bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood-Derived Exosomal hTERT mRNA in Patients with Lung Cancer: Characterization and Correlation with Response to Therapy
Authors: Rotem Ofer , Zer Alona , Yosef Lilach , Beery Einat , Goldvaser Hadar , Gutkin Anna , Levin Ron , Dudnik Elizabeth , Berger Tamar , Feinmesser Meora , Levy-Barda Adva , Lahav Meir , Raanani Pia , Uziel Orit
Published: June 2023

Background: Telomerase (human telomerase reverse transcriptase (hTERT) is considered a hallmark of cancer, being active in cancer cells but repressed in human somatic cells. As such, it has the potential to serve as a valid cancer biomarker. Exosomal hTERT mRNA can be detected in the serum of patients with solid malignancies but not in healthy individuals. We sought to evaluate the feasibility of measuring serum exosomal hTERT transcripts levels in patients with lung cancer. Methods: A prospective analysis of exosomal hTERT mRNA levels was determined in serum-derived exosomes from 76 patients with stage III–IV lung cancer (11 SCLC and 65 NSCLC). An hTERT level above RQ = 1.2 was considered “detectable” according to a previous receiver operating characteristic curve (ROC) curve. Sequential measurements were obtained in 33 patients. Demographic and clinical data were collected retrospectively from patients’ charts. Data on response to systemic therapy (chemotherapy, immunotherapy, and tyrosine kinase inhibitors) were collected by the treating physicians. Results: hTERT was detected in 53% (40/76) of patients with lung cancer (89% of SCLC and 46% of NSLCC). The mean hTERT levels were 3.7 in all 76 patients, 5.87 in SCLC patients, and 3.62 in NSCLC patients. In total, 25 of 43 patients with sequential measurements had detectable levels of hTERT. The sequential exosomal hTERT mRNA levels reflected the clinical course in 23 of them. Decreases in hTERT levels were detected in 17 and 5 patients with partial and complete response, respectively. Eleven patients with a progressive disease had an increase in the level of exosomal hTERT, and seven with stable disease presented increases in its exosomal levels. Another patient who progressed on the first line of treatment and had a partial response to the second line of treatment exhibited an increase in exosomal hTERT mRNA levels during the progression and a decrease during the response. Conclusions: Exosomal hTERT mRNA levels are elevated in over half of patients with lung cancer. The potential association between hTERT levels and response to therapy suggests its utility as a promising cancer biomarker for response to therapy. This issue should be further explored in future studies.
ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model
Authors: Daly Owen , Mahiny Azita Josefine , Majeski Sara , McClintock Kevin , Reichert Julia , Boros Gábor , Szabó Gábor Tamás , Reinholz Jonas , Schreiner Petra , Reid Steve , Lam Kieu , Lepper Marlen , Adler Melanie , Meffen Tracy , Heyes James , Karikó Katalin , Lutwyche Pete , Vlatkovic Irena
Published: June 2023

Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5′ and 3′ untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASLNeo/Neo mouse model of ASLD, intravenous administration of the lead therapeutic candidate LNP-ASL CDS2 drastically improved the survival of the mice. When administered twice a week lower doses partially protected and 3 mg/kg LNP-ASL CDS2 fully protected the mice. These results demonstrate the considerable potential of LNP-formulated, modified ASL-encoding mRNA as an effective alternative to AAV-based approaches for the treatment of ASA.
The Developments of Surface-Functionalized Selenium Nanoparticles and Their Applications in Brain Diseases Therapy
Authors: Hu Rong , Wang Xiao , Han Lu , Lu Xiong
Published: June 2023

Selenium (Se) and its organic and inorganic compounds in dietary supplements have been found to possess excellent pharmacodynamics and biological responses. However, Se in bulk form generally exhibits low bioavailability and high toxicity. To address these concerns, nanoscale selenium (SeNPs) with different forms, such as nanowires, nanorods, and nanotubes, have been synthesized, which have become increasingly popular in biomedical applications owing to their high bioavailability and bioactivity, and are widely used in oxidative stress-induced cancers, diabetes, and other diseases. However, pure SeNPs still encounter problems when applied in disease therapy because of their poor stability. The surface functionalization strategy has become increasingly popular as it sheds light to overcome these limitations in biomedical applications and further improve the biological activity of SeNPs. This review summarizes synthesis methods and surface functionalization strategies employed for the preparation of SeNPs and highlights their applications in treating brain diseases.
A High-Efficient Reinforcement Learning Approach for Dexterous Manipulation
Authors: Zhang Jianhua , Zhou Xuanyi , Zhou Jinyu , Qiu Shiming , Liang Guoyuan , Cai Shibo , Bao Guanjun
Published: June 2023

