In August 2020, the unusual appearance of crown gall symptoms was observed on the tobacco plants (hybrid PVH2310) grown in fields in the Golubinci (Srem district, Serbia) locality. The causal agent isolated from galls located on tobacco roots formed circular, convex, and glistening light blue colonies, and then dark to olive-green-colored bacterial colonies on a semi-selective D1 medium. Molecular analysis based on multiplex PCR and multi-locus sequence analysis (MLSA) using concatenated sequences of the atpD, dnaK, glnA, and rpoB genes as well as 16S rRNA identified Serbian tobacco isolates such as Agrobacterium tumefaciens (biovar 1). Two duplex PCR methods confirmed the presence of the virD2 and virC genes in tobacco isolates. Pathogenicity tests performed on carrot discs and squash fruits resulted in tumor/gall formation after 12 to 16 days post inoculation, respectively. Pathogenicity was also confirmed on tobacco plants, where isolates caused tumor development 21−25 days after inoculation. API 50 CH generated results regarding the biochemical features of the Serbian tobacco isolates. As A. tumefaciens (biovar 1) as a cause of tobacco crown gall has previously been documented solely in Japan, there is presently no data on its wider occurrence. Therefore, this first detailed investigation of A. tumefaciens isolated from naturally infected tobacco in Serbia will contribute to a better understanding of it at the global level. Full article

Per- and polyfluoroalkyl substances (PFASs) are carbon–fluorine compounds with widespread industrial and domestic use, posing potential toxicological risks to humans and ecosystems. Several analytical methods have been developed to assess the occurrence of PFASs in the environment, but a standardized method, applicable to all matrices, is still lacking. This paper reviews the extraction and chromatographic detection methods for PFAS assessment in environmental samples, considering parameters such as the LOD, LOQ, and recoveries. Solid phase extraction (SPE) is commonly used, showing high recovery rates for water, soil, and sediment samples using HBL and WAX polymeric sorbents (85–100% and 93–111.5%, respectively). LC-MS has demonstrated low LODs and LOQs in seawater (0.01–0.08 ng L⁻¹; 0.03–0.24 ng L⁻¹), marine sediment (0.002–0.018 ng g⁻¹; 0.004–0.054 ng g⁻¹), and dust (0.08–0.68 pg g⁻¹; 0.26–2.25 pg g⁻¹), indicating its sensitivity when detecting trace PFAS levels. Evaluating PFASs is crucial for the development of future removal strategies and risk assessments. Potential solutions including the use of PFAS substitutes and innovative adsorption techniques for their adsorption could present promise in reducing their environmental presence. Full article

Hildegard of Bingen (1098–1179) was a medieval mystic. From a young age, she had many colorful visions and became well known and influential not only in her own time but in ours as well. Her music reached the mellow house scene in the 1990s, reviving Hildegard’s spirituality for people today. In this paper, I will approach Hildegard as a philosophical practitioner and conduct an imaginary philosophical consultation. I will study her biography, listen to her words by some authentic text fragments and propose a spiritual exercise on her music in order not to just think about Hildegard of Bingen but to try and think like Hildegard of Bingen, in line with the principles of philosophical practice. This way, I will try to understand Hildegard in a practical way and not (just) annotate the regular (theoretical) interpretations of her life. I will distinguish three phases in her life as movements towards spirituality: (1) her relationship with the world, (2) her relationship with God, and (3) her relationship with herself as a spiritual being. I will argue that her life is an example of a philosophical life. Hildegard’s “not fitting in any place” (being átopos) and her development define such a life as a path towards an authentic self, attained by spirituality. The paper intends to contribute both to the understanding of philosophical consultations and to the understanding of Hildegard of Bingen. Full article

