Pharmacology Progresses and Applications of Chloroquine in Cancer Therapy.

Chloroquine is a common antimalarial drug and is listed in the World Health Organization Standard List of Essential Medicines because of its safety, low cost and ease of use. Besides its antimalarial property, chloroquine also was used in anti-inflammatory and antivirus, especially in antitumor therapy. A mount of data showed that chloroquine mainly relied on autophagy inhibition to exert its antitumor effects. However, recently, more and more researches have revealed that chloroquine acts through other mechanisms that are autophagy-independent. Nevertheless, the current reviews lacked a comprehensive summary of the antitumor mechanism and combined pharmacotherapy of chloroquine. So here we focused on the antitumor properties of chloroquine, summarized the pharmacological mechanisms of antitumor progression of chloroquine dependent or independent of autophagy inhibition. Moreover, we also discussed the side effects and possible application developments of chloroquine. This review provided a more systematic and cutting-edge knowledge involved in the anti-tumor mechanisms and combined pharmacotherapy of chloroquine in hope of carrying out more in-depth exploration of chloroquine and obtaining more clinical applications.

Comparative time-dependent proteomics reveal the tolerance of cancer cells to magnetic iron oxide nanoparticles.

Cancer is one of the most challenging diseases in the world. Recently, iron oxide nanoparticles (IONPs) are emerging materials with rapid development and high application value, and have shown great potential on tumor therapy due to their unique magnetic and biocompatible properties. However, some data hint us that IONPs were toxic to normal cells and vital organs. Thus, more data on biosafety evaluation is urgently needed. In this study, we compared the effects of silicon-coated IONPs (Si-IONPs) on two cell types: the tumor cells (Hela) and the normal cells (HEK293T, as 293 T for short), compared differences of protein composition, allocation and physical characteristics between these two cells. The major findings of our study pointed out that 293 T cells death occurred more significant than that of Hela cells after Si-IONPs treatment, and the rate and content of endocytosis of Si-IONPs in 293 T cells was more prominent than in Hela cells. Our results also showed Si-IONPs significant promoted the production of reactive oxygen species and disturbed pathways related to oxidative stress, iron homeostasis, apoptosis and ferroptosis in both two types of cells, however, Hela cells recovered from these disturbances more easily than 293 T. In conclusion, compared with Hela cells, IONPs are more likely to induce 293 T cells death and Hela cells have their own unique mechanisms to defense invaders, reminding scientists that future in vivo and in vitro studies of nanoparticles need to be cautious, and more safety data are needed for further clinical treatment.

Myricanol prevents aging-related sarcopenia by rescuing mitochondrial dysfunction via targeting peroxiredoxin 5.

Aging is a process that represents the accumulation of changes in organism overtime. In biological level, accumulations of molecular and cellular damage in aging lead to an increasing risk of diseases like sarcopenia. Sarcopenia reduces mobility, leads to fall-related injuries, and diminishes life quality. Thus, it is meaningful to find out novel therapeutic strategies for sarcopenia intervention that may help the elderly maintain their functional ability. Oxidative damage-induced dysfunctional mitochondria are considered as a culprit of muscle wasting during aging. Herein, we aimed to demonstrate whether myricanol (MY) protects aged mice against muscle wasting through alleviating oxidative damage in mitochondria and identify the direct protein target and its underlying mechanism. We discovered that MY protects aged mice against the loss of muscle mass and strength through scavenging reactive oxygen species accumulation to rebuild the redox homeostasis. Taking advantage of biophysical assays, peroxiredoxin 5 was discovered and validated as the direct target of MY. Through activating peroxiredoxin 5, MY reduced reactive oxygen species accumulation and damaged mitochondrial DNA in C2C12 myotubes. Our findings provide an insight for therapy against sarcopenia through alleviating oxidative damage-induced dysfunctional mitochondria by targeting peroxiredoxin 5, which may contribute an insight for healthy aging.

Photoaffinity probe-based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum.

