatography/mass spectrometry (GC/MSD). Monoterpene hydrocarbons formed the predominant fraction of all six EO samples, of which sabinene is one of the major components (from 12.37% to 41.13%). For the leaf petiole EO, limonene (25.01%), sabinene (14.56%), and linalool (12.63%) are the major constituents, while the main constituents of fruit petiole EO were terpinolene (19.66%), terpinen-4-ol (19.07%), and sabinene (17.83%). The major components of stem bark EO are terpinen-4-ol (18.23%), sabinene (12.37%), α-phellandrene (7.34%), β-phellandrene (6.32%), and γ-terpinene (6.12%), while sabinene (38.35%), terpinen-4-ol (13.71%), γ-terpinene (6.47%), and limonene (6.02%) are the major constituents of fresh leaf EO. For the EOs of dried fruits and fresh fruits, sabinene, terpinolene, limonene, and terpinen-4-ol are the major constituents. The essential oils were also tested for their cytotoxic and antimicrobial activities. The results revealed that six EOs at concentrations of 50 μg/mL exhibited inhibitory activity against at least one tested cancer cell line but were nontoxic on Vero normal cells. Most EOs showed moderate antimicrobial activity against F. oxysporum; however, there were no obvious activity against B. subtilis and S. aureus.
Temporal Index Scheme of Hyperledger Fabric System in IoT
Authors: Lu Yongqiang , Liu Zhaobin , Wang Shaoqi , Li Zhiyang , Liu Weijiang , Chen Xuhui
Published: July 2021

As a large number of mobile terminals are connected to the IoT, the security problem of IoT is a challenge to the IoT technology. Blockchain technology has the characteristics of decentralization, data encryption, smart contract, and so on, especially suitable in the complex heterogeneous network. However, sequential access based on block files in the blockchain hinders efficient query processing. The problem is due to current blockchain solutions do not support temporal data processing. In this paper, we propose two index building methods (TISD and TIF) to address this issue in Hyperledger Fabric System. TISD (temporal index based on state databases) segments the historical data by time interval in the time dimension and indexes events at the same time interval. TIF (temporal index based on files) builds the index of files by the block transaction data, which is arranged in chronological order and is stored at a certain time interval. In the experimental part, we compare the query time on two datasets and analyse the query performance. Experiments demonstrated that our two methods are relatively stable in overall time performance on different datasets in the Hyperledger Fabric System.
Small Modification on Modified Euler Method for Solving Initial Value Problems
Authors: Workie Abushet Hayalu
Published: July 2021

In this article, small modification to the Modified Euler Method is proposed. Stability and consistency were tested to determine the end result, and some numerical results were presented, and the CPU time was compared again, and it is recognized that the proposed method is more reliable and compatible with higher efficiency.
Biomechanical Effect of Orthodontic Treatment of Canine Retraction by Using Metallic Orthodontic Mini-Implant (OMI) Covered with Various Angles of Revolving Cap
Authors: Tuntiwong Kuson , Hsu Jui-Ting , Yang Shih-Guang , Yu Jian-Hong , Huang Heng-Li
Published: July 2021

Objective. This study evaluated the biomechanical effects of a metallic orthodontic mini-implant (OMI) covered with various types of angled revolving cap on the peri-OMI bone and the canine periodontal ligament (PDL) by finite element (FE) analyses. Materials and Methods. Three-dimensional FE models included comprised cortical bone and cancellous bone of the maxilla, and the OMIs were created. The forces (0.98 N) pulled in both the canine hook and the revolving cap, pulling towards each other in both directions as loading conditions. The upper surface of the maxilla was fixed as a boundary condition. Results. The bone stresses were increasing in the models by using OMI covered with a revolving cap as compared with that in the conventional model (in which only the OMI was placed). However, no obvious differences in bone stresses were observed among the models with various types of angled revolving cap. The minimum principal strain in the canine PDL was highest for condition 180T, followed by condition 180L. However, the maximum differences in the values between each experimental model and the conventional model were around 5%. Conclusion. This study showed no obvious effects in decreasing or increasing stress/strain in bone and PDL by using various types of angled revolving cap covered metallic mini-implant in orthodontic treatment of canine retraction.
Immunohistochemical Expression of FOXP3+ Regulatory T Cells in Proteinuric Primary Glomerulopathies
Authors: Vlachopanos Georgios , Georgalis Argyrios , Korkolopoulou Pinelopi , Patsouris Efstratios , Gakiopoulou Harikleia
Published: July 2021

