bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-dose CT hounsfield units: a reliable methodology for assessing vertebral bone density in radiographic axial spondyloarthritis
Authors: Marques Mary Lucy , Pereira da Silva Nuno , van der Heijde Desirée , Reijnierse Monique , Baraliakos Xenofon , Braun Juergen , van Gaalen Floris A , Ramiro Sofia
Published: June 2022

Objective

Studying vertebral bone loss in radiographic axial spondyloarthritis (r-axSpA) has been challenging due to ectopic bone formation. We cross-sectionally analysed low-dose CT (ldCT) trabecular bone density Hounsfield units (HU) measurements and calculated inter-reader reliability at the vertebral level in patients with r-axSpA.

Methods

LdCT scans of 50 patients with r-axSpA from the sensitive imaging in ankylosing spondylitis study, a multicentre 2-year prospective cohort were included. Trabecular bone HU taken from a region of interest at the centre of each vertebra (C3-L5) were independently assessed by two trained readers. HU mean (SD), and range were provided at the vertebral level, for each reader and centre separately. Inter-reader reliability and agreement were assessed using intraclass correlation coefficients (ICC; single measurements, absolute agreement, two-way mixed effects models); smallest detectable difference and Bland-Altman plots.

Results

Overall, 1100 vertebrae were assessed by each reader. HU values decreased from cranial to caudal vertebrae. For readers 1 and 2 respectively, the highest mean (SD) HU value was obtained at C3 (354(106) and 355(108)), and the lowest at L3 (153(65) and 150 (65)). Inter-reader reliability was excellent (ICC(2,1):0.89 to 1.00). SDD varied from 4 to 8. For most vertebrae, reader 1 scored somewhat higher than reader 2 (mean difference of scores ranging from −0.6 to 2.9 HU). Bland-Altman plots showed homoscedasticity.

Conclusion

LdCT measurement of HU is a feasible method to assess vertebral bone density in r-axSpA with excellent inter-reader reliability from C3 to L5. These results warrant further validation and longitudinal assessment of reliability.
Clinical and laboratory aspects of condylomata lata lesions of syphilis
Authors: Towns Janet M , Denham Ian , Chow Eric P F , Graves Stephen , Fairley Christopher K , Williamson Deborah , Azzato Francesca , Chen Marcus Y
Published: June 2022

Objectives

Condylomata lata are a less common but distinctive syphilitic lesion. Variable theories as to their nature and origin exist. The aim of this study was to determine the clinical and laboratory characteristics of condylomata lata by determining (1): the most closely aligned stage of syphilis, based on the rapid plasma reagin (RPR) titre; (2) symptom duration and (3) Treponema pallidum PCR cycle threshold (CT) values, as an indicator of organism load.

Methods

This was a retrospective study of patients with T. pallidum PCR-positive condylomata lata lesions, attending a clinic in Melbourne, Australia, between 2011 and 2021. Syphilis serology was undertaken and RPR titres compared between condylomata lata, primary and secondary syphilis cases.

Results

51 cases with T. pallidum PCR-positive condylomata lata were included. 41 cases were in men, 40 of whom were men who have sex with men (MSM), and 10 in women. Twelve of 51 (24%) cases were in HIV-positive MSM. Thirty-three of 51 (65%) had other mucocutaneous signs of secondary syphilis; 18 (35%) had no other signs of secondary syphilis. The median RPR titre among the 51 condylomata lata cases was 1:128, compared with the median RPR titre of primary syphilis (1:4) and of secondary syphilis (1:128). The median duration of lesions was 24 (IQR 10–60) days, with no significant difference between those with and without other signs of secondary syphilis (p=0.75). Median CT values for condylomata lata (CT=31) and primary syphilis (CT=31) were significantly lower than for other secondary syphilis lesion types (CT=33), indicating higher T. pallidum loads for condylomata lata and primary lesions compared with other secondary syphilis lesion types.

Discussion

These findings support condylomata lata as lesions that occur during the secondary stage of syphilis and which are likely to be highly infectious.
Superintegrability in $$\beta $$-deformed Gaussian Hermitian matrix model from W-operators
Authors: Mishnyakov V. , Oreshina A.
Published: June 2022

This paper is devoted to the phenomenon of superintegrability. This phenomenon is manifested in the existence of a formula for character averages, expressed through the same characters at special points and of its various generalization. In this paper we develop a method of proving such formulas from first principle from Virasoro constraints and W-representation. We apply it to prove the formula for the Jack functions averages – appropriate analogue of characters for the $$\beta $$
β
-deformed Hermitian Gaussian matrix model. We also sketch the construction of W-operators from Calogero–Ruijsenaars Hamiltonians.
Target-Specific Drug Discovery of Natural Products against SARS-CoV-2 Life Cycle and Cytokine Storm in COVID-19
Authors: Lee Minjun , Park Junwoo , Cho Ik-Hyun
Published: June 2022

