bluuebunny/crossref_metadata_2025 huggingface dataset:
Decoupling Capability of Levitation Frames for Medium-Low Speed Maglev Trains
Authors: Hu Junxiong , Ma Weihua , Luo Shihui , Liu Wan , Qu Tianwei , Luo Huajun
Published: August 2021

Medium-low speed maglev trains (MSMTs) with a levitation gap of only 8–10[Formula: see text]mm need an adequate decoupling capability on the levitation frames to ensure stability control in levitation, while preventing the train from rolling sideways when in landing. Based on the geometric and kinematic relationships, two types of levitation frames are studied, i.e. levitation frame with end-set air spring (LFEAS) and levitation frame with mid-set air spring (LFMAS). For each levitation frame, the decoupling process and mechanism are analyzed, the analytical equations for the kinematic attitude are derived, the decoupling capability under different excitations is calculated, along with the effect of various structural parameters assessed. In addition, a test method is designed for the rolling of the levitation frame, particularly with the anti-rolling capability of the LFMAS measured. The results indicate that oscillation of the hanger rods and anti-rolling beams can compensate for displacement when the motion of the levitation frame is decoupled, which is the key to the decoupling capability. Also, the position of the anti-rolling devices and the length of hanger rods do not affect significantly the decoupling capability. However, a longer anti-rolling beam is more conducive to decoupling, but it does not affect the anti-rolling capacity of the levitation frame. The maximum roll computed of the LFMAS is 2.84[Formula: see text]mm, which meets the anti-rolling requirement.
The future is big graphs
Authors: Sakr Sherif , Bonifati Angela , Voigt Hannes , Iosup Alexandru , Ammar Khaled , Angles Renzo , Aref Walid , Arenas Marcelo , Besta Maciej , Boncz Peter A. , Daudjee Khuzaima , Valle Emanuele Della , Dumbrava Stefania , Hartig Olaf , Haslhofer Bernhard , Hegeman Tim , Hidders Jan , Hose Katja , Iamnitchi Adriana , Kalavri Vasiliki , Kapp Hugo , Martens Wim , Özsu M. Tamer , Peukert Eric , Plantikow Stefan , Ragab Mohamed , Ripeanu Matei R. , Salihoglu Semih , Schulz Christian , Selmer Petra , Sequeda Juan F. , Shinavier Joshua , Szárnyas Gábor , Tommasini Riccardo , Tumeo Antonino , Uta Alexandru , Varbanescu Ana Lucia , Wu Hsiang-Yun , Yakovets Nikolay , Yan Da , Yoneki Eiko
Published: August 2021

Ensuring the success of big graph processing for the next decade and beyond.
State-space Construction of Hybrid Petri Nets with Multiple Stochastic Firings
Authors: Hüls Jannik , Pilch Carina , Schinke Patricia , Niehaus Henner , Delicaris Joanna , Remke Anne
Published: August 2021

Hybrid Petri nets have been extended to include general transitions that fire after a randomly distributed amount of time. With a single general one-shot transition the state space and evolution over time can be represented either as a
Parametric Location Tree
or as a
Stochastic Time Diagram
. Recent work has shown that both representations can be combined and then allow multiple stochastic firings. This work presents an algorithm for building the
Parametric Location Tree
with multiple general transition firings and shows how its transient probability distribution can be computed using multi-dimensional integration. We discuss the (dis-)advantages of an interval arithmetic and a geometric approach to compute the areas of integration. Furthermore, we provide details on how to perform a Monte Carlo integration either directly on these intervals or convex polytopes, or after transformation to standard simplices. A case study on a battery-backup system shows the feasibility of the approach and discusses the performance of the different integration approaches.
The complex path to quantum resistance
Authors: Mashatan Atefeh , Heintzman Douglas
Published: August 2021

Is your organization prepared?
Protecting the global internet from technology cold wars
Authors: Chander Anupam
Published: August 2021

Considering the perceived dangers of the global information flow.
Welcome to AI Matters 7(2)
Authors: Leite Iolanda , Karpatne Anuj
Published: August 2021

Welcome to the second issue of this year's AI Matters Newsletter.

We start with a report on upcoming SIGAI Events by Dilini Samarasinghe and Conference reports by Louise Dennis, our conference coordination officer. In our regular Education column, Carolyn Rosé discusses the role of AI in education in a post-pandemic reality. We then bring you our regular Policy column, where Larry Medsker covers interesting and timely discussions on AI policy, for example whether governments should play a role in reducing algorithmic bias. This issue closes with an article contribution from Li Dong, one of the runner-ups in the latest AAIS/SIGAI dissertation award, on the use neural models to build natural language interfaces.
AI policy matters
Authors: Medsker Larry
Published: August 2021

AI Policy Matters is a regular column in AI Matters featuring summaries and commentary based on postings that appear twice a month in the AI Matters blog (https://sigai.acm.org/aimatters/blog/). We welcome everyone to make blog comments so we can develop a rich knowledge base of information and ideas representing the SIGAI members.
Influence of External Factors on Airborne Missile’s Horizontal Backward Launching
Authors: Pan Xiao , Jiang Yi , Hu Dong , Guan Huihui
Published: August 2021