FOXP3+ regulatory T-cell (Tregs) detection in renal allograft biopsies has been associated with a less intense immune response. Data about FOXP3+ Tregs’ presence and role in primary glomerulopathies of native kidneys are minimal. We comparatively studied the immunohistochemical expression of FOXP3+ Tregs, CD4+ and CD3+ T cells in IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), and membranous glomerulopathy (MGN). We retrospectively reviewed 71 renal biopsies (28 from patients with IgAN, 22 from patients with FSGS and 21 from patients with MGN) performed with proteinuria as the main indication. FOXP3+ Tregs and CD4+ and CD3+ T cells in inflammatory cell infiltrates of the interstitial tissue and periglomerular space were automatically counted using image analysis software. Univariable and multivariable logistic regressions were applied for statistical analysis. Nuclear FOXP3+ immunohistochemical expression was observed in T cells in 64% of IgAN cases, 77% of FSGS cases, and 76% of MGN cases (

p
>
0.05

). Absolute FOXP3+ Tregs count in the interstitial tissue was higher in patients without arteriolar hyalinosis than in those with arteriolar hyalinosis (1.814 ± 2.160 vs. 831 ± 696;

p
=
0.029

). In patients with a high FOXP3+/CD4+ ratio in the interstitial tissue, the odds ratio for CKD-EPI eGFR ≥60 ml/min/1.73 m2 at biopsy was 4.80 (95% CI: 1.29–17.91;

p
=
0.019

). FOXP3+ Tregs intrarenal infiltration in primary glomerulopathies is common. FOXP3+ Tregs’ increased expression may be associated with milder histological lesions. High FOXP3+/CD4+ ratio in the interstitial tissue may have prognostic significance for renal function preservation.
Toxicology and Biodegradability of a Phthalate-Free and Bio-Based Novel Plasticizer
Authors: Simar-Mentières S. , Nesslany F. , Sola M.-L. , Mortier S. , Raimbault J.-M. , Gondelle F. , Chabot L. , Pandard P. , Wils D. , Chentouf A.
Published: July 2021

Phthalate esters, mainly di-ethylhexylphthalate (DEHP), represent a class of chemicals primarily used as plasticizers for polyvinyl chloride in a wide range of domestic and industrial applications. These phthalate esters are low-toxicity environmental contaminants. To address these drawbacks, POLYSORB® ID 37, a blend of diesters obtained from esterification of isosorbide with plant-based fatty acids, was developed. The company can now offer PVC manufacturers a new product which competes with phthalates and other such chemicals. The market for plasticizers is very important, and ROQUETTE intends to provide a more sustainable and safer product. Isosorbide diester is bio-based (made from glucose and vegetable fatty acids). This plasticizer is registered in REACH regulation for high volumes (>1000 T/year). Risk assessment was obtained by conducting a wide range of biodegradability and toxicological protocols, using rodent models, according to established guidelines. Overall, all of the toxicological and biodegradability studies demonstrated that POLYSORB® ID 37 is nontoxic to mammalian life and is readily biodegradable.
Immunoinformatic Analysis of Calcium-Dependent Protein Kinase 7 (CDPK7) Showed Potential Targets for Toxoplasma gondii Vaccine
Authors: Taghipour Ali , Tavakoli Sanaz , Sabaghan Mohamad , Foroutan Masoud , Majidiani Hamidreza , Soltani Shahrzad , Badri Milad , Ghaffari Ali Dalir , Soltani Sheyda
Published: July 2021