Poor surface quality is one of the drawbacks of metal parts made by additive manufacturing (AM)—they normally possess relatively high surface roughness and different types of surface irregularities. Post-processing operations are usually needed to reduce the surface roughness to have ready-to-use parts. Among all the surface treatment techniques, electrochemical polishing has the highest finishing efficiency and flexibility. However, although the average surface roughness can be reduced effectively (more than 80% roughness reduction), large-scale surface waviness still remains an issue when finishing metal AM parts. To maintain the finishing efficiency while reducing the surface waviness, a novel hybrid surface finishing technique is designed, which involves the combination of electropolishing, ultrasonic vibration, and abrasion. Preliminary experiments to prove the feasibility of novel hybrid finishing methods were conducted on Ti6Al4V coupons manufactured via laser powder bed fusion (LPBF). Electropolishing, a combination of ultrasound and abrasion, and hybrid finishing were conducted for process optimization and comparison purposes. The effects of the voltage, inter-electrode gap, temperature, ultrasonic amplitude, abrasive concentration, and processing time were studied and optimized. When similar optimal arithmetic mean height values (Sa ≈ 1 μm) are achieved for both processes, the arithmetic mean waviness values (Wa) obtained from hybrid finishing are much less than those from sole electropolishing after the same processing time, with the amount being 61.7% less after 30 min and 40.0% after 45 min. Full article

Long-acting injectable (LAI) formulations provide sustained drug release over an extended period ranging from weeks to several months to improve efficacy, safety, and compliance. Nevertheless, many challenges arise in the development and regulatory assessment of LAI drug products due to a limited understanding of the tissue response to injected particles (e.g., inflammation) impacting in vivo performance. Mechanism-based in silico methods may support the understanding of LAI–physiology interactions. The objectives of this study were as follows: (1) to use a mechanistic modeling approach to delineate the in vivo performance of DepoSubQ Provera^® and formulation variants in preclinical species; (2) to predict human exposure based on the knowledge gained from the animal model. The PBPK model evaluated different elements involved in LAI administration and showed that (1) the effective in vivo particle size is potentially larger than the measured in vitro particle size, which could be due to particle aggregation at the injection site, and (2) local inflammation is a key process at the injection site that results in a transient increase in depot volume. This work highlights how a mechanistic modeling approach can identify critical physiological events and product attributes that may affect the in vivo performance of LAIs. Full article

Fatigue is a common non-motor symptom in Parkinson’s disease (PD), but even so, it may still be underdiagnosed or misdiagnosed in current practice due to its non-specific manifestations. The aims of this study were to investigate the prevalence of fatigue in PD patients compared to healthy controls and to identify the main characteristics and associations of fatigue with other non-motor symptoms and the impact of fatigue on sleep disturbances in Parkinson’s disease. Materials and methods: case–control study in which 131 PD patients and 131 age- and sex-matched controls were enrolled. Main characteristics of fatigue, sleep, and other non-motor symptoms were assessed using specific validated questionnaires. Results: According to the Chalder fatigue scale, fatigue is more prevalent in PD patients (38.16%) compared to healthy controls (26.71%). Fatigue was identified in 46.54% of the PD patients using the Parkinson’s Fatigue Scale (PFS-16). PD patients with fatigue presented a worse motor status, more sleep disturbances (insomnia, daytime sleepiness), a broader spectrum of non-motor symptoms (pain, anxiety, urinary disturbances), worse cognitive performances, a lower level of happiness, and worse quality of life compared to PD patients without fatigue. Conclusion: Fatigue is a common symptom of PD and needs to be assessed, considering its consequences on quality of life. Sleep disturbances have a great influence over fatigue in PD patients. Full article