This paper studies the influence of different external disturbance factors on the horizontal backward separation of airborne missiles on large transport aircraft. The method of comparison with experiment was adopted to verify the accuracy of the finite element model during the ejection process. By comparing the finite element model, it was confirmed that the all rigid body model and partly rigid body model are inaccurate in calculating the pitch angle and pitch velocity of the missile separation. Finally, the influences of ejection force, random vibration, and missile loading position on the ejection process are analyzed. The analysis found that the ejection force and the sliding distance will increase the vibration of the launching platform, therefore increase the separation pitch angle and the pitch velocity of the missile, but the influence of random vibration on platform is much greater than the other two factors, and it will also introduce randomness into the movement of the missile.
Creep Fracture Characteristics of Fractured Rock Mass Strengthened with Toughened Epoxy Resin
Authors: Wang Jun , Xu Junjie , Nie Zhipeng , Liu Lin , Qin Min , Ou Rongzi
Published: August 2021

For improving the toughness and long‐term strength of the fractured rock mass reinforced with epoxy resin and reducing the opening displacement of the crack tip, three types of converging cracks are established according to the deformation and failure characteristics of the rock mass, structural planes, and epoxy resin composite structure. The stress intensity factor of the type II compound crack and the analytical formula of the crack surface tip opening displacement are obtained. An improved Kelvin nonlinear creep model is proposed. Through the creep isochronous curve, the time and long‐term strength of accelerated creep failure are obtained, as well as creep rupture coupling characteristics. The ductile plastic deformation is used to characterize the toughness, and the toughness of epoxy resin is enhanced by adding mud powder, and the relationship between toughness and long‐term strength is established. Combined with experimental verification, when the drying mud powder content is 20%, the toughness of the epoxy resin has a good correlation with the long‐term strength; when the mud powder content exceeds 30%, its ductility and long‐term strength decrease, and at the same time the toughness effect is significantly weakened. The research results can provide a useful reference for toughened epoxy resin to strengthen fractured rock mass engineering.
An Influence Analytical Model of Dedicated Bus Lane on Network Traffic by Macroscopic Fundamental Diagram
Authors: Ma Yingying , Xie Yuanqi , Lin Yongjie
Published: August 2021

To study the influence mechanism of dedicated bus lanes on the urban road network, this paper proposes a novel analytical model of macroscopic fundamental diagram (MFD) and passenger macroscopic fundamental diagram (p-MFD) and the corresponding indicators based on MFD and p-MFD to evaluate the operation of the network. Taking the grid network as an example, this paper collects traffic flow to calibrate the developed MFD and p-MFD and evaluates the network performance under different proportions of dedicated bus lanes. The simulation results show that the larger the proportion of dedicated bus lanes, the greater the impact on the rising section and the stable section of MFD and the descending section and post-stable section of p-MFD. Further analysis for the sensitivity of simulation experiments found that the strategy of setting dedicated bus lanes will improve the efficiency of vehicle and passenger transport when the road network is in a smooth state and ensure the continuous output of passengers when the network is in a congested state.
Qualitative Property of Third-Order Nonlinear Neutral Distributed-Delay Generalized Difference Equations
Authors: Sumathy M. , Reddy P. Venkata Mohan , Manuel M. Maria Susai
Published: August 2021

This paper investigates the qualitative property of third-order nonlinear neutral distributed-delay generalized difference equations. By utilizing Philos-type technique and Riccati transformation, some oscillation criteria are presented to ensure that every solution of this equation oscillates or converges to zero. To illustrate the significance of our main result, we provide a suitable example.
Sendeng-4 Suppressed Melanoma Growth by Induction of Autophagy and Apoptosis
Authors: Du Rina , Zhao Pengwei , Wu Shikui , Gao Yaoxing , Wu Rina , Yang Minli , Song Wanying , Gao Haining
Published: August 2021

Sendeng-4 is a traditional Chinese medicine that has been successfully applied to anti-inflammatory diseases in clinical practice. Monomers within Sendeng-4 showed promising antitumor activity against lung cancer, colon cancer, and cutaneous cancer. However, potency of Sendeng-4 in melanoma has not been explored. This study aims to explore the potential application of Sendeng-4 in melanoma treatment. In the present study, we systemically investigate the possibility of Sendeng-4 for treatment of melanoma cancer in vitro by proliferation assay, colony formation, flow cell cytometry, RNA-seq, western blot, and fluorescence-based assay. Our data demonstrated that Sendeng-4 suppresses the proliferation and colony formation capacity of melanoma cells and induces cell cycle block at G2/M phase and eventually cell death. Mechanistically, transcriptome sequencing demonstrates that the PI3K-AKT pathway was significantly inactivated upon Sendeng-4 exposure, which was confirmed by western blot showing decreased phosphorylation of AKT. In addition, decreased BCL-2 expression and increased BAX expression were observed, suggesting programmed cell death via apoptosis. Moreover, LC3-II production as well as autophagosomes formation was observed as demonstrated by western blot and immunofluorescence, indicating elevated autophagy network by Sendeng-4 stimulation. Collectively, we concluded that Sendeng-4 might be used as an anticancer drug for melanoma.
Assessment of Major Animal Health Problems and Their Impact on Beef Cattle Production in Doba District of West Harerghe Zone, Ethiopia
Authors: Geletu Umer Seid , Musa Ahmedin Abdureman , Waqe Sisay Lemma , Usmael Munera Ahmednur , Mummed Yesihak Yusuf , Bari Fufa Dawo , Ibrahim Abdulmuen Mohammed
Published: August 2021