Apicomplexan parasites, including Toxoplasma gondii (T. gondii), express different types of calcium-dependent protein kinases (CDPKs), which perform a variety of functions, including attacking and exiting the host cells. In the current bioinformatics study, we have used several web servers to predict the basic features and specifications of the CDPK7 protein. The findings showed that CDPK7 protein has 2133 amino acid residues with an average molecular weight (MW) of 219085.79 D. The aliphatic index with 68.78 and grand average of hydropathicity (GRAVY) with -0.331 score were estimated. The outcomes of current research showed that the CDPK7 protein included 502 alpha-helix, 1311 random coils, and 320 extended strands with GOR4 method. Considering the Ramachandran plot, the favored region contains more than 92% of the amino acid residues. In addition, evaluation of antigenicity and allergenicity showed that CDPK7 protein has immunogenic and nonallergenic nature. The present research provides key data for more animal-model study on the CDPK7 protein to design an efficient vaccine against toxoplasmosis in the future.
Immune Phenotype and Response to Neoadjuvant Therapy in Triple-Negative Breast Cancer
Authors: Yam Clinton , Yen Er-Yen , Chang Jeffrey T. , Bassett Roland L. , Alatrash Gheath , Garber Haven , Huo Lei , Yang Fei , Philips Anne V. , Ding Qing-Qing , Lim Bora , Ueno Naoto T. , Kannan Kasthuri , Sun Xiangjie , Sun Baohua , Parra Cuentas Edwin Roger , Symmans William Fraser , White Jason B. , Ravenberg Elizabeth , Seth Sahil , Guerriero Jennifer L. , Rauch Gaiane M. , Damodaran Senthil , Litton Jennifer K. , Wargo Jennifer A. , Hortobagyi Gabriel N. , Futreal Andrew , Wistuba Ignacio I. , Sun Ryan , Moulder Stacy L. , Mittendorf Elizabeth A.
Published: July 2021

Purpose:

Increasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR.

Experimental Design:

We obtained pretreatment core-needle biopsies from 105 patients with stage I–III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT.

Results:

The pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 μm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage.

Conclusions:

In patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.
Valency of HER2 Targeting Antibodies Influences Tumor Cell Internalization and Penetration
Authors: Ramos Madeleine K. , Mandikian Danielle , Sermeño Lauren N. , King Anna , Dent Alecia T. , Ho Jason , Ulufatu Sheila , Lombana T. Noelle , Spiess Christoph , Go Mary Ann T. , Yu Shang-Fan , Kamath Amrita V. , Ferl Gregory Z. , Boswell C. Andrew
Published: July 2021

T-cell–dependent bispecific antibodies (TDB) have been a major advancement in the treatment of cancer, allowing for improved targeting and efficacy for large molecule therapeutics. TDBs are comprised of one arm targeting a surface antigen on a cancer cell and another targeting an engaging surface antigen on a cytotoxic T cell. To impart this function, the antibody must be in a bispecific format as opposed to the more conventional bivalent format. Through in vitro and in vivo studies, we sought to determine the impact of changing antibody valency on solid tumor distribution and catabolism. A bivalent anti-HER2 antibody exhibited higher catabolism than its full-length monovalent binding counterpart in vivo by both invasive tissue harvesting and noninvasive single photon emission computed tomography/X-ray computed tomography imaging despite similar systemic exposures for the two molecules. To determine what molecular factors drove in vivo distribution and uptake, we developed a mechanistic model for binding and catabolism of monovalent and bivalent HER2 antibodies in KPL4 cells. This model suggests that observed differences in cellular uptake of monovalent and bivalent antibodies are caused by the change in apparent affinity conferred by avidity as well as differences in internalization and degradation rates of receptor bound antibodies. To our knowledge, this is the first study to directly compare the targeting abilities of monovalent and bivalent full-length antibodies. These findings may inform diverse antibody therapeutic modalities, including T-cell–redirecting therapies and drug delivery strategies relying upon receptor internalization.
PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus
Authors: Mpilla Gabriel B. , Uddin Md. Hafiz , Al-Hallak Mohammed N. , Aboukameel Amro , Li Yiwei , Kim Steve H. , Beydoun Rafic , Dyson Gregory , Baloglu Erkan , Senapedis William T. , Landesman Yosef , Wagner Kay-Uwe , Viola Nerissa T. , El-Rayes Bassel F. , Philip Philip A. , Mohammad Ramzi M. , Azmi Asfar S.
Published: July 2021

