bluuebunny/crossref_metadata_2025 huggingface dataset:
An Improved Method of Polyp Detection Using Custom YOLOv4-Tiny
Authors: Doniyorjon Mukhtorov , Madinakhon Rakhmonova , Shakhnoza Muksimova , Cho Young-Im
Published: October 2022

Automatic detection of Wireless Endoscopic Images can avoid dangerous possible diseases such as cancers. Therefore, a number of articles have been published on different methods to enhance the speed of detection and accuracy. We also present a custom version of the YOLOv4-tiny for Wireless Endoscopic Image detection and localization that uses a You Only Look Once (YOLO) version to enhance the model accuracy. We modified the YOLOv4-tiny model by replacing the CSPDarknet-53-tiny backbone structure with the Inception-ResNet-A block to enhance the accuracy of the original YOLOv4-tiny. In addition, we implemented a new custom data augmentation method to enhance the data quality, even for small datasets. We focused on maintaining the color of medical images because the sensitivity of medical images can affect the efficiency of the model. Experimental results showed that our proposed method obtains 99.4% training accuracy; compared with the previous models, this is more than a 1.2% increase. An original model used for both detection and the segmentation of medical images may cause a high error rate. In contrast, our proposed model could eliminate the error rate of the detection and localization of disease areas from wireless endoscopic images.
Instability of High Liquid Limit Soil Slope for the Expressway Induced by Rainfall
Authors: Jiang Jian-Jie , Cui Zhen-Dong
Published: October 2022

The instability of high liquid limit soil slope is a common engineering problem in highway construction. This study focused on the slope at section K79 + 880 of the Guang-Le Expressway in Guangdong Province, China. In order to reduce the landslide and learn the mechanism of the high liquid limited soil slope, the effects of different rainfall intensities and rainfall time on the high liquid limit soil slope were studied by in-site monitoring and numerical simulation. According to the characteristics of the slope deformation and the monitoring data, the slope landslide is divided into three grades. Numerical simulation results show that the influence of rainfall intensity on the safety factor of high liquid limit soil slope is greater than that of rainfall time. At the slope top, the cumulative changes of Mises stress in Group B and Group C were −2.19 kPa and −2.91 kPa, respectively, and the cumulative decreases were −7.22% and −9.60%, respectively. At the slope bottom, the cumulative changes of Mises stress in Group B and Group C were −2.05 kPa and −4.32 kPa, respectively, and the cumulative decreases were −4.50% and −9.48%, respectively. With the increase of rainfall for 24 h, the safety factor of Group C decreased by an average of 0.0408, and with the increase of rainfall time, the safety factor increased, and the safety factor of 96 h of rainfall in Group C was 0.1249 lower than that of 24 h of rainfall. The greater the rainfall intensity, the greater the change of matrix suction at the top of the slope, and the more prone the top of the slope to shallow landslides. For the high liquid limit soil slope, slope instability phenomena such as surface flow collapse occur easily and have little impact on the deep sliding surface. The dimensionless displacement coefficient K is proposed to quantify the landslide displacement under different rainfall. A general method is proposed to measure the cumulative displacement of the K79 + 880 slope where the sensor is not placed.
Stimulated Brillouin Scattering Threshold in Presence of Modulation Instability for Optical Pulse in Long Optical Fiber
Authors: Hu Xiaoyang , Huang Qiuyang , Lu Yang , Meng Zhou
Published: October 2022

A theoretical and experimental study on the stimulated Brillouin scattering (SBS) threshold for optical pulse in the presence of modulation instability (MI) in long optical fiber is presented. The effects of MI on the SBS gain and threshold are analyzed based on the coupled-wave equation. An analytic expression is obtained to calculate the SBS threshold in the presence of MI. Numerical simulation is conducted to study the effects of the repetition rate and amplified spontaneous emission (ASE) noise on the SBS threshold for optical pulses. An experiment is conducted, and the results agree well with the theoretical analysis. The results clearly reveal how MI affects the Brillouin gain and SBS threshold of optical pulses in long optical fiber. The SBS threshold is affected by the ASE noise level and the repetition rate of the optical pulse. The study is helpful for the power evaluation of interferometric fiber sensing systems and optical power transmission systems.
A 7–13 GHz 10 W High-Efficiency MMIC Power Amplifier in 0.25 µm GaN HEMT Process
Authors: Hu Aizhen , Leng Yongqing , Qiu Xin , Luan Tongyao , Peng Yatao
Published: October 2022

With the increase in applications of the millimeter wave spectrum for phased array radar systems, mobile 7–13 communication systems, and satellite systems, the demand for a wideband, high-efficiency, high-power monolithic microwave integrated circuit (MMIC) power amplifier (PA) is increasing. In this paper, a 7–13 GHz 10 W high-efficiency MMIC PA is designed. This amplifier consists of a two-stage circuit structure with two high electron mobility transistor (HEMT) cells for the driver stage and four HEMT cells for the power stage. To ensure high efficiency and a certain output power (Pout), both the driver–stage and power–stage transistors use a deep Class–AB bias. At the same time, in order to further improve the efficiency, low-loss and second–harmonic tuning techniques are used in the output and inter-stage matching networks, respectively. Finally, the electromagnetic simulation results show that within a frequency of 7–13 GHz, the amplifier achieves an average saturated continuous wave (CW) Pout of 40 dBm, a small signal gain of 14.5–15.5 dB, a power-added efficiency (PAE) of 30–46%, and the input and output return loss are better than 5 dB and 8 dB, respectively.
Strength Characteristics and In Situ Stress Measurement of Rock Cores from a Large Section Underground Station: A Case Study
Authors: Li Diyuan , Zhou Aohui , Wang Lichuan , Chen Yuda , Ma Chunde
Published: October 2022