Coronavirus disease 2019 (COVID-19) is currently a worldwide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, there are no drugs that can specifically combat SARS-CoV-2. Besides, multiple SARS-CoV-2 variants are circulating globally. These variants may lead to immune escape or drug resistance. Natural products may be appropriate for this need due to their cost efficiency, fewer side effects, and antiviral activities. Considering these circumstances, there is a need to develop or discover more compounds that have potential to target SARS-CoV-2. Therefore, we searched for articles on natural products describing anti-SARS-CoV-2 activities by targeting the SARS-CoV-2 life cycle and the cytokine storm in COVID-19 from academic databases. We reviewed anti-SARS-CoV-2 activities of natural products, especially those that target the SARS-CoV-2 life cycle (angiotensin-converting enzyme 2, transmembrane serine protease 2, cathepsin L, 3CL protease, PL protease, RNA-dependent RNA polymerase, and helicase) and cytokine storm in COVID-19. This review may provide a repurposed approach for the discovery of specific medications using natural products to treat COVID-19 through targeting the SARS-CoV-2 life cycle and the cytokine storm in COVID-19.
Approximate counting and NP search problems
Authors: Kołodziejczyk Leszek Aleksander , Thapen Neil
Published: June 2022

We study a new class of NP search problems, those which can be proved total using standard combinatorial reasoning based on approximate counting. Our model for this kind of reasoning is the bounded arithmetic theory [Formula: see text] of [E. Jeřábek, Approximate counting by hashing in bounded arithmetic, J. Symb. Log.  74(3) (2009) 829–860]. In particular, the Ramsey and weak pigeonhole search problems lie in the new class. We give a purely computational characterization of this class and show that, relative to an oracle, it does not contain the problem CPLS, a strengthening of PLS. As CPLS is provably total in the theory [Formula: see text], this shows that [Formula: see text] does not prove every [Formula: see text] sentence which is provable in bounded arithmetic. This answers the question posed in [S. Buss, L. A. Kołodziejczyk and N. Thapen, Fragments of approximate counting, J. Symb. Log.  79(2) (2014) 496–525] and represents some progress in the program of separating the levels of the bounded arithmetic hierarchy by low-complexity sentences. Our main technical tool is an extension of the “fixing lemma” from [P. Pudlák and N. Thapen, Random resolution refutations, Comput. Complexity, 28(2) (2019) 185–239], a form of switching lemma, which we use to show that a random partial oracle from a certain distribution will, with high probability, determine an entire computation of a [Formula: see text] oracle machine. The introduction to the paper is intended to make the statements and context of the results accessible to someone unfamiliar with NP search problems or with bounded arithmetic.
Scheduling IoT Applications in Edge and Fog Computing Environments: A Taxonomy and Future Directions
Authors: Goudarzi Mohammad , Palaniswami Marimuthu , Buyya Rajkumar
Published: June 2022

Fog computing, as a distributed paradigm, offers cloud-like services at the edge of the network with low latency and high-access bandwidth to support a diverse range of IoT application scenarios. To fully utilize the potential of this computing paradigm, scalable, adaptive, and accurate scheduling mechanisms and algorithms are required to efficiently capture the dynamics and requirements of users, IoT applications, environmental properties, and optimization targets. This article presents a taxonomy of recent literature on scheduling IoT applications in Fog computing. Based on our new classification schemes, current works in the literature are analyzed, research gaps of each category are identified, and respective future directions are described.
Distinct mechanisms of light adaptation of elementary responses in photoreceptors of dipteran flies and American cockroach
Authors: Ignatova Irina I. , Frolov Roman V.
Published: June 2022

By studying light adaptation of elementary responses in photoreceptors of the blow fly and the cockroach we found three distinct mechanisms. In the blow fly, one mechanism speeds quantum bump onset and another accelerates quantum bump inactivation, decreasing its size. In the cockroach, quantum bump amplitude decreases without changes in kinetics, indicating decreased availability of transduction channels. The findings can be explained by expression of different transduction channels in the flies and cockroaches.
Software Optimization of Welding Machine Motion System Based on Switch Control Algorithm
Authors: Yin Jingbo , Liu Xing , Guo Xunde , Gudsla Lianwang
Published: June 2022

In order to improve the software optimization of welding machine motion system based on switch control algorithm. Based on soft switch arc welding power source current peak control the stability of the BUCK converter, the method by solving peak current control circuit transfer function, and to analyze the formation mechanism of soft switch arc welding power source external characteristic, the frequency of pulse current in the simulation model is set to 200 Hz, the base value of pulse current is 40 A, the peak value of pulse current is 500 A, and the duty cycle is 40%. The welding wire melting speed during the peak value of pulse current is 480 mm/s, while the base value of pulse current is 20 mm/s. The results show that in the 2 s moment of the simulation model, the welding torch suddenly drops from 40 mm height to 30 mm height. Inevitably, the arc length changes from about 16 mm before the step to about 6 mm, which is basically equal to the step change distance. Using pulse frequency modulation (PFM) and adaptive adjustment of pulse current related parameters, effectively eliminate the interference factors in the welding process, quickly adjust arc welding parameters to make the welding wire melting speed equal to the wire feeding speed, maintain the stability of the welding process, and improve the weld forming effect. It is of great significance to the software optimization of the motion system of the pulse welding machine.
An Effective Local Radial Basis Function Method for Solving the Delay Volterra Integral Equation of Nonvanishing and Vanishing Types
Authors: Khaksari Neda , Paripour Mahmoud , Karamikabir Nasrin
Published: June 2022