Robotic hands have the potential to perform complex tasks in unstructured environments owing to their bionic design, inspired by the most agile biological hand. However, the modeling, planning and control of dexterous hands remain unresolved, open challenges, resulting in the simple movements and relatively clumsy motions of current robotic end effectors. This paper proposed a dynamic model based on generative adversarial architecture to learn the state mode of the dexterous hand, reducing the model’s prediction error in long spans. An adaptive trajectory planning kernel was also developed to generate High-Value Area Trajectory (HVAT) data according to the control task and dynamic model, with adaptive trajectory adjustment achieved by changing the Levenberg–Marquardt (LM) coefficient and the linear searching coefficient. Furthermore, an improved Soft Actor–Critic (SAC) algorithm is designed by combining maximum entropy value iteration and HVAT value iteration. An experimental platform and simulation program were built to verify the proposed method with two manipulating tasks. The experimental results indicate that the proposed dexterous hand reinforcement learning algorithm has better training efficiency and requires fewer training samples to achieve quite satisfactory learning and control performance.
A Two-Species Finite Volume Scalar Model for Modeling the Diffusion of Poly(lactic-co-glycolic acid) into a Coronary Arterial Wall from a Single Half-Embedded Drug Eluting Stent Strut
Authors: Hewlin Rodward L. , Edwards Maegan , Kizito John P.
Published: June 2023

This paper outlines the methodology and results for a two-species finite volume scalar computational drug transport model developed for simulating the mass transport of Poly(lactic-co-glycolic acid (PLGA)) from a half-embedded single strut implanted in a coronary arterial vessel wall. The mathematical drug transport model incorporates the convection-diffusion equation in scalar form (dimensionless) with a two-species (free-drug and bound-drug) mass transport setup, including reversible equilibrium reaction source terms for the free and bound-drug states to account for the pharmaco-kinetic reactions in the arterial wall. The relative reaction rates of the added source terms control the interconversion of the drug between the free and bound-drug states. The model is solved by a 2D finite-volume method for discretizing and solving the free and bound drug transport equations with anisotropic vascular drug diffusivities. This model is an improvement over previously developed models using the finite-difference and finite element method. A dimensionless characteristic scaling pre-analysis was conducted a priori to evaluate the significance of implementing the reaction source terms in the transport equations. This paper reports the findings of an investigation of the interstitial flow profile into the arterial wall and the free and bound drug diffusion profiles with a parametric study of varying the polymer drug concentration (low and high), tortuosity, porosity, and Peclet and DamKöhler numbers over the course of 400 h (16.67 days). The results also reveal how a single species drug delivery model that neglects both a reversible binding reaction source term and the porosity and tortuosity of the arterial wall cannot accurately predict the distribution of both the free and bound drug.
Electrochemical Characterization Using Biosensors with the Coagulant Moringa oleifera Seed Lectin (cMoL)
Authors: de Oliveira Benny Ferreira , de Araújo Hallysson Douglas Andrade , Neves Eloisa Ferreira , Napoleão Thiago Henrique , Paiva Patrícia Maria Guedes , de Freitas Katia Cristina Silva , de Souza Sandra Rodrigues , Coelho Luana Cassandra Breitenbach Barroso
Published: June 2023