Malaria continues to pose a serious global health threat, and artemisinin remains the core drug for global malaria control. However, the situation of malaria resistance has become increasingly severe due to the emergence and spread of artemisinin resistance. In recent years, significant progress has been made in understanding the mechanism of action (MoA) of artemisinin. Prior research on the MoA of artemisinin mainly focused on covalently bound targets that are alkylated by artemisinin-free radicals. However, less attention has been given to the reversible noncovalent binding targets, and there is a paucity of information regarding artemisinin targets at different life cycle stages of the parasite. In this study, we identified the protein targets of artemisinin at different stages of the parasite's intraerythrocytic developmental cycle using a photoaffinity probe. Our findings demonstrate that artemisinin interacts with parasite proteins in vivo through both covalent and noncovalent modes. Extensive mechanistic studies were then conducted by integrating target validation, phenotypic studies, and untargeted metabolomics. The results suggest that protein synthesis, glycolysis, and oxidative homeostasis are critically involved in the antimalarial activities of artemisinin. In summary, this study provides fresh insights into the mechanisms underlying artemisinin's antimalarial effects and its protein targets.

Gambogic acid exhibits promising anticancer activity by inhibiting the pentose phosphate pathway in lung cancer mouse model.

BACKGROUND: The pentose phosphate pathway (PPP) plays a crucial role in the material and energy metabolism in cancer cells. Targeting 6-phosphogluconate dehydrogenase (6PGD), the rate-limiting enzyme in the PPP metabolic process, to inhibit cellular metabolism is an effective anticancer strategy. In our previous study, we have preliminarily demonstrated that gambogic acid (GA) induced cancer cell death by inhibiting 6PGD and suppressing PPP at the cellular level. However, it is unclear whether GA could suppress cancer cell growth by inhibiting PPP pathway in mouse model. PURPOSE: This study aimed to confirm that GA as a covalent inhibitor of 6PGD protein and to validate that GA suppresses cancer cell growth by inhibiting the PPP pathway in a mouse model. METHODS: Cell viability was detected by CCK-8 assays as well as flow cytometry. The protein targets of GA were identified using a chemical probe and activity-based protein profiling (ABPP) technology. The target validation was performed by in-gel fluorescence assay, the Cellular Thermal Shift Assay (CETSA). A lung cancer mouse model was constructed to test the anticancer activity of GA. RNA sequencing was performed to analyze the global effect of GA on gene expression. RESULTS: The chemical probe of GA exhibited high biological activity in vitro. 6PGD was identified as one of the binding proteins of GA by ABPP. Our findings revealed a direct interaction between GA and 6PGD. We also found that the anti-cancer activity of GA depended on reactive oxygen species (ROS), as evidenced by experiments on cells with 6PGD knocked down. More importantly, GA could effectively reduce the production of the two major metabolites of the PPP in lung tissue and inhibit cancer cell growth in the mouse model. Finally, RNA sequencing data suggested that GA treatment significantly regulated apoptosis and hypoxia-related physiological processes. CONCLUSION: These results demonstrated that GA was a covalent inhibitor of 6PGD protein. GA effectively suppressed cancer cell growth by inhibiting the PPP pathway without causing significant side effects in the mouse model. Our study provides in vivo evidence that elucidates the anticancer mechanism of GA, which involves the inhibition of 6PGD and modulation of cellular metabolic processes.

Glycyrrhetinic acid inhibits non-small cell lung cancer via promotion of Prdx6- and caspase-3-mediated mitochondrial apoptosis.

Glycyrrhetinic acid (GA) shows great efficiency against non-small cell lung cancer (NSCLC), but the detailed mechanism is unclear, which has limited its clinical application. Herein, we investigated the potential targets of GA against NSCLC by activity-based protein profiling (ABPP) technology and the combination of histopathology and proteomics validation. In vitro and in vivo results indicated GA significantly inhibited NSCLC via promotion of peroxiredoxin-6 (Prdx6) and caspase-3 (Casp3)-mediated mitochondrial apoptosis. This original finding will provide theoretical and data support to improve the treatment of NSCLC with the application of GA.

Polynary energy harvesting and multi-parameter sensing in the heatwave environment of industrial factory buildings by an integrated triboelectric-thermoelectric hybrid generator.