Neuroplasticity in the central nucleus of the amygdala (CeA) plays a key role in the modulation of pain and its aversive component. The dynorphin/kappa opioid receptor (KOR) system in the amygdala is critical for averse-affective behaviors in pain conditions, but its mechanisms are not well understood. Here, we used chemogenetic manipulations of amygdala KOR-expressing neurons to analyze the behavioral consequences in a chronic neuropathic pain model. For the chemogenetic inhibition or activation of KOR neurons in the CeA, a Cre-inducible viral vector encoding Gi-DREADD (hM4Di) or Gq-DREADD (hM3Dq) was injected stereotaxically into the right CeA of transgenic KOR-Cre mice. The chemogenetic inhibition of KOR neurons expressing hM4Di with a selective DREADD actuator (deschloroclozapine, DCZ) in sham control mice significantly decreased inhibitory transmission, resulting in a shift of inhibition/excitation balance to promote excitation and induced pain behaviors. The chemogenetic activation of KOR neurons expressing hM3Dq with DCZ in neuropathic mice significantly increased inhibitory transmission, decreased excitability, and decreased neuropathic pain behaviors. These data suggest that amygdala KOR neurons modulate pain behaviors by exerting an inhibitory tone on downstream CeA neurons. Therefore, activation of these interneurons or blockade of inhibitory KOR signaling in these neurons could restore control of amygdala output and mitigate pain. Full article

Joining structural components with mechanical fasteners is common in many engineering applications across all industries. This study investigates combining additive manufactured inserts with sandwich composites consisting of aluminum honeycomb cores with carbon fiber reinforced facesheets. The combination of these components offers an integrated, lightweight solution when mechanically fastening sandwich composite components using bolted joints. The experimental and numerical investigation explores the influence insert geometry has on the structural response of a sandwich composite under pull-through load scenarios. Various failure modes are observed during experimental analysis with facesheet debonding being the initial failure mode. In addition, finite element models investigate the stress fields in the honeycomb core and overall panel deflections, validating the mechanics observed experimentally. When comparing additively manufactured inserts to standard inserts, additively manufactured inserts have increases in stiffness, maximum force, and total energy absorption of 7.1%, 53.0%, and 62.3%, respectively. These results illustrate the potential of an integrated approach to mechanical joint technology by combining additively manufactured inserts with sandwich composite components using aluminum honeycomb cores. Full article

The consumption of functional foods in a daily diet is a promising approach for the maintenance of cognitive health. The present study examines the effects of water-soluble prebiotic dietary-fiber, partially hydrolyzed guar gum (PHGG), on cognitive function and mental health in healthy elderly individuals. Participants consumed either 5 g/day of PHGG or a placebo daily for 12 weeks in this randomized, double-blind, placebo-controlled, and parallel-group study. An assessment of cognitive functions, sleep quality, and subjective mood evaluations was performed at baseline and after 8 and 12 weeks of either PHGG or placebo intake. The visual memory scores in cognitive function tests and sleepiness on rising scores related to sleep quality were significantly improved in the PHGG group compared to the placebo group. No significant differences were observed in mood parameters between the groups. Vigor–activity scores were significantly improved, while the scores for Confusion–Bewilderment decreased significantly in the PHGG group when compared to the baseline. In summary, supplementation with PHGG was effective in improving cognitive functions, particularly visual memory, as well as enhancing sleep quality and vitality in healthy elderly individuals (UMIN000049070). Full article

PIPAC is a new and promising technique for the intraperitoneal administration of chemotherapy. It can be used in patients with various peritoneal cancer metastases. It is mainly a palliative treatment, but there is some neoadjuvant treatment potential. We have operated on 41 patients with various intra-abdominal cancers. PIPAC was performed every 6 weeks. The indication was extension of peritoneal carcinomatosis beyond the criteria for cytoreductive surgery and HIPEC. The effect was evaluated according to the peritoneal cancer index, the peritoneal regression grading score and the amount of ascites. Complications were classified according to the Clavien-Dindo system. We have performed 100 PIPAC procedures. There were two major complications, classified as Clavien Dindo III (2%). The number of procedures varied from 1 to 6. Five patients switched to cytoreductive surgery and HIPEC, and one was indicated for the watch and wait strategy due to total regression according to PRGS. Three patients are still continuing treatment. The others stopped treatment mainly because of progression of the disease and loss of metastases. We observed a reduction in ascites production soon after PIPAC application. PIPAC is a safe and well-tolerated treatment modality. It is mainly a palliative treatment that can improve the quality of life by reducing the production of ascites, but in about 10% of cases, it can reduce the extent of the disease and allow for further radical treatment. Full article