Triturated Moringa oleifera seeds have components that adsorb recalcitrant indigo carmine dye. Coagulating proteins known as lectins (carbohydrate-binding proteins) have already been purified from the powder of these seeds, in milligram amounts. The coagulant lectin from M. oleifera seeds (cMoL) was characterized by potentiometry and scanning electron microscopy (SEM) using MOFs, or metal–organic frameworks, of [Cu3(BTC)2(H2O)3]n to immobilize cMoL and construct biosensors. The potentiometric biosensor revealed an increase in the electrochemical potential resulting from the Pt/MOF/cMoL interaction with different concentrations of galactose in the electrolytic medium. The developed aluminum batteries constructed with recycled cans degraded an indigo carmine dye solution; the oxide reduction reactions of the batteries generated Al(OH)3, promoting dye electrocoagulation. Biosensors were used to investigate cMoL interactions with a specific galactose concentration and monitored residual dye. SEM revealed the components of the electrode assembly steps. Cyclic voltammetry showed differentiated redox peaks related to dye residue quantification by cMoL. Electrochemical systems were used to evaluate cMoL interactions with galactose ligands and efficiently degraded dye. Biosensors could be used for lectin characterization and monitoring dye residues in environmental effluents of the textile industry.
Review of the Oscillation of Research Regulations for Bioethics in the Republic of Korea: Comparison with Japan
Authors: Hyeon Seung-Hyo , An Juyoung , Ryoo Hwa-Shin , Lee Min-Kyu
Published: June 2023

The Bioethics Act in the Republic of Korea has undergone great fluctuations akin to the pendulum of a clock. Since Professor Hwang’s research ethics issue, domestic embryonic stem cell research has lost its vitality. This study argues that the Republic of Korea needs a reference point that does not waiver. This study examined the characteristics of life science- and ethics-related systems in the Republic of Korea and Japan. It also examined the pendulum-like policy changes in the Republic of Korea. It then compared the strengths and weaknesses between the Republic of Korea and Japan. Finally, we proposed a system improvement strategy for the development of bioethics research in Asian countries. In particular, this study argues that the advantages of Japan’s slow but stable system should be introduced.
Ocular-Surface Regeneration Therapies for Eye Disorders: The State of the Art
Authors: Posarelli Matteo , Romano Davide , Tucci Davide , Giannaccare Giuseppe , Scorcia Vincenzo , Taloni Andrea , Pagano Luca , Borgia Alfredo
Published: June 2023

The ocular surface is a complex structure that includes cornea, conjunctiva, limbus, and tear film, and is critical for maintaining visual function. When the ocular-surface integrity is altered by a disease, conventional therapies usually rely on topical drops or tissue replacement with more invasive procedures, such as corneal transplants. However, in the last years, regeneration therapies have emerged as a promising approach to repair the damaged ocular surface by stimulating cell proliferation and restoring the eye homeostasis and function. This article reviews the different strategies employed in ocular-surface regeneration, including cell-based therapies, growth-factor-based therapies, and tissue-engineering approaches. Dry eye and neurotrophic keratopathy diseases can be treated with nerve-growth factors to stimulate the limbal stem-cell proliferation and the corneal nerve regeneration, whereas conjunctival autograft or amniotic membrane are used in subjects with corneal limbus dysfunction, such as limbal stem-cell deficiency or pterygium. Further, new therapies are available for patients with corneal endothelium diseases to promote the expansion and migration of cells without the need of corneal keratoplasty. Finally, gene therapy is a promising new frontier of regeneration medicine that can modify the gene expression and, potentially, restore the corneal transparency by reducing fibrosis and neovascularization, as well as by stimulating stem-cell proliferation and tissue regeneration.
Ten Principles for Bird-Friendly Forestry: Conservation Approaches in Natural Forests Used for Timber Production
Authors: Arcilla Nico , Strazds Māris
Published: June 2023

Bird–forestry relationships have been the subject of research and conservation initiatives for decades, but there are few reviews of resulting recommendations for use by forest managers. We define “bird-friendly forestry” as forest management that applies recommendations from research seeking to reconcile logging with bird conservation in natural forests used for timber production. We reviewed relevant studies to synthesize 10 principles of bird-friendly forestry: (1) protect and enhance vertical structure through uneven-aged silviculture; (2) leave abundant dead wood in different decay stages; (3) maintain residual large green trees; (4) create and maintain sufficient amounts of uncut reserves and corridors; (5) maximize forest interior by retaining large contiguous forest tracts in landscapes with sufficient functional connectivity; (6) maintain buffers along streams, rivers, and wetlands cultural and urban landscapes; (7) maintain horizontal stand structure and enhance vegetation diversity by creating canopy gaps; (8) extend the temporal scale of logging cycles; (9) minimize post-logging disturbance to forests, particularly during the bird breeding season; and (10) manage for focal species and guilds. These principles may serve as guidelines in developing bird-friendly management plans customized for regional priority species, with a clearly articulated vision and quantitative objectives through which success can be measured.
Effects of Maternal Separation and Subsequent Stress on Behaviors and Brain Monoamines in Rats
Authors: Mavrenkova Polina V. , Khlebnikova Nadezhda N. , Alchinova Irina B. , Demorzhi Marina S. , Shoibonov Batozhab B. , Karganov Mikhail Yu.
Published: June 2023