This paper presents a numerical method for solving a class of the delay Volterra integral equation of nonvanishing and vanishing types by applying the local radial basis function method. This method converts these types of integral equations into an easily solvable system of algebraic equations. To prove the method, we use the discrete collocation method and the local radial basis function method to approximate the delay Volterra integral equation. Also, we use the nonuniform Gauss–Legendre integration method to calculate the integral part appearing in the method. In addition, the existence, uniqueness, and convergence of the solution are investigated in this paper. Finally, some numerical examples are shown to observe the accuracy and effectiveness of the numerical method. Some problems have been plotted and compared with other methods. Obtained numerical results and their comparison with other methods show the reliability and accuracy of this method.
Privacy Protection and Intrusion Detection System of Wireless Sensor Network Based on Artificial Neural Network
Authors: Shi Lusheng , Li Kai
Published: June 2022

With the increasing openness and development of network technology, the network based on the wireless sensor network system has increasingly become an important tool for human social life and production, but it also brings some network security problems. Among them, focus is on network privacy disclosure and foreign intrusion and the research of intrusion detection and privacy protection has increasingly become an important topic of network security. This paper deeply studies the wireless sensor network system based on neural network on the basis of traditional privacy protection and intrusion detection system. Firstly, it applies particle swarm optimization algorithm and constructs a wireless sensor network intrusion detection system based on particle swarm optimization algorithm. The system includes important modules such as data extraction, data analysis, data feedback, and auxiliary decision-making. Compared with other algorithms, particle swarm optimization algorithm does not rely on problem information. It mainly uses real numbers to solve, so the algorithm has strong universality. At the same time, its corresponding principle is simple and easy to implement and less parameters need to be adjusted. Compared with other algorithms, particle swarm optimization algorithm has fast convergence speed and little memory requirement for the computer. At the same time, this paper uses the leap of particle swarm optimization algorithm to make it easier to find the global optimal solution. At the corresponding level of wireless sensor network privacy protection, based on the original data aggregation privacy protection scheme, this paper proposes a privacy protection scheme based on polynomial regression and a user privacy protection scheme based on the same state encryption, which further improves the security of privacy protection and facilitates the management of information. To realize the integrity of user privacy information protection, this paper realizes the decryption of data based on the correlation between binary metadata and compares the corresponding decrypted data with aggregated data, so as to complete the integrity of privacy data protection. The experimental results show that the binary metadata correlation decryption method proposed in this paper and the introduction of the corresponding particle swarm optimization algorithm improve the stability of the system by about 10%, the corresponding system security by a positive proportion, and the integrity of private data by about 10%; therefore, the algorithm proposed in this paper has obvious advantages.
High-Performance Computing Analysis and Location Selection of Logistics Distribution Center Space Based on Whale Optimization Algorithm
Authors: Yang Lijuan , Song Xiedong
Published: June 2022

As a meta-heuristic algorithm based on swarm intelligence, the WOA algorithm has few control parameters and searches for the optimal solution by encircling the prey, searching for the prey, and attacking the bubble net. During the whole process, only two internal parameters A and C are utilized for the control of the exploration and development process. BWOA is simple to implement. In the process of algorithm execution, the initial population, global exploration, and local development stages have shortcomings. Therefore, it is necessary to optimize the WOA algorithm. Based on WOA, this study conducts a high-performance computing analysis and location selection of logistics distribution center space. It is concluded that: (1) by using the combination of direct logistics distribution and hierarchical logistics distribution, the WOA algorithm optimizes the cross selection strategy, the population fitness S-LO is improved, the quality of LA is guaranteed, and the chaotic S-LO mapping eliminates inferior individuals in the population. Direct distribution is carried out for bulky goods and important distribution customers, and hierarchical logistics distribution is used for customers in intensive logistics distribution destinations. (2) WOA uses the second reverse learning, chaotic mapping, and logistic chaotic mapping to improve the location update mode. The direct distribution method is mostly used for the logistics business with short journeys, fixed distribution points, and more goods delivered at one time, and logistics enterprises do not need to store and distribute goods. The uniform ergodicity of the Tent chaotic map and logistic chaotic map is improved. Ka adaptive inertia weights are a good complement to optimize the limitations of the Ao whale algorithm. (3) The inertia weight of the levy flight behavior can play a powerful role in balancing the global exploration ability and optimization performance of the intelligent algorithm. The long-term short-distance search of HED and the long-distance jump of KVAR are combined. Variant individuals undergo vector synthesis. It reduces the construction and operation costs of logistics sites and is suitable for logistics distribution under specific conditions.
ARL4C Regulates the Progression of Clear Cell Renal Cell Carcinoma by Affecting the Wnt/β-Catenin Signaling Pathway
Authors: Zhang Peizhi , Xu Yingkun , Chen Shaoan , Wang Zicheng , Zhao Leizuo , Chen Chen , Kang Weiting , Han Rongyu , Qiu Jiechuan , Wang Qingliang , Gao Han , Wu Guangzhen , Xia Qinghua
Published: June 2022