Neural machine translation (NMT) typically relies on a substantial number of bilingual parallel corpora for effective training. Mongolian, as a low-resource language, has relatively few parallel corpora, resulting in poor translation performance. Data augmentation (DA) is a practical and promising method to solve problems related to data sparsity and single semantic structure by expanding the size and structure of available data. In order to address the issues of data sparsity and semantic inconsistency in Mongolian–Chinese NMT processes, this paper proposes a new semantic-context DA method. This method adds an additional semantic encoder based on the original translation model, which utilizes both source and target sentences to generate different semantic vectors to enhance each training instance. The results show that this method significantly improves the quality of Mongolian–Chinese NMT tasks, with an increase of approximately 2.5 BLEU values compared to the basic Transformer model. Compared to the basic model, this method can achieve the same translation results with about half of the data, greatly improving translation efficiency. Full article

Deep learning-based models have achieved impressive results across various practical fields. However, these models are susceptible to attacks. Recent research has demonstrated that adversarial samples can significantly decrease the accuracy of deep learning models. This susceptibility poses considerable challenges for their use in security applications. Various methods have been developed to enhance model robustness by training with more effective and generalized adversarial examples. However, these approaches tend to compromise model accuracy. Currently proposed detection methods mainly focus on speech adversarial samples generated by specified white-box attack models. In this study, leveraging manifold learning technology, a method is proposed to detect whether a speech input is an adversarial sample before feeding it into the recognition model. The method is designed to detect speech adversarial samples generated by black-box attack models and achieves a detection success rate of 84.73%. It identifies the low-dimensional manifold of training samples and measures the distance of a sample under investigation to this manifold to determine its adversarial nature. This technique enables the preprocessing detection of adversarial audio samples before their introduction into the deep learning model, thereby preventing adversarial attacks without affecting model robustness. Full article

The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. RB1′s canonical function in cell cycle control and DNA repair mechanisms underscores its significance in restraining aberrant cell growth and maintaining genomic stability. Understanding the complex interplay between RB1 and cellular pathways is beneficial to fully elucidate its tumor-suppressive role across different cancer types and for therapeutic development. As a result, investigating vulnerabilities arising from RB1 deletion-associated mechanisms offers promising avenues for targeted therapy. Recently, several findings highlighted multiple methods as a promising strategy for combating tumor growth driven by RB1 loss, offering potential clinical benefits in various cancer types. This review summarizes the multifaceted role of RB1 in cancer biology and its implications for targeted therapy. Full article

Coronavirus disease 2019 (COVID-19) has affected medical practice. More than 7,000,000 patients died worldwide after being infected with COVID-19; however, no specific laboratory markers have yet been established to predict death related to this disease. In contrast, electrocardiographic changes due to COVID-19 include QT prolongation and ST-T changes; however, there have not been studies on the ambulatory electrocardiographic markers of COVID-19. We encountered three patients diagnosed as having COVID-19 who did not have a prior history of significant structural heart diseases. All patients had abnormalities in ambulatory echocardiogram parameters detected by high-resolution 24 h electrocardiogram monitoring: positive late potentials (LPs) and T-wave alternans (TWA), abnormal heart rate variability (HRV), and heart rate turbulence (HRT). Case 1 involved a 78-year-old woman with a history of chronic kidney disease, Case 2 involved a 76-year-old man with hypertension and diabetes, and Case 3 involved a 67-year-old man with renal cancer, lung cancer, and diabetes. None of them had a prior history of significant structural heart disease. Although no significant consistent increases in clinical markers were observed, all three patients died, mainly because of respiratory failure with mild heart failure. The LP, TWA, HRV, and HRT were positive in all three cases with no significant structural cardiac disease at the initial phase of admission. The further accumulation of data regarding ambulatory electrocardiographic markers in patients with COVID-19 is needed. Depending on the accumulation of data, the LP, TWA, HRV, and HRT could be identified as potential risk factors for COVID-19 pneumonia in the early phase of admission. Full article