Taking advantage of a hybrid generator to simultaneously collect polynary energy from a single energy source provides a feasible solution for the energy dilemma in the new era. Herein, we integrate a triboelectric nanogenerator and a thermoelectric generator for polynary energy harvesting and self-powered sensing of heatwaves in large-scale industrial factory buildings, which contains both thermal energy and wind energy. The new design of the fan-shaped rotation triboelectric nanogenerator (FR-TENG) makes it more compact and easily integrated. After structure modeling, the energy conversion efficiency of the FR-TENG can reach a maximum of 37.2%, which can successfully power a Bluetooth hygrothermograph transmitting environmental information wirelessly every 30 s at a wind speed of 4.67 m s-1. An all-inorganic flexible thermoelectric generator (iThEG) is developed based on copper and constantan with an output power density of 0.73 W m-3, and maintains its original mechanical properties after 10 000 bending tests. Moreover, a self-powered hot wind sensing system based on Labview is established which can display wind-speed and wind-temperature in real time. The working concept presented here is also applicable to other single energy sources containing multiple energy forms, such as falling raindrops and sunlight, which can lift energy utilization and conversion efficiency and alleviate the energy crisis.

Artesunate-Nanoliposome-TPP, a Novel Drug Delivery System That Targets the Mitochondria, Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Oxidative Stress and Inflammatory Effects.

Background: Acute kidney injury (AKI) is a syndrome, posing a substantial healthcare burden. The pathological basis of AKI is associated with inflammation and oxidative stress which cause additional damage to mitochondria. Artesunate (ATS) is a derivative of artemisinin isolated from Artemisia annua L. that is an effective treatment for malaria and favored for the prevention and treatment of kidney diseases. However, there are still challenges related to its efficacy, including poor water solubility, limited oral bioavailability and short half-life. Liposome-based nanoparticles are used for drug delivery due to their ideal biocompatibility and their ability to improve the bioavailability of specific drugs and enhance drug efficacy. Methods: In this study, a novel TPP-based natural ATS-nanoliposome, namely T-A-Ls, was applied for the treatment of AKI. ATS was encapsulated with or without triphenylphosphonium (TPP)-modified nanoliposomes. AKI was induced by cisplatin in C57BL/6J mice and a cisplatin-induced injury model was generated in HK-2 cells in vitro. Blood urea nitrogen (BUN), serum creatinine (Scr) measurements and section staining were utilized to assess renal protective effect of T-A-Ls. Inflammatory-related factors and proteins were quantified via Elisa, Immunofluorescence and Western Blot (WB). The anti-mitochondrial oxidative stress effect of T-A-Ls was determined by ROS, JC-1 and oxygen consumption rate (OCR) kits. Immunohistochemistry and WB were conducted to measure associated protein expressions. In vivo biodistribution and the concentration of T-A-Ls in kidney were also explored. Results: T-A-Ls exhibited good oxidative resistance, preferential renal uptake, mitochondrial targeting, and it ameliorated kidney injury in cisplatin-induced AKI mice. Mitochondrial dysfunction, ATP production and respiratory capacity were improved in damaged HK-2 cells; ROS content decreased while mitochondrial membrane potential recovered. T-A-Ls exerted renal protection by inhibiting inflammation and reducing oxidative stress; these effects were mediated by a downregulation in the expression of RAGE and iNOS and an upregulation in both Nrf2 and HO-1. Conclusion: T-A-Ls could improve the delivery of ATS to the kidney, offering a promising avenue to treat AKI.

Bioactive Alkaloids as Secondary Metabolites from Plant Endophytic Aspergillus Genus.

Alkaloids represent a large family of natural products with diverse structures and bioactivities. These compounds and their derivatives have been widely used in clinics to treat various diseases. The endophytic Aspergillus is a filamentous fungus renowned for its extraordinary ability to produce active natural products of high therapeutic value and economic importance. This review is the first to focus on Aspergillus-derived alkaloids. Through an extensive literature review and data analysis, 263 alkaloids are categorized according to their structural features into those containing cytochalasans, diketopiperazine alkaloids, quinazoline alkaloids, quinoline alkaloids, indole alkaloids, pyrrolidine alkaloids, and others. These metabolites exhibited diverse biological activities, such as antibacterial activity, cytotoxicity, anti-inflammatory activity, and α-glucosidase, ACE, and DPPH inhibitory activities. The bioactivity, structural diversity, and occurrence of these alkaloids are reviewed in detail.

Highly Sensitive Flexible Pressure Sensors with Hybrid Microstructures Similar to Volcano Sponge.