The aim of the current study was to assess the major animal health problems and their impact on beef cattle production in Doba district of West Harerghe Zone, Ethiopia. The study area was purposively selected, and a simple random sampling method was used to selected households’ fatteners from each kebele and interviewed using structured questionnaires. The present study showed that the overall prevalence of the diseases was internal and external parasite 93.3%, bloat 53.3%, black leg 71.1%, pasteurolosis 71.8%, wound 71.8%, FMD 22.2%, and anthrax 13.33% which affect fattening cattle, respectively, in the study area. All the respondents (100%) involved in the study were experienced with deworming of their animals to protect from parasites. But, only 46.7% and 42.2% of the respondents have accessed veterinary services with limited regularity and vaccination program, respectively, in the study area. Hence, the beef cattle fatting sector should be supported through considering alleviating the major disease affecting this sector and encouraging the farmers’ indigenous knowledge practice with technology.
Extended Spectrum Beta-Lactamase (ESBL) Produced by Gram-Negative Bacteria in Trinidad and Tobago
Authors: Akpaka Patrick Eberechi , Vaillant Angel , Wilson Clyde , Jayaratne Padman
Published: August 2021

Gram-negative bacterial infections are a global health problem. The production of beta-lactamase is still the most vital factor leading to beta-lactam resistance. In Trinidad and Tobago, extended spectrum beta-lactamase (ESBL) production has been detected and reported mainly in the isolates of Klebsiella pneumoniae and Escherichia coli and constitutes a public health emergency that causes high morbidity and mortality in some patients. In this literature review, the authors cover vast information on ESBL frequency and laboratory detection using both conventional and molecular methods from clinical data. The aim is to make the reader reflect on how the actual knowledge can be used for rapid detection and understanding of the spread of antimicrobial resistance problems stemming from ESBL production among common Gram-negative organisms in the health care system.
VR Technology to the Adjustment of Piano Playing Mentality
Authors: Zhang Yu
Published: August 2021

Piano performance requires not only skillful and excellent playing skills, but also good psychological quality and improvisation. The perfect performance is the natural language of a pianist's usual skill and mood. The various emotional activities and expressions of the overall situation in relation to the player's performance, mental issues such as the intensity and horror of the scene, seriously affect the pianist’s actual performance while playing. The piano is therefore very important for mind control. Based on this, this paper attempts to apply the current hot VR technology to piano performance and simulate the virtual piano performance scene through VR technology, so as to enhance the on-the-spot experience for piano players and continuously improve their psychological quality, so that they can better adjust their nervous bad mentality in actual combat. This article first has carried on the 3D virtual reality piano stage modeling experiment, and then selected the 20 young pianist piano training involved in day-to-day contrast test, the test group of 10 people for daily training, virtual piano stage under the environment of normal control group of 10 people ordinary daily training, training time four hours a day, for three months, all participants will take part in The Provincial Youth Piano Competition since the end of the training. The final test results showed that in the competition site, the performance level of 10 players in the test group was generally better than that of the control group. Among them, there were 2 subjects in the test group who played for a long time, while one of the control groups gave up playing in the middle. In addition, in the horizontal comparison, it is found that subjects who are older and have been learning piano for a long time have better on-the-spot mental adjustment ability and more stable performance. Boys performed better than girls, and subjects with positive, optimistic, and confident personalities performed better than those with introverted and low self-confidence.
Comparative Transcriptome Analysis Reveals Relationship among mRNAs, lncRNAs, and circRNAs of Slow Transit Constipation
Authors: Yan Shuai , Yue Yinzi , Sun Mingming , Chen Yinghui , Wang Xiaopeng , Qian Haihua
Published: August 2021

Background. Slow transit constipation (STC) is characterized by persistent, infrequent, or incomplete defecation. Systematic analyses of mRNA, lncRNA, and circRNA expression profiling in STC provide insights to understand the molecular mechanisms of STC pathogenesis. The present study is aimed at observing the interaction of mRNAs, lncRNAs, and circRNAs by RNA sequencing in vivo of STC. Methods. A rat model of STC was induced by loperamide. The expression profiles of both mRNAs and miRNAs were performed by RNA sequencing. Enrichment analyses of anomalous expressed mRNAs, lncRNAs, and circRNAs were performed in order to identify the related biological functions and pathologic pathways through the Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results. In total, 26435 mRNAs, 5703 lncRNAs, and 7708 circRNAs differentially expressed were identified between the two groups. The analyses of GO and KEGG show that (1) upregulated genes were enriched in a positive regulation of GTPase activity, cell migration, and protein binding and lipid binding and (2) GO annotations revealed that most trans‐target mRNAs are involved in the regulation process of immune signal together with the proliferation and differentiation of immune cells. Additionally, the protein‐protein interaction (PPI) network of differentially expressed (DE) mRNAs was constructed. Interestingly, all of the core lncRNAs and their coexpression mRNAs in this network are downregulated. Moreover, downregulated circRNAs have a set of target mRNAs related to immunoreaction, which was consistent with the overall tendency. Conclusion. Our investigation enriches the STC transcriptome database and provides a preliminary exploration of novel candidate genes and avenues expression profiles in vivo. The dysregulation of mRNAs, lncRNAs, and circRNAs might contribute to the pathological processes during STC.
Peroxisome Deficiency Dysregulates Fatty Acid Oxidization and Exacerbates Lipotoxicity in β Cells
Authors: Guan Hongbo , Guo Yanyan , Zhu Liangliang , Jiao Yisheng , Liu Xiaomei
Published: August 2021