Childhood adversity can induce maladaptive behaviors and increase risk for affective disorders, post-traumatic stress disorder, personality disorders, and vulnerability to stress in adulthood. Deprivation of maternal care interrupts brain development through the disturbance of various neurotransmitters, however, the details remain unclear. The features of the symptoms of disorders are largely determined by early stress protocol, genetic characteristics (line), and the sex of the animals. The purpose of current study was (1) to assess behavioral changes in adult Wistar rats of both sexes after early life stress; (2) to determine the levels of monoamines in brain structures involved in the motor, emotional, and social reactions in rats aged 1 and 2 months; and (3) to determine the level of monoamines after physical or emotional stress in adult rats. The rat pups were separated from their dams and isolated from siblings in tight boxes at a temperature of 22–23 °C for 6 h during postnatal days 2–18. The data were processed predominantly using two-way analysis of variance and the Newman–Keys test as the post hoc analysis. The adult rats demonstrated an increase in motor activity and aggressiveness and a decrease in levels of anxiety and sociability. Behavioral disturbances were accompanied by region-, sex-, and age-dependent changes in the levels of monoamines and their metabolites. The dopaminergic and noradrenergic systems were found to be sensitive to psycho-emotional stress.
Maternal LPS Exposure Enhances the 5-HT Level in the Prefrontal Cortex of Autism-like Young Offspring
Authors: Lin Fang , Wang Xinyuan , Luo Ruifang , Yuan Binlin , Ye Shasha , Yang Ting , Xiao Lu , Chen Jie
Published: June 2023

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by reduced social interactions, impaired communication, and stereotyped behavior. The aim of this research is to investigate the changes in serotonin (5-HT) in the medial prefrontal cortex (PFC) of autism-like offspring induced by maternal lipopolysaccharide (LPS) exposure. Pregnant Sprague-Dawley rats were intraperitoneally injected with LPS to establish an autism-like model in their offspring. Offspring prenatally exposed to LPS showed autism-like behavior. The serotonin level in the mPFC of 2-week-old offspring was noticeably increased after maternal LPS exposure. Differentially expressed genes (DEGs) were enriched in pathways related to tryptophan metabolism and the serotonin system, as shown in RNA-seq findings. Consistently, tryptophan and serotonin metabolisms were altered in 2-week-old LPS-exposed offspring. The mRNA expression levels of 5-HT catabolic enzymes were remarkably reduced or tended to decrease. Moreover, maternal LPS exposure resulted in a higher serotonin 1B receptor (5-HT1BR) expression level in the mPFC but no difference in tryptophan hydroxylase 2 (TPH2) or serotonin reuptake transporter (SERT). The concentrations of 5-HT in serum and colon were increased in LPS-exposed offspring. Meanwhile, the expression level of tryptophan hydroxylase 1 (TPH1) in the colon was increased after maternal LPS treatment, whereas SERT was reduced. Furthermore, Golgi-Cox staining showed that neuronal dendritic length and spine density were significantly reduced in the mPFC of LPS-exposed offspring. The current study reveals that maternal LPS treatment resulted in an exaltation of the 5-HT of mPFC in ASD-like young rats, which may partly be caused by the abnormal elevation of 5-HT metabolism in its colon.
Proactive Career Orientation and Subjective Career Success: A Perspective of Career Construction Theory
Authors: Chang Po-Chien , Guo Yuanli , Cai Qihai , Guo Hongchi
Published: June 2023