Preparing hybrid microstructures on flexible substrates is a crucial approach to achieving highly sensitive flexible pressure sensors. However, the preparation of hybrid microstructures on soft materials often faces complex, time-consuming, and costly problems, which hampers the advancement of highly sensitive flexible sensors. Herein, based on a 3D-printing template and a household microwave oven, a simple, green, and one-step microwave irradiation process using glucose porogen is applied to develop a flexible pressure sensor with a volcano-sponge-like porous dome structure based on porous polydimethylsiloxane (PDMS). Due to the easily deformable porous dome on the porous PDMS substrate, the flexible pressure sensor showcases exceptional sensitivity of 611.85 kPa-1 in 0-1 and 50.31 kPa-1 over a wide range of 20-80 kPa. Additionally, the sensor takes only 43 ms to respond, 123 ms to recover, and presents excellent stability (>1100 cycles). In application testing, the sensor effectively captures pulse signals, speech signals, tactile signals from a mechanical gripper, and gesture signals, demonstrating its potential applications in medical diagnosis and robotics. In conclusion, the microwave irradiation method based on template and glucose porogen provides a new way for the simple, low-cost, and green preparation of porous-surface hybrid microstructures on polymers and high-performance flexible pressure sensors.

Aerodynamic performance of a ventilation system for droplet control by coughing in a hospital isolation ward.

Over 766 million people have been infected by coronavirus disease 2019 (COVID-19) in the past 3 years, resulting in 7 million deaths. The virus is primarily transmitted through droplets or aerosols produced by coughing, sneezing, and talking. A full-scale isolation ward in Wuhan Pulmonary Hospital is modeled in this work, and water droplet diffusion is simulated using computational fluid dynamics (CFD). In an isolation ward, a local exhaust ventilation system is intended to avoid cross-infection. The existence of a local exhaust system increases turbulent movement, leading to a complete breakup of the droplet cluster and improved droplet dispersion inside the ward. When the outlet negative pressure is 4.5 Pa, the number of moving droplets in the ward decreases by approximately 30% compared to the original ward. The local exhaust system could minimize the number of droplets evaporated in the ward; however, the formation of aerosols cannot be avoided. Furthermore, 60.83%, 62.04%, 61.03%, 60.22%, 62.97%, and 61.52% of droplets produced through coughing reached patients in six different scenarios. However, the local exhaust ventilation system has no apparent influence on the control of surface contamination. In this study, several suggestions with regards to the optimization of ventilation in wards and scientific evidence are provided to ensure the air quality of hospital isolation wards.

High-Accuracy Neural Network Interatomic Potential for Silicon Nitride.

In the field of machine learning (ML) and data science, it is meaningful to use the advantages of ML to create reliable interatomic potentials. Deep potential molecular dynamics (DEEPMD) are one of the most useful methods to create interatomic potentials. Among ceramic materials, amorphous silicon nitride (SiNx) features good electrical insulation, abrasion resistance, and mechanical strength, which is widely applied in industries. In our work, a neural network potential (NNP) for SiNx was created based on DEEPMD, and the NNP is confirmed to be applicable to the SiNx model. The tensile tests were simulated to compare the mechanical properties of SiNx with different compositions based on the molecular dynamic method coupled with NNP. Among these SiNx, Si3N4 has the largest elastic modulus (E) and yield stress (σs), showing the desired mechanical strength owing to the largest coordination numbers (CN) and radial distribution function (RDF). The RDFs and CNs decrease with the increase of x; meanwhile, E and σs of SiNx decrease when the proportion of Si increases. It can be concluded that the ratio of nitrogen to silicon can reflect the RDFs and CNs in micro level and macro mechanical properties of SiNx to a large extent.

Neural Network Based Classification of Breast Cancer Histopathological Image from Intraoperative Rapid Frozen Sections.