Metastatic pancreatic neuroendocrine tumors (PNET) remain an unmet clinical problem. Chronologic treatment in PNETs includes observation (watchful protocol), surgery, targeted therapy, and chemotherapy. However, increasing evidence illustrates that the outcomes of targeted therapeutic options for the treatment of advanced PNETs show minimal response. The FDA-approved mTOR inhibitor everolimus does not shrink these tumors. It only delays disease progression in a subset of patients, while a significant fraction acquires resistance and shows disease progression. Thus, there is a need for more effective targeted approaches to sensitize PNETs to everolimus for better treatment outcomes. Previously, we showed that mTOR regulator p21 activated kinase 4 (PAK4) and nicotinamide adenine dinucleotide biosynthesis enzyme nicotinamide phosphoribosyl transferase (NAMPT) were aberrantly expressed in PNET tissue and promoted everolimus resistance. In this report, we demonstrate that PAK4-NAMPT dual inhibitor KPT-9274 can synergize with everolimus (growth inhibition, colony suppression, and glucose uptake assays). KPT-9274-everolimus disrupted spheroid formation in multiple PNET models. Molecular analysis showed alteration of mTORC2 through downregulation of RICTOR as a mechanism supporting synergy with everolimus in vitro. KPT-9274 suppressed β-catenin activity via inhibition of PAK4, highlighting the cross-talk between Rho GTPases and Wnt signaling in PNETs. KPT-9274, given at 150 mg/kg in combination with sub-MTD everolimus (2.5 mg/kg), significantly suppressed two PNET-derived xenografts. These studies bring forward a well-grounded strategy for advanced PNETs that fail to respond to single-agent everolimus.
Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor ResponsesIn Vivo
Authors: Montes de Oca Rocio , Alavi Alireza S. , Vitali Nick , Bhattacharya Sabyasachi , Blackwell Christina , Patel Krupa , Seestaller-Wehr Laura , Kaczynski Heather , Shi Hong , Dobrzynski Eric , Obert Leslie , Tsvetkov Lyuben , Cooper David C. , Jackson Heather , Bojczuk Paul , Forveille Sabrina , Kepp Oliver , Sauvat Allan , Kroemer Guido , Creighton-Gutteridge Mark , Yang Jingsong , Hopson Chris , Yanamandra Niranjan , Shelton Christopher , Mayes Patrick , Opalinska Joanna , Barnette Mary , Srinivasan Roopa , Smothers James , Hoos Axel
Published: July 2021

B-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody–drug conjugate approved for the treatment of relapsed/refractory multiple myeloma. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation in vitro and in vivo. GSK2857916 treatment enhances intratumor immune cell infiltration and activation, delays tumor growth, and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA). Responding mice are immune to rechallenge with EL4 parental and EL4-hBCMA cells, suggesting engagement of an adaptive immune response, immunologic memory, and tumor antigen spreading, which are abrogated upon depletion of endogenous CD8+ T cells. Combinations with OX40/OX86, an immune agonist antibody, significantly enhance antitumor activity and increase durable complete responses, providing a strong rationale for clinical evaluation of GSK2857916 combinations with immunotherapies targeting adaptive immune responses, including T-cell–directed checkpoint modulators.
Lipidomic Profiles of Plasma Exosomes Identify Candidate Biomarkers for Early Detection of Hepatocellular Carcinoma in Patients with Cirrhosis
Authors: Sanchez Jessica I. , Jiao Jingjing , Kwan Suet-Ying , Veillon Lucas , Warmoes Marc O. , Tan Lin , Odewole Mobolaji , Rich Nicole E. , Wei Peng , Lorenzi Philip L. , Singal Amit G. , Beretta Laura
Published: July 2021