In the current dynamic and flexible work environment, traditional career models are constantly challenged by individuals’ self-concepts of career development. Previous studies have investigated the predictors of subjective career success, yet little is known about the impact of proactive career orientation on subjective career success. This study, grounded in the career construction theory, aims to examine the influence mechanism of proactive career orientation on subjective career success by analyzing questionnaire data from 296 employees. Empirical results indicate that proactive career orientation has a positive impact on subjective career success. Second, career adaptability partially mediates the relationship between proactive career orientation and subjective career success. Third, mentoring moderates the relationship between proactive career orientation and career adaptability, as well as the relationship between career adaptability and subjective career success. Specifically, both the positive impact of proactive career orientation on career adaptability and the positive impact of career adaptability on subjective career success are stronger when the level of mentoring is higher. Fourth, the indirect relationship between proactive career orientation and subjective career success through career adaptability is stronger when mentoring is high compared to when mentoring is low. This study contributes to the career construction theory by identifying the influence mechanism of proactive career orientation on subjective career success through career adaptability, with mentoring moderating the process. As for practical implications, research findings remind managers of the importance of career planning and mentorship in enhancing employees’ subjective career successes.
A BIM-Based Model for Structural Health Monitoring of the Central Body of the Monserrate Palace: A First Approach
Authors: Machete Rita , Neves Mariana , Ponte Madalena , Falcão Ana Paula , Bento Rita
Published: June 2023

The preservation and safeguarding of built cultural heritage is a permanent concern for institutions. These structures were generally poorly prepared for movement triggered by natural disasters, a situation further complicated in the case of earthquakes, as each building has a unique structural dynamic linked to its geometry, materials, method of construction and environmental conditions. The use of structural health monitoring (SHM) systems integrating monitoring techniques as well as inspection and structural analyses has gained great relevance in the appearance of low-cost IoT (Internet of Things) sensors on the market. In this paper, an IoT BIM-based solution is presented for real-time monitoring using low-cost sensors in the scope of building SHM systems. The case study takes place at the central body of the Palace of Monserrate, one of the most distinguished elements of the Cultural Landscape of Sintra. An H-BIM model was created in Autodesk Revit® software (version 2022 and 2023) based on a point cloud, and used as the basis for the numerical model developed in 3MURI. A MeM low-cost sensor was installed on the third floor of the central tower of the Monserrate Palace in Sintra, and the data gathered were recorded in the H-BIM model. The capacity to acquire real-time information on a structure’s vibration, both during normal operation and after an extraordinary occurrence, could allow the application of more effective maintenance and repair practices, resulting in lower operating costs and allowing for the best management of built cultural heritage.
A Hybrid TOPSIS-Structure Entropy Weight Group Subcontractor Selection Model for Large Construction Companies
Authors: Gao Ce , Elzarka Hazem , Yan Hongyan , Chakraborty Debaditya , Zhou Chunmei
Published: June 2023

The selection of suitable subcontractors for large construction companies is crucially important for the overall success of their projects. As the construction industry advances, a growing number of criteria need to be considered in the subcontractor selection process than simply considering the biding prices. This paper proposed a hybrid multi-criteria structure entropy weight (SEW)—TOPSIS group decision-making model that considers 10 criteria. The proposed model was able to handle large amount of subcontractors’ performance data that were collected in different types. Additionally, the model can integrate experts’ judgments while accounting for their varying level of expertise and correcting for their biases. This paper also provided a case study to demonstrate the proposed model’s effectiveness and efficiency, as well as its applicability of large construction companies. While this study was applied to construction subcontractors’ selection, the proposed methodology can also be easily extended to various decision-making scenarios with similar requirements.
Enhanced Ductility and Toughness of Desert Sand Engineered Cementitious Composites
Authors: Wang Dan , Che Jialing , Liu Haifeng , Chin Siew Choo
Published: June 2023

Economical desert sand engineered cementitious composites (DS-ECCs) using a mixture of cement, fly ash, local desert sand, water, low-cost PVA fibers, and chemical additives were developed, aiming for a further enhancement in ductility and toughness. The mechanical behavior of DS-ECCs for two sand samples (from Mu Us and Tengger deserts, China) was determined using uniaxial tension/compression tests and three-/four-point bending tests. The results showed that desert sand-based ECCs with the designed mix ratios had better mechanical properties than the river sand-based ones. Compared with the river sand-based ECCs at 28 and 56 day, the DS-ECCs presented superior ultimate tensile and comparable compression strengths. The excellent ductility was characterized by ultimate tensile and compression strains of 3–7% and over 1%, respectively. Meanwhile, the DS-ECCs showed improved flexural properties with outstanding fracture and bending strengths (4–9 kN and 21–30 kN) and toughness. The findings of this study will further strengthen the mechanical performance of DS-ECCs and broaden their engineering applicability.
Using Network Analysis Theory to Extract Critical Data from a Construction Project
Authors: Kao Chih-Han , Chen Wei-Tong , Ho Chung-Kuang
Published: June 2023