An adverse intrauterine environment impairs the development of pancreatic islets in the fetus and leads to insufficient β cell mass and β cell dysfunction. We previously reported that Pex14, a peroxin protein involved in the biogenesis and degradation of peroxisomes, is markedly reduced in the pancreas of an intrauterine growth restriction fetus and last into adulthood. Peroxisomes function in a wide range of metabolic processes including fatty acid oxidization, ROS detoxification, and anti‐inflammatory responses. To elucidate the impact of downregulation of the Pex14 gene on β cell, Pex14 was knocked down by siRNA in INS‐1 cells. Pex14 knockdown disturbed peroxisomal biogenesis and dysregulated fatty acid metabolism and lipid storage capability, thereby increased ROS level and blunted insulin secretion. Moreover, Pex14 knockdown upregulated inflammation factors and regulators of endoplasmic reticulum stress. The lipotoxicity of fatty acid (including palmitic acid and linoleic acid) in β cells was exacerbated by knockdown of Pex14, as indicated by H2O2 accumulation and increased programmed cell death. The present results demonstrate the vital role of Pex14 in maintaining normal peroxisome function and β cell viability and highlight the importance of a functional peroxisomal metabolism for the detoxification of excess FAs in β cells.
A New Optimal Diagnosis System for Coronavirus (COVID‐19) Diagnosis Based on Archimedes Optimization Algorithm on Chest X‐Ray Images
Authors: Chen Liping , Rezaei Tahereh
Published: August 2021

The new coronavirus, COVID‐19, has affected people all over the world. Coronaviruses are a large group of viruses that can infect animals and humans and cause respiratory distress; these discomforts may be as mild as a cold or as severe as pneumonia. Correct detection of this disease can help to avoid its spreading increasingly. In this paper, a new CAD‐based approach is suggested for the optimal diagnosis of this disease from chest X‐ray images. The proposed method starts with a min‐max normalization to scale all data into a normal scale, and then, histogram equalization is performed to improve the quality of the image before main processing. Afterward, 18 different features are extracted from the image. To decrease the method difficulty, the minimum features are selected based on a metaheuristic called Archimedes optimization algorithm (AOA). The model is then implemented on three datasets, and its results are compared with four other state‐of‐the‐art methods. The final results indicated that the proposed method with 86% accuracy and 96% precision has the highest balance between accuracy and reliability with the compared methods as a diagnostic system for COVID‐19.
The Alterations and Potential Roles of MCMs in Breast Cancer
Authors: Liu Xinyu , Liu Ying , Wang Qiangshan , Song Siqi , Feng Lingjun , Shi Chunying
Published: August 2021

The minichromosome maintenance (MCM) protein family plays a key role in eukaryotic DNA replication and has been confirmed to be associated with the occurrence and progression of many tumors. However, the expression levels, functions, and prognostic values of MCMs in breast cancer (BC) have not been clearly and systematically explained. In this article, we studied the transcriptional levels of MCMs in BC based on the Oncomine database. Kaplan-Meier plotter was used to analyze prognostic value of MCMs in human BC patients. Furthermore, we constructed a MCM coexpression gene network and performed functional annotation analysis through DAVID to reveal the functions of MCMs and coexpressed genes. The data showed that the expression of MCM2–8 and MCM10 but not MCM1 and MCM9 was upregulated in BC. Kaplan-Meier plotter analysis revealed that high transcriptional levels of MCM2, MCM4–7, and MCM10 were significantly related to low relapse-free survival (RFS) in BC patients. In contrast, high levels of MCM1 and MCM9 predicted high RFS for BC patients. This study suggests that MCM2, MCM4–7, and MCM10 possess great potential to be valuable prognostic biomarkers for BC and that MCM1 and MCM9 may serve as potential treatment targets for BC patients.
Day-Ahead Scheduling for Renewable Energy Generation Systems considering Concentrating Solar Power Plants
Authors: Lu Xiaojuan , Cheng Leilei
Published: August 2021

With the advent of the new types of electrical systems that attach more importance to the renewability of the energy resource, issues arising out of the randomness and volatility of the renewable energy resource, such as the safety, reliability, and economic operation of the underlying power generation system, are expected to be challenging. Generally speaking, the power generation company can do a reasonable dispatch of each unit according to weather forecast and load demand information. Focusing on concentrating solar power (CSP) plants (wind power, photovoltaic, battery energy storage, and thermal power plants), this paper proposes a day-ahead scheduling model for renewable energy generation systems. The model also considers demand response and related generator set constraints. The problem is described as a mixed-integer nonlinear programming (MINLP) problem, which can be solved by the CPLEX solver to obtain an optimal solution. At the same time, the paper compares and analyzes the impact of concentrating solar power plants on other renewable energy generation and thermal power operation systems. The results show that the renewable energy generation system can lower power generation costs, reduce load fluctuation, and enhance the energy storage rate.
The Tibial Plateau Map: Fracture Line Morphology of Intra‐Articular Proximal Tibial Fractures
Authors: Kerschbaum Maximilian , Tyczka Morgane , Klute Lisa , Heller Marie Theres , Koch Matthias , Popp Daniel , Lang Siegmund , Alt Volker , Worlicek Michael
Published: August 2021