Novel biomarkers for HCC surveillance in cirrhotic patients are urgently needed. Exosomes and their lipid content in particular represent potentially valuable noninvasive diagnostic biomarkers. We isolated exosomes from plasma of 72 cirrhotic patients, including 31 with HCC. Exosomes and unfractionated plasma were processed for untargeted lipidomics using ultra–high-resolution mass spectrometry. A total of 2,864 lipid species, belonging to 52 classes, were identified. Both exosome fractionation and HCC diagnosis had significant impact on the lipid profiles. Ten lipid classes were enriched in HCC exosomes compared with non-HCC exosomes. Dilysocardiolipins were detected in 35% of the HCC exosomes but in none of the non-HCC exosomes (P < 0.001). Cardiolipins and sphingosines had the highest differential effects (fold change of 133.08, q = 0.001 and 38.57, q < 0.001, respectively). In logistic regression analysis, high abundances of exosomal sphingosines, dilysocardiolipins, lysophosphatidylserines, and (O-acyl)-1-hydroxy fatty acids were strongly associated with HCC [OR (95% confidence interval (CI)), 271.1 (14.0–5,251.9), P < 0.001; 46.5 (2.3–939.9), P = 0.012; 14.9 (4.3–51.2), P < 0.001; 10.3 (3.2–33.1), P < 0.001]. Four lipid classes were depleted in HCC exosomes compared with non-HCC exosomes. In logistic regression analysis, lack of detection of sulfatides and acylGlcSitosterol esters was strongly associated with HCC [OR (95% CI): 215.5 (11.5–4,035.9), P < 0.001; 26.7 (1.4–528.4), P = 0.031]. These HCC-associated changes in lipid composition of exosomes reflected alterations in glycerophospholipid metabolism, retrograde endocannabinoid signaling, and ferroptosis. In conclusion, this study identified candidate biomarkers for early detection of HCC as well as altered pathways in exosomes that may contribute to tumor development and progression.

Prevention Relevance:

This study identifies lipids in circulating exosomes, that could serve as biomarkers for the early detection of hepatocellular carcinoma as well as altered pathways in exosomes that may contribute to tumor development and progression.
A Case of Breast Cancer in a Patient with a Congenital Pectoralis Muscle Defect
Authors: Nakagawa Tsuyoshi , Oda Goshi , Kato Rie , Shinohara Hajime , Osanai Takayuki , Kumaki Yuichi , Takiguchi Noriaki , Mori Hiroki , Oyama Jun , Okamoto Kentaro , Uetake Hiroyuki
Published: July 2021

Congenital pectoral muscle defects are very rare, and when accompanied by limb defects, they are called Poland syndrome. A woman in her 70s, 4 years after partial mastectomy for breast cancer, underwent mastectomy for a local recurrence. During the operation, the pectoralis major and minor muscles were found to be defective. However, the patient did not have any limb defects. Although congenital pectoral muscle defects are very rare, it would be better to confirm defects of the pectoral muscle by preoperative diagnostic imaging such as CT because the postoperative treatment may be affected.
Ocular Injury Caused by the Bombardier Beetle
Authors: Villada Jose Ramon , Panos Maria Inmaculada , Del Cerro Irene , Granados Jose Manuel
Published: July 2021

We report a case of ocular injury caused by a bombardier beetle in a young boy. Ocular injuries due to this coleoptera have not previously been reported. An 11-year-old boy experienced an eye injury while trying to place a bombardier beetle inside an anthill. The boy was diagnosed with a second-degree burn on the skin of the upper right eyelid and conjunctival and corneal erosion in the right eye. The condition resolved completely after 2 weeks of appropriate treatment. Education about the dangers of playing with insects is crucial to prevent this type of lesions.
ERBB4 and Multiple MicroRNAs That Target ERBB4 Participate in Pregnancy-Related Cardiomyopathy
Authors: Feyen Eline , Ricke-Hoch Melanie , Van fraeyenhove Jens , Vermeulen Zarha , Scherr Michaela , Dugaucquier Lindsey , Viereck Janika , Bruyns Tine , Thum Thomas , Segers Vincent F.M. , Hilfiker-Kleiner Denise , De Keulenaer Gilles W.
Published: July 2021