Purpose. To investigate the expression of the ADP-ribosylation factor (ARF)-like proteins (ARLs) and ARL4C in clear cell renal cell carcinoma (ccRCC) based on bioinformatics analysis and experimentally determine the effect and mechanism of ARL4C on cellular properties involved in ccRCC progression. Methods. After downloading the data of cancer patients from the TCGA database, we used various bioinformatics analysis websites and methods to analyze the expression and function of ARLs and ARL4C. The differential expression of ARL4C in clinical renal cancer tissues versus adjacent normal tissues was further verified using immunohistochemistry and real-time quantitative reverse-transcription (qRT-PCR). qRT-PCR was used to explore the expression of ARL4C mRNA in normal renal cells versus different ccRCC cell lines, and the protein expression of ARL4C was further verified using western blotting. CCK-8, colony formation, and EdU assays were used to determine the effect of ARL4C knockdown on ccRCC cell proliferation. We also used wound healing and Transwell assays to analyze the changes in ccRCC cell migration and invasion following ARL4C knockdown. Finally, we used western blotting to probe the molecular mode of action of ARL4C in ccRCC cells after exposure to Wnt signaling pathway agonists. Results. Biological function analysis showed that methylation of ARL4C and changes in immune cell infiltration and targeted drug sensitivity caused by altered ARL4C expression affected the prognosis of ccRCC. Further bioinformatics analysis suggested that the expression of ARL4C mRNA was increased in ccRCC, and this was associated with a poor prognosis in ccRCC patients. Increased expression of ARL4C was further verified using qRT-PCR and western blotting of human ccRCC tissue samples. Downregulation of ARL4C significantly inhibited the proliferation, migration, and invasion of ccRCC cells, and activation of the Wnt/β-catenin pathway promoted the expression of ARL4C. As an essential downstream effector of the Wnt signaling pathway, ARL4C increased the expression of cyclin D1 and c-myc, thereby increasing the ability of the cells to undergo epithelial-mesenchymal transition (EMT) and ccRCC progression. Conclusions. As a critical factor in the Wnt/β-catenin pathway, ARL4C regulates EMT and progression in ccRCC.
Maackiain Prevents Amyloid‐Beta–Induced Cellular Injury via Priming PKC‐Nrf2 Pathway
Authors: Lu Na , Tan Guojun , Tan Hongling , Zhang Xing , Lv Yunling , Song Xiujuan , You Daofeng , Gao Ziyuan
Published: June 2022

Amyloid‐beta (Aβ) peptide induces neurotoxicity through oxidative stress and inflammatory response. Brain deposition of a large amount of amyloid‐beta (Aβ), in particular Aβ42, promotes the development of Alzheimer’s disease (AD). Maackiain is extracted from traditional Chinese medicine peony root and possesses antioxidative, antiosteoporosis, antitumor, and immunoregulatory effects. Whether Maackiain can reduce neurotoxicity caused by Aβ accumulation remains elusive. Herein, we found that Maackiain downregulated Aβ42‐induced cell injury and apoptosis in PC12 cells. Moreover, Maackiain prevented Aβ42 stimulation‐induced generation of oxidative stress and reduced Aβ42‐caused impairment of mitochondrial membrane potential in PC12 cells. Maackiain increased the superoxide dismutase activity and decreased malondialdehyde content that was induced by Aβ42. Mechanistic studies showed that Maackiain increased intranuclear Nrf2 expression. Consistently, Nrf2 silencing by RNA interference weakened the protective role of Maackiain against Aβ exposure. In addition, calphostin C, a specific antagonist of protein kinase C, attenuated the promoting effects of Maackiain on Nrf2 nuclear translocation. Moreover, calphostin C attenuated the antioxidant and anti‐inflammatory capabilities of Maackiain in PC12 cells. Collectively, Maackiain promoted Nrf2 activation through the PKC signaling pathway, thus preventing PC12 cells from Aβ‐induced oxidative stress and cell injury, suggesting that Maackiain is a potential drug for AD treatment.
Short-Term Stock Price Prediction Based on CAE-LSTM Method
Authors: Liu Hui , Qi Liangchen , Sun Mingsong
Published: June 2022

Artificial intelligence methods are important tools for mining information for forecasting in the stock market. Most of the literature related to short-term stock price prediction focuses on the technical data, but in the real market, many individual investors make investment decisions more from stock price shape characteristics rather than specific stock price values. Compared with traditional measurement methods, deep neural networks perform better in processing high-dimensional complex data such as images. This paper proposes a model that combines CAE (convolutional autoencoder) and LSTM (long short-term memory) neural network, uses CAE to extract stock price image feature data, and combines technical data to predict short-term stock prices. The results show that the CAE-LSTM model, based on stock price image morphological feature data and technical data, performs well in short-term stock price prediction and has good generalization ability. The root mean square error of the CAE-LSTM model decreased by about 4% from that of LSTM. CAE-LSTM models have better predictive power than LSTM models that only use technical indicator data as valid inputs.
Novel Analytical and Numerical Approximations to the Forced Damped Parametric Driven Pendulum Oscillator: Chebyshev Collocation Method
Authors: Alharthi M.R. , Salas Alvaro H. , Albalawi Wedad , El-Tantawy S.A.
Published: June 2022