The purpose of this study was to characterize the patterns of a large series of tibial plateau fractures with the use of fracture mapping, with regard to different fracture types using the OTA/AO and Schatzker classification. Patients with intra‐articular fractures of the tibial plateau were evaluated, using the OTA/AO and Schatzker classification on CT scans. For fracture mapping, the axial slice that completely displayed the tibial joint plane was first identified, then matched to a template congruently, and the fracture lines were identified and reproduced. In addition to epidemiological data (age and gender), the trauma mechanism (high‐energy, low‐energy, and pathological fracture) was recorded. In total, 271 patients with 278 intra‐articular fractures of the tibial head were analyzed, including seven patients with both sides affected. The mean age was 49.1 years (men 46.3 years, women 53.5 years). The majority of fractures was caused by high‐energy trauma. No significant difference could be shown with respect to trauma mechanism and resulting fracture type in terms of OTA/AO (p = 0.352) or Schatzker classification (p = 0.884). A significant difference could be found with respect to gender and resulting fracture type in terms of OTA/AO (p = 0.031). 170 (61.2%) were OTA/AO type B fractures, and 108 (38.8%) were type C fractures. Using the Schatzker classification, we found 53 type I (19.1%), 60 type II (21.6%), 27 type III (9.7%), 32 type IV (11.5%), 16 type V (5.8%), and 90 type VI (32.4%) fractures. The main affection was found in the lateral and intermedial column of the tibial plateaus, concerning both OTA/AO and Schatzker classification. The variability of intra‐articular tibial head fractures is very high. In consequence, an individual analysis of fracture patterns and therapy planning by using CT scans is crucial.
Integration of Umbilical Cord Mesenchymal Stem Cell Application in Hydroxyapatite-Based Scaffolds in the Treatment of Vertebral Bone Defect due to Spondylitis Tuberculosis: A Translational Study
Authors: Rahyussalim Ahmad Jabir , Nugroho Ahmad , Zufar Muhammad Luqman Labib , Fathurrahman Irfan , Kurniawati Tri
Published: August 2021

Background. Vertebral bone defect represents one of the most commonly found skeletal problems in the spine. Progressive increase of vertebral involvement of skeletal tuberculosis (TB) is reported as the main cause, especially in developed countries. Conventional spinal fusion using bone graft has been associated with donor-site morbidity and complications. We reported the utilization of umbilical cord mesenchymal stem cells (UC-MSCs) combined with hydroxyapatite (HA) based scaffolds in treating vertebral bone defect due to spondylitis tuberculosis. Materials and Methods. Three patients with tuberculous spondylitis in the thoracic, thoracolumbar, or lumbar region with vertebral body collapse of more than 50 percent were included. The patient underwent a 2-stage surgical procedure, consisting of debridement, decompression, and posterior stabilization in the first stage followed by anterior fusion using the lumbotomy approach at the second stage. Twenty million UC-MSCs combined with HA granules in 2 cc of saline were transplanted to fill the vertebral bone defect. Postoperative alkaline phosphatase level, quality of life, and radiological healing were evaluated at one-month, three-month, and six-month follow-up. Results. The initial mean ALP level at one-month follow-up was

48.33
±
8.50
 
U
/
L

. This value increased at the three-month follow-up but decreased at the six-month follow-up time,

97
±
8.19
 
U
/
L

and

90.33
±
4.16
 
U
/
L

, respectively. Bone formation of 50-75% of the defect site with minimal fracture line was found. Increased bone formation comprising 75-100% of the total bone area was reported six months postoperation. A total score of the SF-36 questionnaire showed better progression in all 8 domains during the follow-up with the mean total score at six months of

2912.5
±
116.67

from all patients. Conclusion. Umbilical cord mesenchymal stem cells combined with hydroxyapatite-based scaffold utilization represent a prospective alternative therapy for bone formation and regeneration of vertebral bone defect due to spondylitis tuberculosis. Further clinical investigations are needed to evaluate this new alternative.
TRPV1 Channel Activated by the PGE2/EP4 Pathway Mediates Spinal Hypersensitivity in a Mouse Model of Vertebral Endplate Degeneration
Authors: Liu Sijing , Wang Qiong , Li Ziyi , Ma Lei , Li Ting , Li Yukun , Wang Na , Liu Chang , Xue Peng , Wang Chuan
Published: August 2021

Low back pain (LBP) is the primary cause of disability globally. There is a close relationship between Modic changes or endplate defects and LBP. Endplates undergo ossification and become highly porous during intervertebral disc (IVD) degeneration. In our study, we used a mouse model of vertebral endplate degeneration by lumbar spine instability (LSI) surgery. Safranin O and fast green staining and μCT scan showed that LSI surgery led to endplate ossification and porosity, but the endplates in the sham group were cartilaginous and homogenous. Immunofluorescent staining demonstrated the innervation of calcitonin gene‐related peptide‐ (CGRP‐) positive nerve fibers in the porous endplate of LSI mice. Behavior test experiments showed an increased spinal hypersensitivity in LSI mice. Moreover, we found an increased cyclooxygenase 2 (COX2) expression and an elevated prostaglandin E2 (PGE2) concentration in the porous endplate of LSI mice. Immunofluorescent staining showed the colocalization of E‐prostanoid 4 (EP4)/transient receptor potential vanilloid 1 (TRPV1) and CGRP in the nerve endings in the endplate and in the dorsal root ganglion (DRG) neurons, and western blotting analysis demonstrated that EP4 and TRPV1 expression significantly increased in the LSI group. Our patch clamp study further showed that LSI surgery significantly enhanced the current density of the TRPV1 channel in small‐size DRG neurons. A selective EP4 receptor antagonist, L161982, reduced the spinal hypersensitivity of LSI mice by blocking the PGE2/EP4 pathway. In addition, TRPV1 current and neuronal excitability in DRG neurons were also significantly decreased by L161982 treatment. In summary, the PGE2/EP4 pathway in the porous endplate could activate the TRPV1 channel in DRG neurons to cause spinal hypersensitivity in LSI mice. L161982, a selective EP4 receptor antagonist, could turn down the TRPV1 current and decrease the neuronal excitability of DRG neurons to reduce spinal pain.
Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor
Authors: Huang Yung-Hsin , Chen Chun-Wei , Sundaramurthy Venkatasubramaniam , Słabicki Mikołaj , Hao Dapeng , Watson Caroline J. , Tovy Ayala , Reyes Jaime M. , Dakhova Olga , Crovetti Brielle R. , Galonska Christina , Lee Minjung , Brunetti Lorenzo , Zhou Yubin , Tatton-Brown Katrina , Huang Yun , Cheng Xiaodong , Meissner Alexander , Valk Peter J.M. , Van Maldergem Lionel , Sanders Mathijs A. , Blundell Jamie R. , Li Wei , Ebert Benjamin L. , Goodell Margaret A.
Published: August 2021

Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations are unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, and found that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and acute myeloid leukemia development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease.

Significance:

DNMT3A has emerged as the most important epigenetic regulator and tumor suppressor in the hematopoietic system. Our study represents a systematic and high-throughput method to characterize the molecular impact of DNMT3A missense mutations and the discovery of a regulated destruction mechanism of DNMT3A offering new prognostic and future therapeutic avenues.

See related commentary by Ma and Will, p. 23.

This article is highlighted in the In This Issue feature, p. 1
Neck Circumference and Incidence of Type 2 Diabetes in Chinese Elderly Individuals: A Community-Based Cohort Study
Authors: Yan Qun , Sun Dongmei , Li Xu , Zheng QingHu , Long HaiNing , Feng Bo
Published: August 2021

Introduction: This study aimed to investigate whether neck circumference (NC) was associated with the incidence of type 2 diabetes in Chinese elderly individuals. Methods: A community-based cohort study was conducted on elderly inhabitants in Shanghai with a mean age of 71.0 ± 5.8 years (n = 2,646). Binary logistic regression analysis was performed to evaluate the association between NC and the prevalence of type 2 diabetes, while a Cox regression model was used to determine the association between NC and the incidence of type 2 diabetes after a follow-up of 2 years. Results: Logistic regression analysis showed that a larger NC was significantly associated with an increased risk for type 2 diabetes in men (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.07–1.31; p = 0.001) and women (OR 1.25, 95% CI 1.13–1.38; p < 0.001). Cox regression analysis revealed that NC was independently associated with the incidence of type 2 diabetes in both men (hazard ratio [HR] 1.14, 95% CI 1.05–1.23; p = 0.002) and women (HR 1.18, 95% CI 1.10–1.27; p < 0.001). Conclusions: A larger NC was associated with a higher risk of developing type 2 diabetes in Chinese elderly individuals. However, studies with larger sample sizes and longer follow-up durations are needed to definitively determine the relationship between NC and the risk of developing type 2 diabetes.
Stronger Association of Albuminuria with the Risk of Vascular Complications than Estimated Glomerular Filtration Rate in Type 2 Diabetes
Authors: Hong Xinyu , Huang Lingning , Zhang Yongze , Shen Ximei , Weng Suiyan , Zeng Feihui , Zhao Fengying , Yan Sunjie
Published: August 2021

Introduction: Albuminuria is a risk factor for macro- and microvascular complications of type 2 diabetes (T2D).With an increasing trend of normoalbuminuria, however, of the 2 predictors – estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) – which one is a better predictor of vascular complications of T2D is not clear. Objective: This study aimed to compare the impacts of albuminuria and eGFR on patients with T2D associated with micro- and macrovascular complications. Methods: This retrospective study recruited 4,715 patients with T2D and grouped them based on the values of UACR (high UACR: ≥30 mg/g, low UACR: <30 mg/g) and eGFR (mL/[min × 1.73 m2]) (G1: eGFR ≥ 90; G2: eGFR = 60–89; G3–5: eGFR < 60) from April 2008 to November 2018. Logistic regression analysis was carried out for risk factors in patients with diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD), left ventricular remodeling, diastolic disorders, and carotid atherosclerotic plaque in 6 different groups: low UACR + G1 (control group), low UACR + G2, low UACR + G3–5, high UACR + G1, high UACR + G2, and high UACR + G3–5. Patients were grouped according to the change in the UACR value (UACR-decreased group: ≤−30%, UACR-stable group: −30 to 30%, and UACR-increased group ≥30%), eGFR value (eGFR-decreased group: >3%, and eGFR-stable group: ≤3%) and followed up. Results: Compared with the control group, patients with higher albuminuria and lower eGFR had higher adjusted odds ratio (OR) trends of complications, especially in the high UACR + G3–5 group. The OR of 2.010, 3.444, 1.633, 2.742, and 3.014 were obtained for DR, DPN, PAD, left ventricular remodeling, and diastolic disorders, respectively. No statistically significant difference was found in the risk of complications within each one of 2 phenotypes, regardless of the change in the eGFR. After grouping by eGFR, the regression analysis of the urinary protein level in each stage revealed that a majority of complications had a statistically significant difference, except for DR and PAD in the high UACR + G3–5 group. DR in the follow-up study had a higher risk in the UACR-stable/increased group than the UACR-decreased group (UACR stable: OR = 2.568; 95% confidence interval (CI): 1.128–5.849; p = 0.025; UACR increased: OR = 2.489; 95% CI: 1.140–5.433; p = 0.022). Conclusion: UACR is a more predictive risk factor for diabetic complications compared with a reduced eGFR.
T-Cell Immune Imbalance in Rheumatoid Arthritis Is Associated with Alterations in NK Cells and NK-Like T Cells Expressing CD38
Authors: Wang Hongxing , Fang Kehua , Yan Weining , Chang Xiaotian
Published: August 2021