Background:

Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without previously known cardiovascular disease. It is characterized by a sudden onset of heart failure before or after delivery. Previous studies revealed that the generation of a 16-kDa PRL (prolactin) metabolite, the subsequent upregulation of miR-146a, and the downregulation of the target gene
Erbb4
is a common driving factor of PPCM.

Methods:

miRNA profiling was performed in plasma of PPCM patients (n=33) and postpartum-matched healthy CTRLs (controls; n=36). Elevated miRNAs in PPCM plasma, potentially targeting ERBB4 (erythroblastic leukemia viral oncogene homolog 4), were overexpressed in cardiomyocytes using lentiviral vectors. Next, cardiac function, cardiac morphology, and PPCM phenotype were investigated after recurrent pregnancies of HZ (heterozygous) cardiomyocyte-specific
Erbb4
mice (

Erbb4
F/+
αMHC-Cre
+

, n=9) with their age-matched nonpregnant CTRLs (n=9–10).

Results:

Here, we identify 9 additional highly conserved miRNAs (miR-199a-5p and miR-199a-3p, miR-145a-5p, miR-130a-3p, miR-135a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, and miR19b-3p) that target tyrosine kinase receptor ERBB4 and are over 4-fold upregulated in plasma of PPCM patients at the time of diagnosis. We confirmed that miR-146a, miR-199a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, miR-130a-5p, and miR-135-3p overexpression decreases ERBB4 expression in cardiomyocytes (−29% to −50%;
P
<0.05). In addition, we demonstrate that genetic cardiomyocyte-specific downregulation of
Erbb4
during pregnancy suffices to induce a variant of PPCM in mice, characterized by left ventricular dilatation (postpartum second delivery: left ventricular internal diameter in diastole, +19±7% versus HZ-CTRL;
P
<0.05), increased atrial natriuretic peptide (ANP) levels (4-fold increase versus HZ-CTRL mice,
P
<0.001), decreased VEGF (vascular endothelial growth factor) and VE-cadherin levels (−33±17%,
P
=0.07; −27±20%,
P
<0.05 versus HZ-CTRL), and histologically enlarged cardiomyocytes (+20±21%, versus HZ-CTRL,
P
<0.05) but without signs of myocardial apoptosis and inflammation.

Conclusions:

ERBB4 is essential to protect the maternal heart from peripartum stress. Downregulation of ERBB4 in cardiomyocytes induced by multiple miRNAs in the peripartum period may be crucial in PPCM pathophysiology.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00998556.
PDE5 Inhibition Suppresses Ventricular Arrhythmias by Reducing SR Ca
2+
Content
Authors: Hutchings David C. , Pearman Charles M. , Madders George W.P. , Woods Lori S. , Eisner David A. , Dibb Katharine M. , Trafford Andrew W.
Published: July 2021

Rationale:

PDE5 (phosphodiesterase 5) inhibition reduces the occurrence of ventricular arrhythmias following myocardial ischemia. However, the mechanisms of the antiarrhythmic effects of PDE5 inhibition are unknown. Diastolic calcium (Ca
2+
) waves lead to arrhythmias by inducing delayed afterdepolarizations (DADs). Ca
2+
waves are initiated when sarcoplasmic reticulum (SR) Ca
2+
content reaches a threshold level and the SR releases Ca
2+
spontaneously and generates a depolarizing inward sodium-calcium exchange current.

Objective:

To determine the effects of PDE5 inhibition on the propensity for ventricular arrhythmias in a proarrhythmic large animal model and establish the role of alterations of intracellular Ca
2+
cycling/SR Ca
2+
content.