The separation of Li⁺ and [Bmim]⁺(1-Butyl-3-methylimidazolium) using a cation exchange membrane in an electric field is studied in this work. The effects of the type of cation exchange membrane, current density, total cation concentration, temperature, and anion types on the separation efficiency are investigated. The results indicate that it is feasible to achieve the efficient separation of Li⁺ and [Bmim]⁺ using the selectivity of cation exchange membranes under an electric field. The CIMS membrane (a type of cation exchange membrane produced by ASTOM Corporation) shows obvious selectivity of Li⁺ from [Bmim]⁺. When the current density is 5 mA/cm² and the feed concentrations of Li⁺ and [Bmim]⁺ are 0.3 mol/L and 0.2 mol/L, respectively, the selective transport coefficient of CIMS can reach 5.9 in the first 120 min of the process. The separation efficiency can be effectively improved by reducing the current density and increasing the total cation concentration. Decreasing the feed temperature can slightly improve the separation efficiency. Changing the type of anion in the feed from chloride to acetate has no detectable effect on the separation. Full article

Olive leaf contains plenty of phenolic compounds, among which oleuropein (OP) is the main component and belongs to the group of secoiridoids. Additionally, phenolic compounds such as oleocanthal (OL) and oleacein (OC), which share a structural similarity with OP and two aldehyde groups, are also present in olive leaves. These compounds have been studied for several health benefits, such as anti-cancer and antioxidant effects. However, their impact on the skin remains unknown. Therefore, this study aims to compare the effects of these three compounds on melanogenesis using B16F10 cells and human epidermal cells. Thousands of gene expressions were measured by global gene expression profiling with B16F10 cells. We found that glutaraldehyde compounds derived from olive leaves have a potential effect on the activation of the melanogenesis pathway and inducing differentiation in B16F10 cells. Accordingly, the pro-melanogenesis effect was investigated by means of melanin quantification, mRNA, and protein expression using human epidermal melanocytes (HEM). This study suggests that secoiridoid and its derivates have an impact on skin protection by promoting melanin production in both human and mouse cell lines. Full article

Exploring phytochemicals from ethnomedicinal plants for pharmacological applications is a promising research area. By studying ethnomedicine, researchers can identify plants used for centuries to treat ailments and investigate their phytochemicals. Consequently, phytochemicals can be isolated, characterized, and tested for pharmacological activities, leading to new drug development. This research also helps preserve traditional knowledge and biodiversity. Lithospermum officinale L., found in Eurasia, Argentina (South), Colombia, and the United States, is valued for its medicinal properties, including anti-inflammatory, antioxidant, and antimicrobial effects. The current review emphasizes L. officinale L. as a significant reservoir of bioactive phytochemicals, with alkaloids, quinones, glucosides, phenolics, flavonoids, and lipids identified as the principal metabolites. It also unveils the unexplored potential of this plant for future research endeavors. Continued research on L. officinale L. can unlock its full potential, providing insights into its medicinal uses and contributing to biodiversity preservation. Full article