Chongqing is a mountain city in western China with a complex geological environment, which brings many difficulties to the construction of large sections of underground projects. In order to avoid serious problems in the construction of Guobo Station with large sections, intensive coring and laboratory tests were carried out to obtain the rock mass properties in detail. The boreholes reveal that the lithology of the rock mass in the project area consists mainly of mudstone and a small area of sandstone. The uniaxial compressive strength (UCS) and the Brazilian tensile strength (BTS) of mudstone are highly scattered, which are 4.43~42.43 MPa and 0.66~4.30 Mpa, respectively, but they all show a lognormal distribution. The average UCS of sandstone is 65.31 MPa, and the BTS is 3.06 MPa. Meanwhile, the softening coefficients of mudstone and sandstone are 0.33 and 0.73, which indicate that the water content has a great influence on the mechanical properties of the rock. For the in situ stress field, the relationship between the three principal stresses is as follows: the maximum horizontal principal stress > minimum horizontal principal stress > vertical principal stress, and the lateral pressure coefficient is 2.11~5.71. Based on the present experimental results, it is proposed that the potential risks of excavation include: (1) bias pressure (2) high in situ stress; (3) surrounding rock deterioration.
Machine Learning Based Predictive Modeling of Electrical Discharge Machining of Cryo-Treated NiTi, NiCu and BeCu Alloys
Authors: Jatti Vijaykumar S. , Dhabale Rahul B. , Mishra Akshansh , Khedkar Nitin K. , Jatti Vinaykumar S. , Jatti Ashwini V.
Published: October 2022

The advancement in technology has attracted researchers to electric discharge machining (EDM) for providing a practical solution for overcoming the limitations of conventional machining. The current study focused on predicting the Material Removal Rate (MRR) using machine learning (ML) approaches. The process parameters considered are namely, workpiece electrical conductivity, gap current, gap voltage, pulse on time and pulse off time. Cryo-treated workpiece viz, Nickel-Titanium (NiTi) alloys, Nickel Copper (NiCu) alloys, and Beryllium copper (BCu) alloys and cryo-treated pure copper as tool electrode was considered. In the present research work, four supervised machine learning regression and three supervised machine learning classification-based algorithms are used for predicting the MRR. Machine learning result showed that gap current, gap voltage and pulse on time are most significant parameters that effected MRR. It is observed from the results that the Gradient boosting regression-based algorithm resulted in the highest coefficient of determination value for predicting MRR while Random Forest classification based resulted in the highest F1-Score for obtaining MRR.
Measurement of Sulfur-Dioxide Emissions from Ocean-Going Vessels in Belgium Using Novel Techniques
Authors: Van Roy Ward , Van Nieuwenhove Annelore , Scheldeman Kobe , Van Roozendael Benjamin , Schallier Ronny , Mellqvist Johan , Maes Frank
Published: October 2022

Air pollutants emitted by ocean-going vessels (OGVs) cause numerous environmental and human health problems. In 2016, the Belgian Coastguard aircraft was equipped with a sniffer sensor to monitor compliance with MARPOL Annex VI Regulation 14. However, the sensor was susceptible to NO and Volatile Organic Compounds (VOCs), which had a negative impact on the measurement uncertainty. The elimination of measurement errors was achieved by modifying the sensor, including among others the addition of a NOx sensor and a custom-designed hydrocarbon kicker. This resulted in a substantial improvement in the measurement quality and uncertainty of the derived Fuel Sulfur Content (FSC). As a direct result of this, the reporting thresholds for non-compliance drastically improved. The data analysis of sampled OGVs showed that compliance levels notably improved between 2019 and 2020 (from 95.9% to 97.3%), coinciding with the implementation of the Global Sulfur Cap. Findings in this study have also demonstrated that OGVs equipped with emission abatement technology (scrubbers) are more susceptible to non-compliance with Regulation 14 of MARPOL Annex VI. Given these results, this article provides an answer to the question of how to monitor effective implementation of NO emissions from OGVs.
K X-ray Emission for Slow Oxygen Ions Approaching a Copper Metal Surface
Authors: Song Zhangyong , Liu Xuan , Zhang Mingwu , Xu Junkui , Feng Yong , Zhang Bingzhang , Wang Wei , Liu Junliang , Shao Caojie , Yu Deyang , Guo Yanling , Chen Lin
Published: October 2022