In this work, some novel approximate analytical and numerical solutions to the forced damped driven nonlinear (FDDN) pendulum equation and some relation equations of motion on the pivot vertically for arbitrary angles are obtained. The analytical approximation is derived in terms of the Jacobi elliptic functions with arbitrary elliptic modulus. For the numerical approximations, the Chebyshev collocation numerical method is introduced for analyzing the equation of motion. Moreover, the analytical approximation and numerical approximation using the Chebyshev collocation numerical method and the MATHEMATICA command Fit are compared with the Runge–Kutta (RK) numerical solution. Also, the maximum distance error to all obtained approximations is estimated with respect to the RK numerical solution. The obtained results help many authors to understand the mechanism of many phenomena related to the plasma physics, classical mechanics, quantum mechanics, optical fiber, and electronic circuits.
A Study on Using Glass Fiber‐Reinforced Polymer Composites for Shear and Flexural Enhancement of Reinforced Concrete Beams
Authors: Kassa Hibretu Kaske , Melesse Getinet , Yabasa Gashahun
Published: June 2022

In the concrete construction sector, issues such as tensile strength of structural elements, brittle mode of failure, rapid crack propagation, and increased overload are common. The experimental evaluation of the flexural strengths of glass fiber‐reinforced polymers with various percent of glass fiber content is the focus of this study. Fiber‐reinforced polymer is the focus of numerous studies right now all over the world. Experimental investigations done on the behavior of the concrete strengthened using discontinuous chopped glass fiber were carried out with C‐25 concrete mix and 50 mm of glass fiber at various percentages (0.25%, 0.50%, 0.75%) of addition by the total weight of concrete. Experimental data on load for flexural tests have been carried out. Strength variations and failure modes of each specimen have been obtained. According to ASTM standards, at 7, 21, and 28 days after casting, all beams, such as control and fiber‐reinforced concrete beams, are tested by third point loading. The results of the flexural test indicated that the presence of glass fiber tends to increase the flexural strength of concrete at higher fiber content, and the bending test results indicated that the modulus of rupture of concrete in set I increases by 2.5% at 0.25% glass fiber, 11.3% at 0.50% glass fiber, 13.2% at 0.75% glass fiber at the end of 7 days, 1.19% at 0.25% glass fiber, 2.38% at 0.50% glass fiber and 9.94% at 0.75% glass fiber at the end of 21 days, 0.54% at 0.25% glass fiber, 1.89 at 0.50% glass fiber, and 2.45% at 0.75% glass fiber at the end of 28 days. Thus, ductility improves after concrete cracking, with 2.19% at 0.25% glass fiber, 10.19% at 0.50% glass fiber, and 13.60% at 0.75% glass fiber at the end of 28 days. As a result, the flexural strength of the content improves as well.
Investigation of the Bleeding Tendency in Sudanese Female Carriers of Hemophilia B
Authors: Abker Ismail Ali Abdallah , Elzaki Salaheldein G. , Elmahdi Salih Abdelgader , Tayrab Jowaria Eltayeb , Ahmed Samia Mahdi , Tayrab Eltayeb
Published: June 2022

Background. Hemophilia (HB) is an X‐linked, recessive bleeding disorder characterized by the deficiency or absence of the coagulation factor IX. Usually, females are carriers of the trait, while males are affected. FIX deficiency leads to uncontrollable bleeding events, and the severity is dependent on the levels of the clotting factor. The objective of this research was to measure the prevalence of bleeding tendency in Sudanese carriers of HB. Materials and Methods. In this cross‐sectional study, 88 Sudanese carriers of HB participated. The activated partial thromboplastin time test (APTT) and FIX test were performed for each carrier. The frequencies of DNA polymorphism and FIX‐linked restriction fragments BamHI, HhaI, and MnII were also assessed. The study was conducted in Khartoum, Sudan, during the period from 2015 to 2017. Results. The study showed that 55 (62.5%) HB carriers were from the Laban village in the White Nile State, and all of them were members of the Shinkheb tribe. The mean age of the study population was 26.3 years. Among the carriers, 57 (64.7%) had abnormal coagulation profiles. The mean value of the APTT level among carriers was significantly increased (P value: 0.000), while the mean concentration of the FIX levels among the carriers was significantly decreased (P value: 0.000). The study also showed a negative correlation between PTT and F assay with P value of 0.000 and R value of 0.578. Conclusion. The APTT is high in most carriers and the FIX assay level is low in most carriers. Most carriers had no symptoms and were not bleeding. The Shinkheb tribe is the most ethnic tribe carrying HB (62.5%). HhaII is more informative for carrier detection than others, but it is of significant value if both (MnII and HhaII) were performed in parallel. In Sudanese, BamHI was informative but MnII and HhaII were best in the mutation detection and for prenatal diagnosis.
Optimal Tracking Control for a Discrete Time Nonlinear Nuclear Power System
Authors: Luan Zhenhua , Wang Mengxuan , Zhang Yuzhen , Wei Qinglai , Zhou Tianmin , Guo Zhiwu , Ling Jun
Published: June 2022

Recently, increasing attention has been paid to nuclear power control with the appeals of clean energy and demands of power regulation to integrate into the power grid. However, a nuclear power system is a discrete-time (DT) nonlinear and complicated system, where the parameters entangle with intrinsic states. Furthermore, the need for huge computational ability due to the high-level order property in the nuclear reactor model causes many difficulties in the power control of nuclear industries. In this study, a new scheme of optimal tracking control for DT nonlinear nuclear power systems is provided to accomplish the power control of a 2500-MW pressurized water reactor (PWR) nuclear power plant. The proposed approach based on the value iteration method is a novel algorithm in the human intelligence community, which has a basic actor-critic structure with neural networks (NNs). The new approach has some modifications, where the cost function is redefined by leveraging the higher-order polynomial to substitute neural networks in the entire actor critic architecture. Simulation results of the 2500-MW PWR nuclear power plant are given to demonstrate the effectiveness of the developed method.
Calculation and Function of Composition Proportion in Photography Based on Digital Information Technology
Authors: Feng Guodong
Published: June 2022