Background: The impaction of the maxillary canine is a common occurrence, and orthodontists must be prepared to manage it. The purpose of this article is to present a study of the efficacy of a double-wire orthodontic appliance compared to a control group in the alignment of impacted maxillary canines in the dental arch. Methods: To diagnose an impacted maxillary canine, a panoramic radiograph was taken and a detailed analysis was performed by the same orthodontist. This article presents the results of 28 impacted maxillary canines with inclusion criteria of A2 (tooth angulation to the midline 16°–45°), V1 (vertical height of the tooth crown above the cementoenamel junction but less than half the length of the root of the maxillary lateral incisor), and O3 (medial position of the canine crown of more than half but less than the entire root width of the lateral incisor) positions in 21 patients (7 males and 14 females) with a mean age of 14.02 years (SD = 1.61) who were treated by the same orthodontist for impacted maxillary canines using a fixed double-wire orthodontic appliance. The analyzed data were compared with the control group (treated with a fixed orthodontic appliance and active ligature), which was matched for pretreatment age and the A2, V1, and O3 positions of the impacted maxillary canine. Results: With both methods, the impacted maxillary canines were aligned and guided into a correct position in the dental arch, but the mean active orthodontic traction of 31 ± 4.2 weeks in the SG was statistically significantly shorter (p < 0.05) in comparison to 37 ± 6.3 weeks in the CG, and the number of visits was statistically significantly (p < 0.05) fewer in the SG (5 ± 2) than in the CG (11 ± 5). Conclusions: The findings of this study are important to the field of orthodontics and show that the alignment of impacted maxillary canines with A2, V1, and O3 positions can be achieved with both methods, but with the double-wire appliance, the treatment time was shorter and the number of visits was statistically significantly fewer. The results of this study suggest that this approach may be more efficient and cost-effective compared to conventional methods. Full article

Thunderstorms endanger life and infrastructure. The accurate and precise prediction of thunderstorms is therefore helpful to enable protection measures and to reduce the risks. This manuscript presents the latest developments to improve thunderstorm forecasting in the first few hours. This includes the description and discussion of a new Julia-based method (JuliaTSnow) for the temporal extrapolation of thunderstorms and the blending of this method with the numerical weather prediction model (NWP) ICON. The combination of ICON and JuliaTSnow attempts to overcome the limitations associated with the pure extrapolation of observations with atmospheric motion vectors (AMVs) and thus increase the prediction horizon. For the blending, the operational ICON-D2 is used, but also the experimental ICON-RUC, which is implemented with a faster data assimilation update cycle. The blended products are evaluated against lightning data. The critical success index (CSI) for the blended RUC product is higher for all forecast time steps. This is mainly due to the higher resolution of the AMVs (prediction hours 0–2) and the rapid update cycle of ICON-RUC (prediction hours 2–6). The results demonstrate the potential of the rapid update cycle to improve the short-term forecasts of thunderstorms. Moreover, the transition between AMV-driven nowcasting to NWP is much smoother in the blended RUC product, which points to the advantages of fast data assimilation for seamless predictions. The CSI is well above the critical value of 0.5 for the 0–2 h forecasts. Values below 0.5 mean that the number of hits (correct informations) is lower than the number of failures, which results from the missed cells plus false alarms. The product is then no longer useful in forecasting thunderstorms with a spatial accuracy of 0.3 degrees. Unfortunately, with RUC, the CSI also drops below 0.5 when the last forecast is more than 3 h away from the last data assimilation, indicating the lack of model physics to accurately predict thunderstorms. This lack is simply a result of chaos theory. Within this context, the role of NWP in comparison with artificial intelligence (AI) is discussed, and it is concluded that AI could replace physical short-term forecasts in the near future. Full article