Construction projects are inherently complex and entail extensive information processing. Thus, they require effective information management, which, in turn, requires the preservation of critical construction data (CD). Although BIM and blockchain methodology use the “change type of query and storage for data management” to improve the service quality of data, data redundancy still causes inefficient retrieval. Moreover, project managers face various source limitations, which prevent the contents of the database from being managed efficiently. This study uses network analysis theory to design an information network (IN). Critical CD were extracted, and an IN structure was built using data from construction practices (network nodes) and data relation (network links). Three metrics were used for performance evaluation of the data references and data delivery. The refurbishment of heritage buildings in Kinmen, Taiwan, was used as a case study to extract critical CD such as the “inspection record checklist” and “architect design plan drawing”. Lastly, CD can be applied as the elementary item of a backstage database for BIM and blockchain applications of DM. The combined system of critical DM can play an important role in obtaining comprehensive information for a construction project. Customized metrics of IN analysis can be developed as an integrated composite to decide the priority of CD.
Applicability of Deep Learning Algorithms for Predicting Indoor Temperatures: Towards the Development of Digital Twin HVAC Systems
Authors: Norouzi Pooria , Maalej Sirine , Mora Rodrigo
Published: June 2023

The development of digital twins leads to the pathway toward intelligent buildings. Today, the overwhelming rate of data in buildings carries a high amount of information that can provide an opportunity for a digital representation of the buildings and energy optimization strategies in the Heating, Ventilation, and Air Conditioning (HVAC) systems. To implement a successful energy management strategy in a building, a data-driven approach should accurately forecast the HVAC features, in particular the indoor temperatures. Accurate predictions not only increase thermal comfort levels, but also play a crucial role in saving energy consumption. This study aims to investigate the capabilities of data-driven approaches and the development of a model for predicting indoor temperatures. A case study of an educational building is considered to forecast indoor temperatures using machine learning and deep learning algorithms. The algorithms’ performance is evaluated and compared. The important model parameters are sorted out before choosing the best architecture. Considering real data, prediction models are created for indoor temperatures. The results reveal that all the investigated models are successful in predicting indoor temperatures. Hence, the proposed deep neural network model obtained the highest accuracy with an average RMSE of 0.16 °C, which renders it the best candidate for the development of a digital twin.
Nigericin Boosts Anti-Tumor Immune Response via Inducing Pyroptosis in Triple-Negative Breast Cancer
Authors: Wu Lisha , Bai Shoumin , Huang Jing , Cui Guohui , Li Qingjian , Wang Jingshu , Du Xin , Fu Wenkui , Li Chuping , Wei Wei , Lin Huan , Luo Man-Li
Published: June 2023

Although immune checkpoint inhibitors improved the clinical outcomes of advanced triple negative breast cancer (TBNC) patients, the response rate remains relatively low. Nigericin is an antibiotic derived from Streptomyces hydrophobicus. We found that nigericin caused cell death in TNBC cell lines MDA-MB-231 and 4T1 by inducing concurrent pyroptosis and apoptosis. As nigericin facilitated cellular potassium efflux, we discovered that it caused mitochondrial dysfunction, leading to mitochondrial ROS production, as well as activation of Caspase-1/GSDMD-mediated pyroptosis and Caspase-3-mediated apoptosis in TNBC cells. Notably, nigericin-induced pyroptosis could amplify the anti-tumor immune response by enhancing the infiltration and anti-tumor effect of CD4+ and CD8+ T cells. Moreover, nigericin showed a synergistic therapeutic effect when combined with anti-PD-1 antibody in TNBC treatment. Our study reveals that nigericin may be a promising anti-tumor agent, especially in combination with immune checkpoint inhibitors for advanced TNBC treatment.
Innate Immune Cells in the Tumor Microenvironment of Liver Metastasis from Colorectal Cancer: Contribution to a Comprehensive Therapy
Authors: Sampaio-Ribeiro Gabriela , Ruivo Ana , Silva Ana , Santos Ana Lúcia , Oliveira Rui Caetano , Gama João , Cipriano Maria Augusta , Tralhão José Guilherme , Paiva Artur
Published: June 2023