In order to take better pictures, a method of composition proportion in photography based on digital information technology is proposed. Feature extraction is carried out from the captured pictures, and the modular customized design of digital information technology is adopted. The research is carried out in the two fields of image blur and approximate repeated image de redundancy. An improved image blur algorithm based on bag of words (bag of words) kernel function is proposed. The experimental results show that the coarse matching time is the time spent in matching a query image with thousands of images in the database, and the fine matching time is the time spent in matching a query image with eight candidate images with orb. The total query time is about 0.7 seconds, while it takes about 500 seconds to match thousands of images only with orb algorithm. In general, we combine coarse matching and fine matching, which can balance the accuracy and speed well. It is proved that the digital information technology proposed in this paper has a good effect in the calculation and function of composition proportion in photography.
Abstract A07: Activating mutations in uveal melanoma convey sensitivity to g-alpha q inhibition
Authors: Hitchman Tyler D. , Ceraudo Emilie , Moore Amanda R. , Shoushtari Alexander N. , Francis Jasmine H. , Guan Youxin , Chen Juliet , Chang Matthew T. , Taylor Barry S. , Sakmar Thomas P. , Huber Thomas , Chi Ping , Chen Yu
Published: June 2022

Uveal melanoma (UVM) is the most common intraocular malignancy, which represents about 5% of all melanoma cases per year in the United States. Half of all patients eventually develop metastatic disease, resulting in an average survival rate of six months and a five-year survival rate of ~15%. Recent studies have revealed the underlying genetic landscape of uveal melanoma but have not resulted in any therapeutic options to effectively treat UVM. UVMs harbor mutually exclusive activating mutations in GPCR signaling: ~90% in G-protein alpha q (Gq) subunits GNAQ/GNA11, ~5% in the GPCR CYSLTR2, and ~4% in a downstream effector. These mutations aberrantly activate canonical PLCβ signaling: cleavage of PIP2 into DAG and IP3, both of which lead to PKC activation. In addition to uveal melanoma, recent studies have shown this exact pathway to be activated in a subset of cutaneous and mucosal melanomas as well as other diseases like blue nevi, leptomeningeal melanocytic neoplasms (LMNs), and Sturge-Weber syndrome. My project focuses on understanding how Gq signals in UVM tumorigenesis and if Gq inhibition has therapeutic potential in UVM by addressing the following aims: 1) Using a highly specific Gq inhibitor, I will ask how Gq inhibition effects different activating mutations in UVM using representative in vitro models. I have generated melanocytes dependent on different mutations in the PLCβ pathway to study pathway inhibition and therapeutic efficacy. Based on my preliminary data I will also interrogate the mechanistic basis for Gq inhibition sensitivity in GNAQQ209L driven melanocytes. 2) Determining clinical potential of this drug by testing its pharmacologic properties in vivo. Using the melanocytes I have generated along with UVM cell lines and our GEMM, we will be able to thoroughly test the drug’s efficacy against a variety of xenografts. 3) Taking advantage of the ability to inhibit active Gq, I will aim to identify other pathways activated downstream of Gq using proteomic and transcriptomic approaches. This may provide alternative therapeutic strategies to target this recalcitrant disease. The outcome of this research will indicate the effectiveness of Gq inhibition in UVM as well as elucidate currently unknown signaling pathways essential for UVM tumorigenesis.

Citation Format: Tyler D. Hitchman, Emilie Ceraudo, Amanda R. Moore, Alexander N. Shoushtari, Jasmine H. Francis, Youxin Guan, Juliet Chen, Matthew T. Chang, Barry S. Taylor, Thomas P. Sakmar, Thomas Huber, Ping Chi, Yu Chen. Activating mutations in uveal melanoma convey sensitivity to g-alpha q inhibition [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A07.
Abstract A15: New treatment opportunities by in vivo and in vitro screening approaches in melanoma
Authors: Marocchi Federica , Granieri Letizia , Lotti Fiorenza , Palluzzi Fernando , Costanza Jole , Riva Laura , Bossi Daniela , Lanfrancone Luisa
Published: June 2022

Treatment of metastatic melanoma has been recently revolutionized by the use of targeted and immune inhibitors, though efficiently working only in a fraction of patients. Adverse effects still represent major challenges, as well as the rapid development of drug resistance upon treatment, thus suggesting that it is of utmost importance to elucidate additional molecular pathways and targets to better understand the biology of this tumor. In vivo RNAi screens done in patient-derived xenografts (PDXs) that fully phenocopy the original tumor of the patient represent a powerful tool to identify new putative essential and druggable candidates, and to repurpose drugs already approved for other indications. To this end we have recently generated a platform of melanoma PDXs with which we can recapitulate both melanoma growth and metastasization. We have performed in vivo shRNA screens, where we have found numerous and patient-specific epigenetic genes essential for tumor growth in vivo. With this platform, we have isolated novel frailties whose depletion favors cell senescence. Preliminary data using shRNA libraries of actionable genes for which drugs are already available suggest that specific drugs can be repurposed for melanoma treatment. We have proved that this approach can work in vivo, and we propose to convert it in an in vitro assay to rapidly translate new discoveries to the patient.