We report on the K X-ray emission for 9–140 keV oxygen ions with initial charge states from 3 to 7 approaching a copper surface. The peak center of the measured X-ray spectrum slightly shifts towards higher energies with the increasing of the initial charge state of the incident ions. For the collisions of oxygen ions with no K-vacancies (q = 3–6), the X-ray yield per incident ion increases gradually with the projectile’s kinetic energy, while for the O7+ ions (with a K-vacancy) it is nearly independent of the energy. The K-shell ionization cross-sections for the oxygen ions with no K-vacancies obtained from the experiments are well consistent with the calculations of the binary encounter approximation model when the collision energy is larger than 30 keV, whereas they are several times larger than the theoretical values at collision energies of less than 30 keV.
Optimal Location of Exit Doors for Efficient Evacuation of Crowds at Gathering Places
Authors: Alvarez-Vázquez Lino J. , García-Chan Néstor , Martínez Aurea , Rodríguez Carmen , Vázquez-Méndez Miguel E.
Published: October 2022

This work deals with the optimal design for the location of the exit doors at meeting places (such as sports centers, public squares, street markets, transport stations, etc.) to guarantee a safer emergency evacuation in events of a sporting, social, entertainment or religious type. This problem is stated as an optimal control problem of nonlinear partial differential equations, where the state system is a reformulation of the Hughes model (coupling the eikonal equation for a density-weighted walking velocity of pedestrians and the continuity equation for conservation of the pedestrian density), the control is the location of the exit doors at the domain boundary (subject to several geometric constraints), and the cost function is related to the evacuation rate. We provide a full numerical algorithm for solving the problem (a finite element technique for the discretization and a gradient-free procedure for the optimization), and show several numerical results for a realistic case.
Pseudo Overlap Functions, Fuzzy Implications and Pseudo Grouping Functions with Applications
Authors: Zhang Xiaohong , Liang Rong , Bustince Humberto , Bedregal Benjamin , Fernandez Javier , Li Mengyuan , Ou Qiqi
Published: October 2022

Overlap and grouping functions are important aggregation operators, especially in information fusion, classification and decision-making problems. However, when we do more in-depth application research (for example, non-commutative fuzzy reasoning, complex multi-attribute decision making and image processing), we find overlap functions as well as grouping functions are required to be commutative (or symmetric), which limit their wide applications. For the above reasons, this paper expands the original notions of overlap functions and grouping functions, and the new concepts of pseudo overlap functions and pseudo grouping functions are proposed on the basis of removing the commutativity of the original functions. Some examples and construction methods of pseudo overlap functions and pseudo grouping functions are presented, and the residuated implication (co-implication) operators derived from them are investigated. Not only that, some applications of pseudo overlap (grouping) functions in multi-attribute (group) decision-making, fuzzy mathematical morphology and image processing are discussed. Experimental results show that, in many application fields, pseudo overlap functions and pseudo grouping functions have greater flexibility and practicability.
Facial Age Estimation Using Machine Learning Techniques: An Overview
Authors: ELKarazle Khaled , Raman Valliappan , Then Patrick
Published: October 2022

Automatic age estimation from facial images is an exciting machine learning topic that has attracted researchers’ attention over the past several years. Numerous human–computer interaction applications, such as targeted marketing, content access control, or soft-biometrics systems, employ age estimation models to carry out secondary tasks such as user filtering or identification. Despite the vast array of applications that could benefit from automatic age estimation, building an automatic age estimation system comes with issues such as data disparity, the unique ageing pattern of each individual, and facial photo quality. This paper provides a survey on the standard methods of building automatic age estimation models, the benchmark datasets for building these models, and some of the latest proposed pieces of literature that introduce new age estimation methods. Finally, we present and discuss the standard evaluation metrics used to assess age estimation models. In addition to the survey, we discuss the identified gaps in the reviewed literature and present recommendations for future research.
Traumatic Brain Injury Biomarkers, Simulations and Kinetics
Authors: Hicks Celeste , Dhiman Akshima , Barrymore Chauntel , Goswami Tarun
Published: October 2022

This paper reviews the predictive capabilities of blood-based biomarkers to quantify traumatic brain injury (TBI). Biomarkers for concussive conditions also known as mild, to moderate and severe TBI identified along with post-traumatic stress disorder (PTSD) and chronic traumatic encephalopathy (CTE) that occur due to repeated blows to the head during one’s lifetime. Since the pathways of these biomarkers into the blood are not fully understood whether there is disruption in the blood–brain barrier (BBB) and the time it takes after injury for the expression of the biomarkers to be able to predict the injury effectively, there is a need to understand the protein biomarker structure and other physical properties. The injury events in terms of brain and mechanics are a result of external force with or without the shrapnel, in the wake of a wave result in local tissue damage. Thus, these mechanisms express specific biomarkers kinetics of which reaches half-life within a few hours after injury to few days. Therefore, there is a need to determine the concentration levels that follow injury. Even though current diagnostics linking biomarkers with TBI severity are not fully developed, there is a need to quantify protein structures and their viability after injury. This research was conducted to fully understand the structures of 12 biomarkers by performing molecular dynamics simulations involving atomic movement and energies of forming hydrogen bonds. Molecular dynamics software, NAMD and VMD were used to determine and compare the approximate thermodynamic stabilities of the biomarkers and their bonding energies. Five biomarkers used clinically were S100B, GFAP, UCHL1, NF-L and tau, the kinetics obtained from literature show that the concentration values abruptly change with time after injury. For a given protein length, associated number of hydrogen bonds and bond energy describe a lower bound region where proteins self-dissolve and do not have long enough half-life to be detected in the fluids. However, above this lower bound, involving higher number of bonds and energy, we hypothesize that biomarkers will be viable to disrupt the BBB and stay longer to be modeled for kinetics for diagnosis and therefore may help in the discoveries of new biomarkers.
Effect of Rho–Associated Kinase Inhibitor on Growth Behaviors of Human Induced Pluripotent Stem Cells in Suspension Culture
Authors: Matsumoto Takaki , Kim Mee-Hae , Kino-oka Masahiro
Published: October 2022