Horizontal wells within the roof are an effective method to develop gas in broken and soft coal seams, and layer-penetrating fracturing is a key engineering method for the stimulating of horizontal wells within the roof of a coal seam. To understand the propagation law of fracture in the composite roof of coal seams, this study conducted research using numerical simulation and physical similarity simulation methods. Furthermore, engineering experiments were carried out at the Panxie coal mine in the Huainan Mining Area and the Luling coal mine in Huaibei Mining Area, to further validate this technology. The numerical simulation results indicated that fracture within the coal seam roof can propagate from the roof to the target coal seam, effectively fracturing the coal seam. Due to the coal seam’s plasticity being greater than that of the roof mudstone, the coal seam forms a broader fracture than the roof. With the increase in pseudo roof mudstone thickness and being under constant fracturing displacement, the energy consumed by the pseudo roof mudstone during fracturing causes a decrease in pore pressure when fracture extends to the coal seam, resulting in a reduction in fracture width. Therefore, the pseudo roof mudstone is an adverse factor for the expansion of hydraulic fracturing. Physical similarity simulation results demonstrated that when horizontal boreholes were arranged within the siltstone of the coal seam roof, were under reasonable vertical distance and high flow rate fracturing via fluid injection conditions, and if the coal seam had a thin pseudo roof mudstone, the fracture could propagate through the direct roof-pseudo roof interface and the pseudo roof-coal seam interface, extending to the lower coal seam. The fracture form was curved and had irregular vertical fractures, indicating that hydraulic fracturing can achieve production enhancement and the transformation of soft and hard coal seams. However, when the coal seam had a thick pseudo roof mudstone, the mudstone posed strong resistance to hydraulic fracturing, making it difficult for the fracture to propagate to the lower coal seam. Therefore, the pseudo roof mudstone plays a detrimental role in hydraulic fracturing and the production enhancement of coal seams. The engineering verification conducted at Panxie coal mine and Luling coal mine showed that by utilizing a construction drainage rate of 7.5 cubic meters per minute at Panxie coal mine, the maximum fracture length reached 218.3 m, with a maximum fracture height of 36.8 m. The maximum daily gas production of a single well reached 1450 cubic meters per day, with a total gas extraction volume of 43.62 × 10⁴ cubic meters across 671 days. At Luling coal mine, utilizing a construction drainage rate of 10 cubic meters per minute, the maximum fracture length reached 169.1 m, with a maximum fracture height of 20.5 m. The maximum daily gas production of a single well reached 10,775 cubic meters per day, with a total gas extraction volume of 590 × 10⁴ cubic meters for 1090 days. This indicated that the fracture within the roof of coal seams can penetrate the composite roof of coal seams and extend to the interior of the coal seams, achieving the purpose of transforming fractured and low-permeability coal seams and providing an effective mode of gas extraction. Full article

Although endometriosis is a benign disease, it is associated with cancer-related gene mutations, such as KRAS or PIK3CA. Endometriosis is associated with elevated levels of inflammatory factors that cause severe pain. In a previous study, we demonstrated that KRAS or PIK3CA mutations are associated with the activation of cell proliferation, migration, and invasion in a patient-derived immortalized endometriotic cell line, HMOsisEC10. In this study, we investigated the effects of these mutations on progesterone resistance. Since the HMOsisEC10 had suppressed progesterone receptor (PR) expression, we transduced PR-B to HMOsisEc10 cell lines including KRAS mutant and PIK3CA mutant cell lines. We conducted a migration assay, invasion assay, and MTT assay using dienogest and medroxyprogestrone acetate. All cell lines showed progesterone sensitivity with or without mutations. Regarding inflammatory factors, real-time quantitative RT-PCR revealed that the KRAS mutation cell line exhibited no suppression of Cox-2 and mPGES-1 on progesterone treatment, whereas IL-6, MCP-1, VEGF, and CYP19A1 were significantly suppressed by progesterone in both mutated cell lines. Our results suggest that KRAS mutation and PIK3CA mutation in endometriotic cells may not be associated with progesterone resistance in terms of aggressiveness. However, KRAS mutations may be associated with progesterone resistance in the context of pain. Full article

The uncertainty of surrounding rock parameters varies due to changes in the boundary conditions of the tunnel model, and no suitable method to ensure that the updated parameters of the finite element model (FEM) are applicable throughout the constructional environment. To address this issue, a probabilistic baseline model method was introduced to invert the rock parameters and obtain values suitable for the complete constructional environment. First, the probabilistic statistical theory was applied to statistically analyze the measurement data from tunnels under different constructional environments, which provides insight into the variation in rock parameters. Then, an objective optimization function based on a genetic algorithm (GA) was constructed to optimize the accuracy by minimizing the error between the measurement data and the simulation data. Next, a Kriging model was built that utilized Young’s modulus and cohesion as updated parameters. This approach contributes to overcoming the inefficiency of multi-objective optimization computations. By using the Kriging model, optimal values for the rock parameters were obtained. Finally, the effectiveness and applicability of the proposed method were validated by comparing the measured data with the updated model data under different constructional environments. Full article