Note: This abstract was not presented at the conference.

Citation Format: Federica Marocchi, Letizia Granieri, Fiorenza Lotti, Fernando Palluzzi, Jole Costanza, Laura Riva, Daniela Bossi, Luisa Lanfrancone. New treatment opportunities by in vivo and in vitro screening approaches in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A15.
Abstract A20: 17-Aminogeldanamycin inhibits cytoprotective UPR pathways and cooperates with inhibitors of the MAPK signaling cascade in apoptosis induction
Authors: Mielczarek-Lewandowska Aleksandra H. , Hartman Mariusz L. , Sztiller-Sikorska Malgorzata M. , Osrodek Marta , Gajos-Michniewicz Anna E. , Czyz Malgorzata E.
Published: June 2022

Geldanamycin is an inhibitor of Heat Shock Protein 90 (HSP90). Attenuation of HSP90 activity results in accumulation of unfolded proteins, induction of endoplasmic reticulum (ER) stress, and activation of unfolded protein response (UPR). HSP90 is a chaperone protein participating in appropriate folding of more than 100 proteins, including IRE1α and BRAFV600E. In melanoma cells, BRAFV600E was correlated with chronically induced ER stress and involved in UPR-induced resistance to apoptosis. As geldanamycin is highly hepatotoxic, geldanamycin derivatives exerting similar proapoptotic properties but higher selectivity towards cancer cells are needed. In the present study, 17-aminogeldanamycin exerted higher proapoptotic activity than geldanamycin in patient-derived melanoma cell populations as demonstrated by using fluorescence time-lapse imaging (IncuCyte ZOOM). We have also shown that 17-aminogeldanamycin inhibits ERK1/2 activity and cell proliferation,as well as induces apoptosis transiently, enhancing expression of HSP70 and GRP78. GRP78 regulates activity of the UPR pathway, and we have demonstrated that 17-aminogeldanamycin inhibits IRE1α-dependent pathway of UPR responsible for degradation of unfolded proteins and reduces levels of 36 kDa product of ATF6 cleavage in selected melanoma cell populations. Moreover, we have shown that combination of 17-aminogeldanamycin and trametinib induces apoptosis earlier and more efficiently. Our study suggests that cooperation of 17-aminogeldanamycin and trametinib might result from concurrent inhibition of the MAPK and protective UPR pathways but can be also associated with the basal UPR activity, which is diverse among drug-naïve melanoma cell populations. Further studies are necessary to fully explore antimelanoma capabilities of 17-aminogeldanamycin and its combination with targeted therapy. This work was financially supported by Grant 2014/15/B/NZ7/00947 from National Science Centre (Poland), and 502-03/1-156-01/502-14-318 from Medical University of Lodz.

Citation Format: Aleksandra H. Mielczarek-Lewandowska, Mariusz L. Hartman, Malgorzata M. Sztiller-Sikorska, Marta Osrodek, Anna E. Gajos-Michniewicz, Malgorzata E. Czyz. 17-Aminogeldanamycin inhibits cytoprotective UPR pathways and cooperates with inhibitors of the MAPK signaling cascade in apoptosis induction [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A20.
Abstract A22: Effects of CDK4/6/MAPK targeting combinations on melanoma and the tumor immune microenvironment
Authors: Teh Jessica L.F. , Cheng Phil F. , Erkes Dan E. , Purwin Timothy J. , Field Conroy , Hollingworth Connor , Aguirre-Ghiso Julio , Levesque Mitch P. , Dummer Reinhard , Aplin Andrew E.
Published: June 2022

Trials utilizing cyclin-dependent kinases 4/6 (CDK4/6) inhibitor alone or in combination with BRAF and MEK inhibitors are under way in melanoma, but their use needs to be optimized. MEK plus CDK4/6i combinations lead to tumor regressions in vivo; however, residual disease and acquired resistance frequently persisted. Previously, we showed that amplification or mutation of NRAS was associated with acquired resistance in in vivo mutant NRAS models and mutant BRAF patient samples, respectively. These mechanisms led to upregulation of mTOR-S6 pathway. Here, we observed upregulation of dormancy signature and increased NR2F1 expression in residual disease. To further identify targetable pathway alterations associated with these resistance mechanisms, we have established longitudinal cell lines from multiple metastases from a single patient on the LOGIC2 (BRAF-MEK-CDK4/6i) trial. RPPA analysis highlights differences between the lines that we are further analyzing in functional assays. There is also increasing evidence that CDK4/6 inhibitors (CDK4/6i) may regulate the tumor immune microenvironment. We show that MEK plus CD4/6i led to better control of tumor growth in syngeneic models compared to immune-deficient NSG mice. The response to MEK plus CDK4/6i was associated with increased infiltration of CD8 positive T cells and T-cell activation markers. Together, we aim to identify mechanisms underlying resistance/tolerance to MEK plus CDK4/6i and to determine effects on the tumor immune microenvironment to inform potential new treatment strategies.