Rho–associated protein kinase (ROCK) inhibitors are used for the survival of single-dissociated human induced pluripotent stem cells (hiPSCs); however, their effects on the growth behaviors of hiPSCs in suspension culture are unexplored. Therefore, we investigated the effect of ROCK inhibitor on growth behaviors of two hiPSC lines (Tic and 1383D2) with different formation of aggregate that attached between single cells in suspension culture. The apparent specific growth rate by long-term exposure to Y-27632, a ROCK inhibitor, was maintained throughout the culture. Long-term exposure to ROCK inhibitor led to an increase in cell division throughout the culture in both lines. Immunofluorescence staining confirmed that hiPSCs forming spherical aggregates showed localization of collagen type I on its periphery. In addition, phosphorylated myosin (pMLC) was localized at the periphery in culture under short-term exposure to ROCK inhibitor, whereas pMLC was not detected at whole the aggregate in culture under long-term exposure. Scanning electron microscopy indicated that long-term exposure to ROCK inhibitor blocked the structural alteration on the surface of cell aggregates. These results indicate that pMLC inhibition by long-term ROCK inhibition leads to enhanced growth abilities of hiPSCs in suspension culture by maintaining the structures of extracellular matrices.
The Northern Root-Knot Nematode Meloidogyne hapla: New Host Records in Portugal
Authors: Rusinque Leidy , Nóbrega Filomena , Serra Clara , Inácio Maria L.
Published: October 2022

Root-knot nematodes (RKNs), Meloidogyne spp., are a group of plant-parasitic nematodes (PPNs) of great economic significance worldwide. The northern root-knot nematode, Meloidogyne hapla, is one of the most important species of RKNs occurring in cold regions. In Portugal so far, M. hapla has been found parasitizing potato and fig trees. During surveys carried out in 2019–2022 in fields for horticultural and ornamental production, soil and root samples were collected. Roots were observed under a stereomicroscope to determine the presence of galls. Nematodes were extracted from the soil. Morphological features showed a high similarity and consistency with previous descriptions of the genus. For molecular analysis, total genomic DNA was isolated from single nematodes and used to amplify in multiplex reaction using the species-specific primers JMV1, JMV2 and JMVhapla, and for sequencing of the ITS region with the primers TW81/AB28. Multiplex PCR amplification produced a specific fragment of 440 bp and PCR amplification of the ITS region yielded a single fragment of 550 bp, as expected. The obtained sequences showed a similarity ranging from 99.8% to 100% with the sequences of M. hapla available in the database. The phylogenetic tree revealed that the isolates grouped with M. hapla isolates. From the 690 samples collected, M. hapla was detected in three different hosts (grapevine, eucalyptus and potato) in four districts of mainland Portugal and on Madeira Island. To our knowledge, this is the first report of M. hapla infecting the grapevine and eucalyptus in Portugal.
Metabolome Profiling in Aging Studies
Authors: Balashova Elena E. , Maslov Dmitry L. , Trifonova Oxana P. , Lokhov Petr G. , Archakov Alexander I.
Published: October 2022

Organism aging is closely related to systemic metabolic changes. However, due to the multilevel and network nature of metabolic pathways, it is difficult to understand these connections. Today, scientists are trying to solve this problem using one of the main approaches of metabolomics—untargeted metabolome profiling. The purpose of this publication is to review metabolomic studies based on such profiling, both in animal models and in humans. This review describes metabolites that vary significantly across age groups and include carbohydrates, amino acids, carnitines, biogenic amines, and lipids. Metabolic pathways associated with the aging process are also shown, including those associated with amino acid, lipid, and energy metabolism. The presented data reveal the mechanisms of aging and can be used as a basis for monitoring biological age and predicting age-related diseases in the early stages of their development.
The Pharmacorank Search Tool for the Retrieval of Prioritized Protein Drug Targets and Drug Repositioning Candidates According to Selected Diseases
Authors: Gnilopyat Sergey , DePietro Paul J. , Parry Thomas K. , McLaughlin William A.
Published: October 2022