Background: CD38+ NK (CD3− CD16+ CD38+ CD56+) cells were increased in rheumatoid arthritis (RA), which suppressed Treg cell differentiation. This study explored how CD38+ NK cells regulated CD4+ T-cell differentiation into Treg cells in RA. Methods: Proportions of CD38+ NK cells and their counterpart CD38+ NK-like T (CD3+ CD16+ CD38+ CD56+) cells were measured in RA and rats with collagen-induced arthritis (CIA). CD38+ NK cells and CD38+ NK-like T cells were cocultured with CD4+ T cells, respectively. Results: A significantly increased proportion of CD38+ NK cells and a decreased proportion of CD38+ NK-like T cells were detected in RA and CIA blood and synovial fluids. When CD4+ T cells were cocultured with CD38+ NK cells, mammalian target of rapamycin (mTOR) signaling was activated, and Th1/Th2 and Th17/Treg ratios were increased. When CD38+ NK cells were pretreated with anti-CD38 antibody, Treg cell proportion was increased, and Th1/Th2 and Th17/Treg ratios were decreased. CD38+ NK-like T cells showed the opposite results. CD38+ NK cells and CD38+ NK-like-T cells activated differential gene expressions and pathways in CD4+ T cells and initiated Th1 and Th2 cell differentiation by differential gene nodes. Conclusions: This study suggest that the high CD38+ NK cell proportion and low CD38+ NK-like T cell proportion in RA suppress Treg cell differentiation by stimulating mTOR signaling in CD4+ T cells, which consequentially disturbs the immune tolerance.
Celastrol Exerts Cardioprotective Effect in Rheumatoid Arthritis by Inhibiting TLR2/HMGB1 Signaling Pathway-Mediated Autophagy
Authors: Lu Xiaohong , Gong Sha , Wang Xiaojun , Hu Nan , Pu Dan , Zhang Jing , Wang Yanhua , Luo Jing , An Qi , Ju Bomiao , He Lan
Published: August 2021

Objective: Rheumatoid arthritis (RA) is a kind of chronic inflammatory disease characterized by the release of inflammatory cytokines and cardiomyocyte apoptosis, which lead to increased riskfor heart diseases. This study aims to explore the possible effect and mechanism of Celastrol on RA induced cardiac impairments in rats. Methods: Collagen induced RA wistar rat models (CIA) were established for the measurement on secondary foot swelling degree, polyarthritis index score, spleen and thymus index. Pathological morphology was observed using H&E staining. Heart fibrosis was measured after Sirius red staining, while cell apoptosis was determined by TUNEL staining. For in vitro experiments, rat cardiomyocytes were isolated to determine the inflammatory cytokine secretion and cell apoptosis using ELISA and flow cytometry, respectively. Protein expressions of related index and autophagy were detected by Western blot and immunofluorescence. Results: CIA rat model was successfully established and characterized by severe secondary foot swelling degree, and increased polyarthritis index score and spleen and thymus index. Synovial hyperplasia, disordered cardiomyocytes, cell infiltration and fibrosis were also observed in CIA rat model. Compared with CIA model, Celastrol treatment could suppress the release of inflammatory cytokines, including TNF-α, IL-6, IL-1β, as well as inhibiting the expressions of Bax, cleaved caspase3, collagen I, collagen III and α-SMA. In addition to that, Celastrol treatment can attenuate cell apoptosis and fibrosis of cardiomyocytes and elevate Bcl-2 expression. RA induced cell autophagy can be suppressed by Celastrol through inhibiting the activation of TLR2/HMGB1 signal pathway. Conclusion: Celastrol can regulate TLR2/HMGB1 signal pathway to suppress autophagy and therefore exert cardioprotective effect in RA.
Early-Onset Vascular Dementia in a 43-Year-Old Man with Accelerated Atherosclerotic Disease, Elevated Lipoprotein (a), and a Missense DNAJC5 Variant with Potential Association to Adult-Onset Ceroid Lipofuscinosis
Authors: Faruq Ridwan Naim , D’Silva Prajna , Lau Freddy Duarte , Zhao Chen , Majumdar Sachin
Published: August 2021