Citation Format: Jessica L.F. Teh, Phil F. Cheng, Dan E. Erkes, Timothy J. Purwin, Conroy Field, Connor Hollingworth, Julio Aguirre-Ghiso, Mitch P. Levesque, Reinhard Dummer, Andrew E. Aplin. Effects of CDK4/6/MAPK targeting combinations on melanoma and the tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A22.
Abstract A26: Humanized mouse model: A model to understand mechanisms of immune non-responsiveness to immune checkpoint inhibitors in melanoma
Authors: Somasundaram Rajasekharan , Samarkina Anastasia , Connelly Thomas , Choi Robin , Choi Hedy , Muthumani Kar , Xu Xiaowei , Kaestner Klaus , Herlyn Meenhard
Published: June 2022

Immune checkpoint inhibitor therapy (anti-CTLA4 or anti-PD1 antibodies) is rapidly emerging as a front-line treatment option for many solid tumors. However, only a third of melanoma patients respond to immune checkpoint blockade. Currently available mouse xenograft and transgenic models have many shortcomings and are unable to address the basis of therapy resistance and immune nonresponsiveness that are observed in patients. Thus, there is an urgent need to establish an in vivo model with a human immune microenvironment that can address issues of therapy resistance. Our laboratory has developed a novel humanized mouse melanoma model. Immunodeficient NSG mice were reconstituted with human CD34+ cells and after 8-12 weeks, mice are fully reconstituted with human innate (monocyte/myeloid lineage cells, dendritic cells and NK cells) and adaptive (T and B cells) immune cells. Humanized mice were then challenged with HLA-matched melanoma cells, and the functional ability of human immune cells to restrict tumor growth was monitored. Delayed tumor growth was observed in humanized mice, indicating in vivo sensitization of human immune cells to melanoma. This was confirmed by in vitro demonstration of human lymphocytes from tumor-bearing mice showing enhanced cytokine expression after stimulation with melanoma antigen peptides. In therapy studies, tumor-bearing humanized mice treated with anti-PD-1 showed restricted tumor growth. Anti-PD-1 therapy resulted in enhanced infiltration of T cells that correlated with tumor response. MassCyTOF studies were performed using a panel of immune markers to understand the mechanism of therapy nonresponsiveness in some tumors. Downmodulation of HLA-class I molecules and increased presence of FOXP3+ cells in the tumor region were seen. Our results suggest that humanized mouse melanoma model can be explored further to understand the causes of therapy resistance and immune nonresponsiveness.

Citation Format: Rajasekharan Somasundaram, Anastasia Samarkina, Thomas Connelly, Robin Choi, Hedy Choi, Kar Muthumani, Xiaowei Xu, Klaus Kaestner, Meenhard Herlyn. Humanized mouse model: A model to understand mechanisms of immune non-responsiveness to immune checkpoint inhibitors in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A26.
Abstract A28: Identification of NGLY1-mediated protein deglycosylation as a vulnerable point in melanoma
Authors: Lin Victor , Zolekar Ashwini , Mishra Nigam , Ho Yin Ying , Hayatshahi Hamed , Parab Abhishek , Sampat Rohit , Liao Xiaoyan , Hoffmann Peter , Liu Jin , Emmitte Kyle , Wang Yu-Chieh
Published: June 2022

Although NGLY1 is known as a pivotal enzyme that catalyzes the deglycosylation of denatured glycoproteins, information regarding the responses of human cancer and normal cells to NGLY1 suppression is limited. While studying the NGLY1 deficiency-caused neurodevelopmental variations in patients with a congenital deglycosylation disorder, we made an intriguing discovery that the expression of NGLY1 appears to be dysregulated in human melanoma cells. We have examined how NGLY1 expression affects viability, tumor growth, and responses to therapeutic agents in melanoma cells and an animal model. Molecular mechanisms contributing to NGLY1 suppression-induced anticancer responses were revealed by systems biology and chemical biology studies. Using computational and medicinal chemistry-assisted approaches, we established novel NGLY1-inhibitory small molecules. Compared with normal cells, NGLY1 was upregulated in melanoma cell lines and patient tumors. NGLY1 knockdown caused melanoma cell death and tumor growth retardation. Targeting NGLY1 in melanoma cells induced pleiotropic responses, predominantly stress signaling-associated apoptosis and cytokine surges, which synergize with the antimelanoma activity of standard chemotherapy and targeted therapy agents. Pharmacologic and molecular biology tools that inactivate NGLY1 elicited highly similar responses in melanoma cells. Unlike normal cells, melanoma cells presented distinct responses and high vulnerability to NGLY1 suppression. Our work demonstrated the significance of NGLY1 in melanoma cells, provided mechanistic insights into how NGLY1 inactivation leads to eradication of melanoma with limited impact on normal cells, and suggested that targeting NGLY1 represents a novel antimelanoma strategy with the opportunity of a broad therapeutic window.

Citation Format: Victor Lin, Ashwini Zolekar, Nigam Mishra, Yin Ying Ho, Hamed Hayatshahi, Abhishek Parab, Rohit Sampat, Xiaoyan Liao, Peter Hoffmann, Jin Liu, Kyle Emmitte, Yu-Chieh Wang. Identification of NGLY1-mediated protein deglycosylation as a vulnerable point in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A28.