We present the Pharmacorank search tool as an objective means to obtain prioritized protein drug targets and their associated medications according to user-selected diseases. This tool could be used to obtain prioritized protein targets for the creation of novel medications or to predict novel indications for medications that already exist. To prioritize the proteins associated with each disease, a gene similarity profiling method based on protein functions is implemented. The priority scores of the proteins are found to correlate well with the likelihoods that the associated medications are clinically relevant in the disease’s treatment. When the protein priority scores are plotted against the percentage of protein targets that are known to bind medications currently indicated to treat the disease, which we termed the pertinency score, a strong correlation was observed. The correlation coefficient was found to be 0.9978 when using a weighted second-order polynomial fit. As the highly predictive fit was made using a broad range of diseases, we were able to identify a general threshold for the pertinency score as a starting point for considering drug repositioning candidates. Several repositioning candidates are described for proteins that have high predicated pertinency scores, and these provide illustrative examples of the applications of the tool. We also describe focused reviews of repositioning candidates for Alzheimer’s disease. Via the tool’s URL, https://protein.som.geisinger.edu/Pharmacorank/, an open online interface is provided for interactive use; and there is a site for programmatic access.
Molecular Insights into Epigenetics and Cannabinoid Receptors
Authors: Basavarajappa Balapal S. , Subbanna Shivakumar
Published: October 2022

The actions of cannabis are mediated by G protein-coupled receptors that are part of an endogenous cannabinoid system (ECS). ECS consists of the naturally occurring ligands N-arachidonylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB1 and CB2 cannabinoid receptors. Epigenetics are heritable changes that affect gene expression without changing the DNA sequence, transducing external stimuli in stable alterations of the DNA or chromatin structure. Cannabinoid receptors are crucial candidates for exploring their functions through epigenetic approaches due to their significant roles in health and diseases. Epigenetic changes usually promote alterations in the expression of genes and proteins that can be evaluated by various transcriptomic and proteomic analyses. Despite the exponential growth of new evidence on the critical functions of cannabinoid receptors, much is still unknown regarding the contribution of various genetic and epigenetic factors that regulate cannabinoid receptor gene expression. Recent studies have identified several immediate and long-lasting epigenetic changes, such as DNA methylation, DNA-associated histone proteins, and RNA regulatory networks, in cannabinoid receptor function. Thus, they can offer solutions to many cellular, molecular, and behavioral impairments found after modulation of cannabinoid receptor activities. In this review, we discuss the significant research advances in different epigenetic factors contributing to the regulation of cannabinoid receptors and their functions under both physiological and pathological conditions. Increasing our understanding of the epigenetics of cannabinoid receptors will significantly advance our knowledge and could lead to the identification of novel therapeutic targets and innovative treatment strategies for diseases associated with altered cannabinoid receptor functions.
Adenosine-Mimicking Derivatives of 3-Aminopyrazine-2-Carboxamide: Towards Inhibitors of Prolyl-tRNA Synthetase with Antimycobacterial Activity
Authors: Pallabothula Vinod Sukanth Kumar , Kerda Marek , Juhás Martin , Janďourek Ondřej , Konečná Klára , Bárta Pavel , Paterová Pavla , Zitko Jan
Published: October 2022

Multidrug-resistant tuberculosis (MDR-TB) poses a significant threat to mankind and as such earned its place on the WHO list of priority pathogens. New antimycobacterials with a mechanism of action different to currently used agents are highly required. This study presents the design, synthesis, and biological evaluation of 3-acylaminopyrazine-2-carboxamides derived from a previously reported inhibitor of human prolyl-tRNA synthetase. Compounds were evaluated in vitro against various strains of mycobacteria, pathogenic bacteria, and fungi of clinical significance. In general, high activity against mycobacteria was noted, while the antibacterial and antifungal activity was minimal. The most active compounds were 4’-substituted 3-(benzamido)pyrazine-2-carboxamides, exerting MIC (Minimum Inhibitory Concentration) from 1.95 to 31.25 µg/mL. Detailed structure–activity relationships were established and rationalized in silico with regard to mycobacterial ProRS as a probable target. The active compounds preserved their activity even against multidrug-resistant strains of Mycobacterium tuberculosis. At the same time, they were non-cytotoxic against HepG2 human hepatocellular carcinoma cells. This project is the first step in the successful repurposing of inhibitors of human ProRS to inhibitors of mycobacterial ProRS with antimycobacterial activity.
Immune Checkpoint Inhibitors and RAS–ERK Pathway-Targeted Drugs as Combined Therapy for the Treatment of Melanoma
Authors: Morante Marta , Pandiella Atanasio , Crespo Piero , Herrero Ana
Published: October 2022

Metastatic melanoma is a highly immunogenic tumor with very poor survival rates due to immune system escape-mechanisms. Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and the programmed death-1 (PD1) receptors, are being used to impede immune evasion. This immunotherapy entails an increment in the overall survival rates. However, melanoma cells respond with evasive molecular mechanisms. ERK cascade inhibitors are also used in metastatic melanoma treatment, with the RAF activity blockade being the main therapeutic approach for such purpose, and in combination with MEK inhibitors improves many parameters of clinical efficacy. Despite their efficacy in inhibiting ERK signaling, the rewiring of the melanoma cell-signaling results in disease relapse, constituting the reinstatement of ERK activation, which is a common cause of some resistance mechanisms. Recent studies revealed that the combination of RAS–ERK pathway inhibitors and ICI therapy present promising advantages for metastatic melanoma treatment. Here, we present a recompilation of the combined therapies clinically evaluated in patients.
Semicarbazide-Sensitive Amine Oxidase (SSAO) and Lysyl Oxidase (LOX) Association in Rat Aortic Vascular Smooth Muscle Cells
Authors: Manasieva Vesna , Thakur Shori , Lione Lisa A. , Patel Jessal , Baydoun Anwar , Skamarauskas John
Published: October 2022