Colorectal cancer (CRC) is the third most prevalent type of cancer, and liver metastasis is the most common site of metastatic development. In the tumor microenvironment (TME), various innate immune cells are known to influence cancer progression and metastasis occurrence. CD274 (PD-L1) and CD206 (MRC1) are proteins that have been associated with poor prognosis and disease progression. We conducted a study on tumoral and non-tumoral biopsies from 47 patients with CRC liver metastasis, using flow cytometry to phenotypically characterize innate immune cells. Our findings showed an increase in the expression of CD274 on classical, intermediate, and non-classical monocytes when comparing tumor with non-tumor samples. Furthermore, tumor samples with a desmoplastic growth pattern exhibited a significantly decreased percentage of CD274- and CD206-positive cells in all monocyte populations compared to non-desmoplastic samples. We found a correlation between a lower expression of CD206 or CD274 on classical, intermediate, and non-classical monocytes and increased disease-free survival, which points to a better prognosis for these patients. In conclusion, our study has identified potential new targets and biomarkers that could be incorporated into a personalized medicine approach to enhance the outcome for colorectal cancer patients.
Nuclear Delivery of Nanoparticle-Based Drug Delivery Systems by Nuclear Localization Signals
Authors: Nie Yuhan , Fu Guo , Leng Yuxin
Published: June 2023

Nanomedicine 2.0 refers to the next generation of nanotechnology-based medical therapies and diagnostic tools. This field focuses on the development of more sophisticated and precise nanoparticles (NPs) for targeted drug delivery, imaging, and sensing. It has been established that the nuclear delivery of NP-loaded drugs can increase their therapeutic efficacy. To effectively direct the NPs to the nucleus, the attachment of nuclear localization signals (NLSs) to NPs has been employed in many applications. In this review, we will provide an overview of the structure of nuclear pore complexes (NPCs) and the classic nuclear import mechanism. Additionally, we will explore various nanoparticles, including their synthesis, functionalization, drug loading and release mechanisms, nuclear targeting strategies, and potential applications. Finally, we will highlight the challenges associated with developing nucleus-targeted nanoparticle-based drug delivery systems (NDDSs) and provide insights into the future of NDDSs.
Spatiotemporal Coordination of Rac1 and Cdc42 at the Whole Cell Level during Cell Ruffling
Authors: Hladyshau Siarhei , Stoop Jorik P. , Kamada Kosei , Nie Shuyi , Tsygankov Denis
Published: June 2023

Rho-GTPases are central regulators within a complex signaling network that controls cytoskeletal organization and cell movement. The network includes multiple GTPases, such as the most studied Rac1, Cdc42, and RhoA, along with their numerous effectors that provide mutual regulation through feedback loops. Here we investigate the temporal and spatial relationship between Rac1 and Cdc42 during membrane ruffling, using a simulation model that couples GTPase signaling with cell morphodynamics and captures the GTPase behavior observed with FRET-based biosensors. We show that membrane velocity is regulated by the kinetic rate of GTPase activation rather than the concentration of active GTPase. Our model captures both uniform and polarized ruffling. We also show that cell-type specific time delays between Rac1 and Cdc42 activation can be reproduced with a single signaling motif, in which the delay is controlled by feedback from Cdc42 to Rac1. The resolution of our simulation output matches those of time-lapsed recordings of cell dynamics and GTPase activity. Our data-driven modeling approach allows us to validate simulation results with quantitative precision using the same pipeline for the analysis of simulated and experimental data.
Identification of Small Molecules Affecting the Secretion of Therapeutic Antibodies with the Retention Using Selective Hook (RUSH) System
Authors: Coulet Mathilde , Lachkar Sylvie , Leduc Marion , Trombe Marc , Gouveia Zelia , Perez Franck , Kepp Oliver , Kroemer Guido , Basmaciogullari Stéphane
Published: June 2023