Methods and Results:

Arrhythmia burden, monophasic action potentials, and beat-to-beat variability of repolarization were measured in a sheep model using the
I
Kr
inhibitor dofetilide to induce QT prolongation and arrhythmia. Ca
2+
transients, Ca
2+
waves, and SR Ca
2+
content were measured in isolated ventricular myocytes. PDE5 inhibition was achieved using acute application of sildenafil, and PKG (protein kinase G) was inhibited with KT5823. PDE5 inhibition reduced beat-to-beat variability of repolarization and suppressed afterdepolarizations, premature ventricular complexes, and torsade de pointes in vivo. In single cells, dofetilide-induced delayed afterdepolarizations and triggered action potentials were suppressed by PDE5 inhibition. PDE5 inhibition decreased Ca
2+
wave frequency in all cells and abolished waves in 12 of 22 cells. A decrease in SR Ca
2+
uptake, increased trans-sarcolemmal Ca
2+
efflux, and reduced trans-sarcolemmal Ca
2+
influx led to a reduction of SR Ca
2+
content and Ca
2+
wave abolition. These effects were dependent on PKG activation.

Conclusions:

PDE5 inhibition acutely suppresses triggered ventricular arrhythmias in vivo, and cellular data suggests this occurs via suppression of cellular Ca
2+
waves. These novel antiarrhythmic properties of PDE5 inhibition are mediated by a reduction of SR Ca
2+
content and are PKG dependent.
Epigenetic Regulation by
Suv4-20h1
in Cardiopulmonary Progenitor Cells Is Required to Prevent Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease
Authors: Qi Hui , Liu Hang , Pullamsetti Soni Savai , Günther Stefan , Kuenne Carsten , Atzberger Ann , Sommer Natascha , Hadzic Stefan , Günther Andreas , Weissmann Norbert , Zhou Yonggang , Yuan Xuejun , Braun Thomas
Published: July 2021

Background:

The pathogenesis of life-threatening cardiopulmonary diseases such as pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) originates from a complex interplay of environmental factors and genetic predispositions that is not fully understood. Likewise, little is known about developmental abnormalities or epigenetic dysregulations that might predispose for PH or COPD in adult individuals.

Methods:

To identify pathology-associated epigenetic alteration in diseased lung tissues, we screened a cohort of human patients with PH and COPD for changes of histone modifications by immunofluorescence staining. To analyze the function of H4K20me2/3 in lung pathogenesis, we developed a series of
Suv4-20h1
knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types, followed by hemodynamic studies and morphometric assessment of tissue samples. Molecular, cellular, and biochemical techniques were applied to analyze the function of Suv4-20h1–dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives.

Results:

We discovered a strong reduction of the histone modifications of H4K20me2/3 in human patients with COPD but not patients with PH that depend on the activity of the H4K20 di-methyltransferase SUV4-20H1. Loss of
Suv4-20h1
in cardiopulmonary progenitor cells caused a COPD-like/PH phenotype in mice including the formation of perivascular tertiary lymphoid tissue and goblet cell hyperplasia, hyperproliferation of smooth muscle cells/myofibroblasts, impaired alveolarization and maturation defects of the microvasculature leading to massive right ventricular dilatation and premature death. Mechanistically, SUV4-20H1 binds directly to the 5′-upstream regulatory element of the superoxide dismutase 3 (
Sod3
) gene to repress its expression. Increased levels of the extracellular SOD3 enzyme in
Suv4-20h1
mutants increases hydrogen peroxide concentrations, causing vascular defects and impairing alveolarization.

Conclusions:

Our findings reveal a pivotal role of the histone modifier SUV4-20H1 in cardiopulmonary codevelopment and uncover the developmental origins of cardiopulmonary diseases. We assume that the study will facilitate the understanding of pathogenic events causing PH and COPD and aid the development of epigenetic drugs for the treatment of cardiopulmonary diseases.