Vascular smooth muscle cells (VSMCs) are the main stromal cells in the medial layer of the vascular wall. These cells produce the extracellular matrix (ECM) and are involved in many pathological changes in the vascular wall. Semicarbazide-sensitive amine oxidase (SSAO) and lysyl oxidase (LOX) are vascular enzymes associated with the development of atherosclerosis. In the vascular smooth muscle cells, increased SSAO activity elevates reactive oxygen species (ROS) and induces VSMCs death; increased LOX induces chemotaxis through hydrogen peroxide dependent mechanisms; and decreased LOX contributes to endothelial dysfunction. This study investigates the relationship between SSAO and LOX in VSMCs by studying their activity, protein, and mRNA levels during VSMCs passaging and after silencing the LOX gene, while using their respective substrates and inhibitors. At the basal level, LOX activity decreased with passage and its protein expression was maintained between passages. βAPN abolished LOX activity (** p < 0.01 for 8 vs. 3 and * p < 0.05 for 5 vs. 8) and had no effect on LOX protein and mRNA levels. MDL72527 reduced LOX activity at passage 3 and 5 (## p < 0.01) and had no effect on LOX protein, and mRNA expression. At the basal level, SSAO activity also decreased with passage, and its protein expression was maintained between passages. MDL72527 abolished SSAO activity (**** p < 0.0001 for 8 vs. 3 and * p < 0.05 for 5 vs. 8), VAP-1 expression at passage 5 (** p < 0.01) and 8 (**** p < 0.0001), and Aoc3 mRNA levels at passage 8 (* p < 0.05). βAPN inhibited SSAO activity (**** p < 0.0001 for 5 vs. 3 and 8 vs. 3 and * p < 0.05 for 5 vs. 8), VAP-1 expression at passage 3 (* p < 0.05), and Aoc3 mRNA levels at passage 3 (* p < 0.05). Knockdown of the LOX gene (**** p < 0.0001 for Si6 vs. Sictrl and *** p < 0.001 for Si8 vs. Sictrl) and LOX protein (** p < 0.01 for Si6 and Si8 vs. Sictrl) in VSMCs at passage 3 resulted in a reduction in Aoc3 mRNA (#### p < 0.0001 for Si6 vs. Sictrl and ### p < 0.001 for Si8 vs. Sictrl) and VAP-1 protein (# p < 0.05 for Si8 vs. Sictrl). These novel findings demonstrate a passage dependent decrease in LOX activity and increase in SSAO activity in rat aortic VSMCs and show an association between both enzymes in early passage rat aortic VSMCs, where LOX was identified as a regulator of SSAO activity, protein, and mRNA expression.
A Novel Tandem-Tag Purification Strategy for Challenging Disordered Proteins
Authors: Mészáros Attila , Muwonge Kevin , Janvier Steven , Ahmed Junaid , Tompa Peter
Published: October 2022

Intrinsically disordered proteins (IDPs) lack well-defined 3D structures and can only be described as ensembles of different conformations. This high degree of flexibility allows them to interact promiscuously and makes them capable of fulfilling unique and versatile regulatory roles in cellular processes. These functional benefits make IDPs widespread in nature, existing in every living organism from bacteria and fungi to plants and animals. Due to their open and exposed structural state, IDPs are much more prone to proteolytic degradation than their globular counterparts. Therefore, the purification of recombinant IDPs requires extra care and caution, such as maintaining low temperature throughout the purification, the use of protease inhibitor cocktails and fast workflow. Even so, in the case of long IDP targets, the appearance of truncated by-products often seems unavoidable. The separation of these unwanted proteins can be very challenging due to their similarity to the parent target protein. Here, we describe a tandem-tag purification method that offers a remedy to this problem. It contains only common affinity-chromatography steps (HisTrap and Heparin) to ensure low cost, easy access and scaling-up for possible industrial use. The effectiveness of the method is demonstrated with four examples, Tau-441 and two of its fragments and the transactivation domain (AF1) of androgen receptor.
Gut Inflammation Induced by Finasteride Withdrawal: Therapeutic Effect of Allopregnanolone in Adult Male Rats
Authors: Diviccaro Silvia , Giatti Silvia , Cioffi Lucia , Falvo Eva , Herian Monika , Caruso Donatella , Melcangi Roberto Cosimo
Published: October 2022