Early-onset dementia is defined as dementia occurring prior to the age of 65. Given its impact on physical, mental, and socioeconomic well-being, it is crucial to identify modifiable risk factors. Here, we report a 43-year-old man with early-onset dementia associated with elevated lipoprotein (a) and a missense variant in the DNAJC5 gene. He presented to the hospital with memory loss and multiple cerebrovascular infarcts. Eight months prior, an MRI revealed small acute and subacute infarcts involving the left PCA for which he was treated with antiplatelet agents and a statin. Three months later, he was readmitted for progressive memory loss. CT imaging showed evolving and new infarcts compared to prior scans. A cardiac echocardiogram excluded thrombus and PFO, and he was diagnosed with early vascular dementia. He was readmitted again 5 months later with additional evaluation revealing multifocal moderate to severe stenosis and irregularities involving the bilateral ICA and bilateral PCAs. MRI showed more pronounced infarcts compared to a previous MRI as well as new infarcts. CSF studies, VDRL, RF, ANA, ANCA, homocysteine, and MMA levels were normal. Lipoprotein (a) was found to be markedly elevated, and genetic testing revealed a missense variant of the DNAJC5 gene, the mutation of which is associated with ceroid lipofuscinosis. In conclusion, in patients with early-onset dementia and evidence of accelerated atherosclerosis, it is reasonable to measure Lp(a) and consider testing for variants in genes such as DNAJC5 and others, particularly when disease severity appears unexplained by known risk factors or circumstances.
Intraocular Endoscopy Resolved Tube Occlusion of an Ahmed Glaucoma Valve
Authors: Kawashima Rumi , Baba Keita , Matsushita Kenji , Soma Takeshi , Kurashige Masako , Umeda Daisuke , Nakamura Makoto , Morii Eiichi , Nishida Kohji
Published: August 2021

We report a case in which intraocular endoscopy clarified the cause of Ahmed glaucoma valve (AGV) failure with a cloudy cornea. A 42-year-old patient with glaucoma underwent AGV implant surgery to treat secondary glaucoma due to chronic iridocyclitis in his left eye. After AGV, he developed bullous keratopathy (BK) in that eye. After Descemet stripping automated endothelial keratoplasty (DSAEK) was performed to treat BK, the intraocular pressure (IOP) increased and early failure of the DSAEK resulted again in a cloudy cornea. We could not precisely detect any cause of AGV failure with ordinary imaging instrumentation. An intraocular endoscope was used to determine that cause, and we found that the fibrous tissue occluded the tube of the AGV. The IOP decreased soon after the tissue was removed. We conclude that intraocular endoscopy was useful for diagnosing AGV failure with BK.
St. John’s Wort (Hypericum perforatum)-Related Acute Kidney Injury
Authors: Adibelli Zelal , Karacay Ilayda , Demir Murat , Duran Cevdet
Published: August 2021

Some herbal products were reported to cause nephrotoxicity through different mechanisms. This case report defines an acute kidney injury (AKI) in a patient who used Hypericum perforatum tea as a sleep disorder remedy. The patient developed AKI after ingestion of tea prepared from Hypericum perforatum and underwent hemodialysis because of acute kidney failure. After 1 week, the kidney recovered, and she was discharged with normal kidney function. This is the first case reported having acute kidney failure caused by ingestion of Hypericum perforatum.
A Relapsing Meningeal Acute Myeloid Leukaemia FLT3-ITD+ Responding to Gilteritinib
Authors: Perrone Salvatore , Ortu La Barbera Elettra , Viola Federica , Cipollone Elena , Scerpa Maria Cristina , Siniscalchi Roberta , Ottone Tiziana , Voso Maria Teresa , Cimino Giuseppe
Published: August 2021

A patient with a therapy-related acute myeloid leukaemia (AML), NPM1mut, and FLT3-ITD+ was treated with induction and consolidation with CPX-351, obtaining a complete response (CR) but minimal residual disease persisted positive. Later, she complained progressive burning leg pain, weakening of the right hand and leg muscles, associated with absence of osteotendinous leg reflexes. Examination of cerebrospinal fluid (CSF) showed a meningeal relapse of AML. Moreover, a magnetic resonance imaging (MRI) showed 2 right meningeal implants of myeloid sarcoma and bone marrow revealed haematologic relapse of disease. She was treated with medicated lumbar punctures (LPs) followed by an FLA-Ida scheme, and she achieved a 2nd CR. Unfortunately, the patient developed hyperleucocytosis and reappearance of meningeal myeloid sarcoma at MRI. For this reason, a monotherapy with gilteritinib (an FLT3 inhibitor) was started: after 3 months of therapy, central nervous system (CNS)-disease shrunken and then faded, while AML in the bone marrow achieved only a partial response. This is the 1st report of a positive biological effect of gilteritinib on CNS (meningeal) myeloid sarcoma. There are no studies of gilteritinib concentration into CSF and penetration of gilteritinib into the blood-brain barrier should be further studied, given the paucity of drugs active on CNS relapse of AML. In patients receiving CPX-351 only, diagnostic LP should be considered after induction.
Localized Tenosynovial Giant Cell Tumor: An Incidentally Found Lesion in the Shoulder
Authors: Lopes Jorge Gomes , Gutierres Manuel , Vital Luisa , Relvas-Silva Miguel , São-Simão Ricardo , Serdoura Francisco
Published: August 2021

The concept of localized and diffuse tenosynovial giant cell tumors (TSGCT) is recent and may still cause some confusion among surgeons. This disorder constitutes a family of proliferative lesions characterized by their origin in the articular synovium, tendon sheaths, or bursa. It is not always easy to diagnose this pathology, especially due to its multitude of presentation. We describe an incidentally found localized TSGCT intra-articularly located in the shoulder. The localized lesions are considered a more benign form that usually present not with specific symptoms but rather a manifestation of the disturbance in the affected joint or the surrounding soft tissues. MRI is indispensable for its diagnosis, and the standard treatment is complete surgical resection. Due to its low incidence, it is difficult to find literature that goes beyond clinical reports or small case series. With this report, we intend to call readers’ attention for the variable presentations, the different diagnostic and treatment strategies, and the expected outcomes.