Breast cancer is the leading cause of cancer-related mortality in women worldwide. Despite the rapid developments in diagnostic techniques and medical sciences, pathologic diagnosis is still recognized as the gold standard for disease diagnose. Pathologic diagnosis is a time-consuming task performed for pathologists, needing profound professional knowledge and long-term accumulated diagnostic experience. Therefore, the development of automatic and precise histopathological image classification is essential for medical diagnosis. In this study, an improved VGG network was used to classify the breast cancer histopathological image from intraoperative rapid frozen sections. We adopt a transformed loss function by adding a penalty to cross-entropy in our training stage, which improved the accuracy on test data by 4.39%. Laplacian-4 was used for the enhancement of images, which contributes to the improvement of the accuracy. The accuracy of the proposed model on training data and test data reached 88.70% and 82.27%, respectively, which outperforms the original model by 9.39% of accuracy in test data. The process time was less than 0.25 s per image on average. Meanwhile, the heat maps of predictions were given to show the evidential regions in histopathological images, which could drive improvements in the accuracy, speed, and clinical value of pathological diagnoses. In addition to helping with the actual diagnosis, this technology may be a benefit to pathologists, surgeons, and patients. It might prove to be a helpful tool for pathologists in the future.

Affinity-based protein profiling-driven discovery of myricanol as a Nampt activator.

Herein, we synthesized an affinity-based probe of myricanol (pMY) with a photo-affinity cross-linker to initiate a bioconjugation reaction, which was applied for target identification in live C2C12 myotubes. Pull-down of biotinylated pMY coupled with mass spectroscopy and Western blotting revealed that pMY can bind with nicotinamide phosphoribosyltransferase (Nampt), a rate-limiting enzyme in the nicotinamide adenine dinucleotide salvage pathway. Cellular thermal shift assay, drug affinity responsive target stability assay and recombinant protein labeling further validated the direct interaction between myricanol and Nampt. Myricanol did not affect the protein expression of Nampt, but enhanced its activity. Knock-down of Nampt totally abolished the promoting effect of myricanol on insulin-stimulated glucose uptake in C2C12 myotubes. Taken together, myricanol sensitizes insulin action in myotubes through binding with and activating Nampt.

Neuroprotective Effects of Celastrol in Neurodegenerative Diseases-Unscramble Its Major Mechanisms of Action and Targets.

There are rarely new therapeutic breakthroughs present for neurodegenerative diseases in the last decades. Thus, new effective drugs are urgently needed for millions of patients with neurodegenerative diseases. Celastrol, a pentacyclic triterpenoid compound, is one of the main active ingredients isolated from Tripterygium wilfordii Hook. f. that has multiple biological activities. Recently, amount evidence indicates that celastrol exerts neuroprotective effects and holds therapeutic potential to serve as a novel agent for neurodegenerative diseases. This review focuses on the therapeutic efficacy and major regulatory mechanisms of celastrol to rescue damaged neurons, restore normal cognitive and sensory motor functions in neurodegenerative diseases. Importantly, we highlight recent progress regarding identification of the drug targets of celastrol by using advanced quantitative chemical proteomics technology. Overall, this review provides novel insights into the pharmacological activities and therapeutic potential of celastrol for incurable neurodegenerative diseases.

The role of irisin in metabolic flexibility: Beyond adipose tissue browning.

Metabolic flexibility is the ability to adapt to physiological and environmental changes in metabolic demand. Irisin was originally discovered as an exercise-induced myokine involved in fat browning. In this review, we summarize emerging evidence for the roles of irisin in regulating glucose metabolism and insulin sensitivity in skeletal muscle, neuroplasticity and satiety in central nervous system, ß cell function and insulin secretion in the pancreas, bone remodeling, and adipose tissue function, which together orchestrate whole-body metabolic flexibility. Irisin is a key communicating mediator between skeletal muscle and other organs, and its manipulation could be a promising therapeutic strategy for treating obesity and related metabolic disorders.

The role of melatonin in the treatment of type 2 diabetes mellitus and Alzheimer's disease.

In type 2 diabetes mellitus (T2DM) and its related disorders like obesity, the abnormal protein processing, oxidative stress and proinflammatory cytokines will drive the activation of inflammatory pathways, leading to low-grade chronic inflammation and insulin resistance (IR) in the periphery and impaired neuronal insulin signaling in the brain. Studies have shown that such inflammation and impaired insulin signaling contribute to the development of Alzheimer's disease (AD). Therefore, new therapeutic strategies are needed for the treatment of T2DM and T2DM-linked AD. Melatonin is primarily known for its circadian role which conveys message of darkness and induces night-state physiological functions. Besides rhythm-related effects, melatonin has anti-inflammatory and antioxidant properties. Melatonin levels are downregulated in metabolic disorders with IR, and activation of melatonin signaling delays disease progression. The aim of this Review is to highlight the therapeutic potentials of melatonin in preventing the acceleration of AD in T2DM individuals through its therapeutic mechanisms, including antioxidative effects, anti-inflammatory effects, restoring mitochondrial function and insulin sensitivity.