The treatment with finasteride (i.e., an inhibitor of 5α-reductase) may be associated with different side effects (i.e., depression, anxiety, cognitive impairment and sexual dysfunction) inducing the so-called post finasteride syndrome (PFS). Moreover, previous observations in PFS patients and an experimental model showed alterations in gut microbiota populations, suggesting an inflammatory environment. To confirm this hypothesis, we have explored the effect of chronic treatment with finasteride (i.e., for 20 days) and its withdrawal (i.e., for 1 month) on the levels of steroids, neurotransmitters, pro-inflammatory cytokines and gut permeability markers in the colon of adult male rat. The obtained data demonstrate that the levels of allopregnanolone (ALLO) decreased after finasteride treatment and after its withdrawal. Following the drug suspension, the decrease in ALLO levels correlates with an increase in IL-1β and TNF-α, serotonin and a decrease in dopamine. Importantly, ALLO treatment is able to counteract some of these alterations. The relation between ALLO and GABA-A receptors and/or pregnenolone (ALLO precursor) could be crucial in their mode of action. These observations provide an important background to explore further the protective effect of ALLO in the PFS experimental model and the possibility of its translation into clinical therapy.
Replicative Instability Drives Cancer Progression
Authors: Morris Benjamin B. , Smith Jason P. , Zhang Qi , Jiang Zhijie , Hampton Oliver A. , Churchman Michelle L. , Arnold Susanne M. , Owen Dwight H. , Gray Jhanelle E. , Dillon Patrick M. , Soliman Hatem H. , Stover Daniel G. , Colman Howard , Chakravarti Arnab , Shain Kenneth H. , Silva Ariosto S. , Villano John L. , Vogelbaum Michael A. , Borges Virginia F. , Akerley Wallace L. , Gentzler Ryan D. , Hall Richard D. , Matsen Cindy B. , Ulrich C. M. , Post Andrew R. , Nix David A. , Singer Eric A. , Larner James M. , Stukenberg Peter Todd , Jones David R. , Mayo Marty W.
Published: October 2022

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.
Role of AMPK in Regulation of Oxaliplatin-Resistant Human Colorectal Cancer
Authors: Park Sun Young , Chung Ye Seo , Park So Yeon , Kim So Hee
Published: October 2022

Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29, SW480 and SW620 were established by gradually increasing the drug concentration to 2.5 μM. The inhibitory concentrations of cell growth by 50% (IC50) of oxaliplatin were 4.40–12.7-fold significantly higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly, an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs.
Combined Expression of HGFR with Her2/neu, EGFR, IGF1R, Mucin-1 and Integrin α2β1 Is Associated with Aggressive Epithelial Ovarian Cancer
Authors: Czogalla Bastian , Dötzer Katharina , Sigrüner Nicole , von Koch Franz Edler , Brambs Christine E. , Anthuber Sabine , Frangini Sergio , Burges Alexander , Werner Jens , Mahner Sven , Mayer Barbara
Published: October 2022

Hepatocyte growth factor receptor (HGFR), also known as c-mesenchymal–epithelial transition factor (c-MET), plays a crucial role in the carcinogenesis of epithelial ovarian cancer (EOC). In contrast, the mechanisms contributing to aberrant expression of HGFR in EOC are not fully understood. In the present study, the expression of HGFR with its prognostic and predictive role was evaluated immunohistochemically in a cohort of 42 primary ovarian cancer patients. Furthermore, we analyzed the dual expression of HGFR and other druggable biomarkers. In the multivariate Cox regression analysis, high HGFR expression was identified as an independent prognostic factor for a shorter progression-free survival (PFS) (hazard ratio (HR) 2.99, 95% confidence interval (CI95%) 1.01–8.91, p = 0.049) and overall survival (OS) (HR 5.77, CI95% 1.56–21.34, p = 0.009). In addition, the combined expression of HGFR, human epidermal growth factor receptor 2 (Her2/neu), epithelial growth factor receptor (EGFR), insulin-like growth factor 1 (IGF1R), Mucin-1 and Integrin α2β1 further significantly impaired PFS, platinum-free interval (PFI) and OS. Protein co-expression analyses were confirmed by transcriptomic data in a large, independent cohort of patients. In conclusion, new biomarker-directed treatment targets were identified to fight poor prognosis of primary EOC.
Usefulness of Complete Blood Count (CBC) to Assess Cardiovascular and Metabolic Diseases in Clinical Settings: A Comprehensive Literature Review
Authors: Seo In-Ho , Lee Yong-Jae
Published: October 2022

Complete blood count (CBC) is one of the most common blood tests requested by clinicians and evaluates the total numbers and characteristics of cell components in the blood. Recently, many investigations have suggested that the risk of cancer, cardiovascular disease (CVD), arteriosclerosis, type 2 diabetes (T2DM), and metabolic syndrome can be predicted using CBC components. This review introduces that white blood cell (WBC), neutrophil-to-lymphocyte ratio (NLR), hemoglobin (Hb), mean corpuscular volume (MCV), red cell distribution width (RDW), platelet count, mean platelet volume (MPV), and platelet-to-lymphocyte ratio (PLR) are useful markers to predict CVD and metabolic diseases. Furthermore, we would like to support various uses of CBC by organizing pathophysiology that can explain the relationship between CBC components and diseases.
High-Frequency Transcranial Random Noise Stimulation for Auditory Hallucinations of Schizophrenia: A Case Series
Authors: Mondino Marine , Janin Delphine , Galvao Filipe , Brunelin Jérôme
Published: October 2022

Transcranial electrical stimulation has been proposed as a noninvasive therapeutic approach for reducing treatment-resistant symptoms of schizophrenia—in particular, auditory hallucinations. However, the high variability observed in the clinical response leaves much room to optimize the stimulation parameters and strengthen its benefits. We proposed to investigate the effects of high-frequency transcranial random noise stimulation (hf-tRNS), which is supposed to induce larger effects than conventional direct current stimulation. Here, we present an initial case series of ten patients with schizophrenia who underwent 10 sessions of 20 min hf-tRNS (2 mA, 100–500 Hz, 1 mA offset), with the anode placed over the left dorsolateral prefrontal cortex and the cathode over the left temporoparietal junction. Patients showed a significant reduction in auditory hallucinations after the hf-tRNS sessions (−36.1 +/− 21.8%, p = 0.0059). In this preliminary, open-label study conducted in ten patients with treatment-resistant symptoms of schizophrenia, frontotemporal hf-tRNS was shown to induce a substantial improvement in auditory hallucinations. Additional sham-controlled studies are needed to further evaluate hf-tRNS as a treatment for schizophrenia.
Alteration of Mitochondrial DNA Copy Number and Increased Expression Levels of Mitochondrial Dynamics-Related Genes in Sjögren’s Syndrome
Authors: De Benedittis Giada , Latini Andrea , Colafrancesco Serena , Priori Roberta , Perricone Carlo , Novelli Lucia , Borgiani Paola , Ciccacci Cinzia
Published: October 2022

Sjögren’s syndrome (SS) is a chronic autoimmune multifactorial disease characterized by inflammation and lymphocytic infiltration of the exocrine glands. Several studies have highlighted the involvement of oxidative stress in this pathology, suggesting that it could induce mitochondrial dysfunctions. Mitochondria could have a role in inflammatory and immune processes. Since the mitochondrial DNA (mtDNA) copy number could change in response to physiological or environmental stimuli, this study aimed to evaluate possible alterations in the mtDNA copy number in SS. We have analyzed the amount of mtDNA in the peripheral blood of 74 SS patients and 61 healthy controls by qPCR. Then, since mitochondrial fusion and fission play a crucial role in maintaining the number of mitochondria, we investigated the expression variability of the genes most commonly involved in mitochondrial dynamics in a subgroup of SS patients and healthy controls. Interestingly, we observed a highly significant decrease in mtDNA copies in the SS patients compared to healthy controls (p = 1.44 × 10−12). Expression levels of mitochondrial fission factor (MFF), mitofusin-1 (MFN1), and mitochondrial transcription factor A (TFAM) genes were analyzed, showing a statistically significant increase in the expression of MFF (p = 0.003) and TFAM (p = 0.022) in the SS patients compared to healthy controls. These results give further insight into the possible involvement of mitochondrial dysfunctions in SS disease.
Photodynamic Therapy
Authors: Kang Kyungsu , Bacci Stefano
Published: October 2022

In 1903, Von Tappeiner and Jesionek [...]
Cisplatin Induces Senescent Lung Cancer Cell-Mediated Stemness Induction via GRP78/Akt-Dependent Mechanism
Authors: Sriratanasak Nicharat , Chunhacha Preedakorn , Ei Zin Zin , Chanvorachote Pithi
Published: October 2022

Cellular senescence is linked with chemotherapy resistance. Based on previous studies, GRP78 is a signal transducer in senescent cells. However, the association between GRP78 and stem cell phenotype remains unknown. Cisplatin treatment was clarified to induce cellular senescence leading to stemness induction via GRP78/Akt signal transduction. H460 cells were treated with 5 μM of cisplatin for 6 days to develop senescence. The colony formation assay and cell cycle analysis were performed. SA-β-galactosidase staining indicated senescence. Western blot analysis and RT-PCR were operated. Immunoprecipitation (IP) and immunocytochemistry assays (ICC) were also performed. Colony-forming activity was completely inhibited, and 87.07% of the cell population was arrested in the G2 phase of the cell cycle. mRNA of p21 and p53 increased approximately by 15.91- and 19.32-fold, respectively. The protein level of p21 and p53 was elevated by 9.57- and 5.9-fold, respectively. In addition, the c-Myc protein level was decreased by 0.2-fold when compared with the non-treatment control. Even though, the total of GRP78 protein was downregulated after cisplatin treatment, but the MTJ1 and downstream regulator, p-Akt/Akt ratio were upregulated by approximately 3.38 and 1.44-fold, respectively. GRP78 and MTJ1 were found at the cell surface membrane. Results showed that the GRP78/MTJ1 complex and stemness markers, including CD44, CD133, Nanog, Oct4, and Sox2, were concomitantly increased in senescent cells. MTJ1 anchored GRP78, facilitating the signal transduction of stem-like phenotypes. The strategy that could interrupt the binding between these crucial proteins or inhibit the translocation of GRP78 might beuseful for cancer therapy.