3D printing of bioinspired compartmentalized capsular structure for controlled drug release.

Drug delivery with customized combinations of drugs, controllable drug dosage, and on-demand release kinetics is critical for personalized medicine. In this study, inspired by successive opening of layered structures and compartmentalized structures in plants, we designed a multiple compartmentalized capsular structure for controlled drug delivery. The structure was designed as a series of compartments, defined by the gradient thickness of their external walls and internal divisions. Based on the careful choice and optimization of bioinks composed of gelatin, starch, and alginate, the capsular structures were successfully manufactured by fused deposition modeling three-dimensional (3D) printing. The capsules showed fusion and firm contact between printed layers, forming complete structures without significant defects on the external walls and internal joints. Internal cavities with different volumes were achieved for different drug loading as designed. In vitro swelling demonstrated a successive dissolving and opening of external walls of different capsule compartments, allowing successive drug pulses from the capsules, resulting in the sustained release for about 410 min. The drug release was significantly prolonged compared to a single burst release from a traditional capsular design. The bioinspired design and manufacture of multiple compartmentalized capsules enable customized drug release in a controllable fashion with combinations of different drugs, drug doses, and release kinetics, and have potential for use in personalized medicine.

Alkyl-benzofuran dimers from Eupatorium chinense with insulin-sensitizing and anti-inflammatory activities.

Five new racemic alkyl-benzofuran dimers, (±)-dieupachinins I-M (1-5), were isolated from the root tubers of Eupatorium chinense, a well-known traditional Chinese medicine for the treatment of diphtheria in Guangdong province. The structures of these compounds, especially the first examples of 12,10'-epoxy dimer dieupachinin I (1), 12-nor-dimer dieupachinin J (2), and 12,12'-dinor-dimer dieupachinin K (3), were elucidated by spectroscopic data analysis. Chiral resolution were further carried out on a cellulose column by HPLC, and compounds 2-5 were successfully separated into two enantiomers, respectively. The absolute configurations of (+)-(2-5) and (-)-(2-5) were established by theoretical ECD calculation. All the compounds were evaluated for insulin-stimulated glucose uptake in C2C12 myotubes and (±)-dieupachinin I (1) exhibited the best activity. Compound 1 enhanced insulin-stimulated glucose uptake via activating the insulin receptor substrate 1/protein kinase B/glycogen synthase kinase-3ß signaling pathway. Moreover, all the isolates were tested for their nitric oxygen (NO) inhibitory effects in lipopolysaccharide-treated RAW264.7 macrophages, and compounds (±)-1, (±)-2, and (±)-4 showed promising inhibitory effects with IC50 values of 6.42 ± 1.85, 6.29 ± 1.94, and 16.03 ± 2.07 µM, respectively. (±)-Dieupachinin I (1) again dose-dependently suppressed LPS-induced expression of inducible NO synthase and nuclear translocation of p65.

Investigation of Potting-Adhesive-Induced Thermal Stress in MEMS Pressure Sensor.

Thermal stress is one of the main sources of micro-electro-mechanical systems (MEMS) devices error. The Wheatstone bridge is the sensing structure of a typical piezoresistive MEMS pressure sensor. In this study, the thermal stress induced by potting adhesive in MEMS pressure sensor was investigated by experiments, calculated by analytics and analyzed by simulations. An experiment system was used to test the sensor at different air pressures and temperatures. The error becomes greater with the decrease in pressure. A set of novel formulas were proposed to calculate the stress-strain on Wheatstone bridge. The error increases with the temperature deviating from 25 °C. A full-scale geometric model was developed, and finite element simulations were performed, to analyze the effect of the stress on MEMS pressure sensor induced by different temperatures and thicknesses of potting adhesive. Simulation results agree well with the experiments, which indicated that there is a 3.48% to 6.50% output error in 0.35 mm potting adhesive at 150 °C. With the thickness of potting adhesive increasing, the variations of output error of the Wheatstone bridge present an N-shaped curve. The output error meets a maximum of 5.30% in the potting adhesive of 0.95 mm and can be reduced to 2.47%, by increasing the potting adhesive to 2.40 mm.