Unlocking cell secretion capacity is of paramount interest for the pharmaceutical industry focused on biologics. Here, we leveraged retention using a selective hook (RUSH) system for the identification of human osteosarcoma U2OS cell secretion modulators, through automated, high-throughput screening of small compound libraries. We created a U2OS cell line which co-expresses a variant of streptavidin addressed to the lumen-facing membrane of the endoplasmic reticulum (ER) and a recombinant anti-PD-L1 antibody. The heavy chain of the antibody was modified at its C-terminus, to which a furin cleavage site, a green fluorescent protein (GFP), and a streptavidin binding peptide (SBP) were added. We show that the U2OS cell line stably expresses the streptavidin hook and the recombinant antibody bait, which is retained in the ER through the streptavidin–SBP interaction. We further document that the addition of biotin to the culture medium triggers the antibody release from the ER, its trafficking through the Golgi where the GFP-SBP moiety is clipped off, and eventually its release in the extra cellular space, with specific antigen-binding properties. The use of this clone in screening campaigns led to the identification of lycorine as a secretion enhancer, and nigericin and tyrphostin AG-879 as secretion inhibitors. Altogether, our data support the utility of this approach for the identification of agents that could be used to improve recombinant production yields and also for a better understanding of the regulatory mechanism at work in the conventional secretion pathway.
Cell-Penetrating Peptides as Valuable Tools for Nose-to-Brain Delivery of Biological Drugs
Authors: De Martini Lisa Benedetta , Sulmona Claudia , Brambilla Liliana , Rossi Daniela
Published: June 2023

Due to their high specificity toward the target and their low toxicity, biological drugs have been successfully employed in a wide range of therapeutic areas. It is yet to be mentioned that biologics exhibit unfavorable pharmacokinetic properties, are susceptible to degradation by endogenous enzymes, and cannot penetrate biological barriers such as the blood–brain barrier (i.e., the major impediment to reaching the central nervous system (CNS)). Attempts to overcome these issues have been made by exploiting the intracerebroventricular and intrathecal routes of administration. The invasiveness and impracticality of these procedures has, however, prompted the development of novel drug delivery strategies including the intranasal route of administration. This represents a non-invasive way to achieve the CNS, reducing systemic exposure. Nonetheless, biotherapeutics strive to penetrate the nasal epithelium, raising the possibility that direct delivery to the nervous system may not be straightforward. To maximize the advantages of the intranasal route, new approaches have been proposed including the use of cell-penetrating peptides (CPPs) and CPP-functionalized nanosystems. This review aims at describing the most impactful attempts in using CPPs as carriers for the nose-to-brain delivery of biologics by analyzing their positive and negative aspects.
Rlip Reduction Induces Oxidative Stress and Mitochondrial Dysfunction in Mutant Tau-Expressed Immortalized Hippocampal Neurons: Mechanistic Insights
Authors: Reddy P. Hemachandra , Kshirsagar Sudhir , Bose Chhanda , Pradeepkiran Jangampalli Adi , Hindle Ashly , Singh Sharda P. , Reddy Arubala P. , Baig Javaria
Published: June 2023

RalBP1 (Rlip) is a stress-activated protein that is believed to play a large role in aging and neurodegenerative diseases such as Alzheimer’s disease (AD) and other tauopathies. The purpose of our study was to understand the role of Rlip in mutant Tau-expressed immortalized hippocampal HT22 cells. In the current study, we used mutant Tau (mTau)-expressed HT22 neurons and HT22 cells transfected with Rlip-cDNA and/or silenced RNA, and studied the cell survival, mitochondrial respiration, mitochondrial function, immunoblotting, and immunofluorescence analysis of synaptic and mitophagy proteins and the colocalization of Rlip and mTau proteins. We found Rlip protein levels were reduced in mTau-HT22 cells, Rlip silenced HT22 cells, and mTau + Rlip RNA silenced HT22 cells; on the other hand, increased Rlip levels were observed in Rlip cDNA transfected HT22 cells. We found cell survival was decreased in mTau-HT22 cells and RNA-silenced HT22 cells. However, cell survival was increased in Rlip-overexpressed mTau-HT22 cells. A significantly reduced oxygen consumption rate (OCR) was found in mTau-HT22 cells and in RNA-silenced Rlip-HT22 cells, with an even greater reduction in mTau-HT22 + Rlip RNA-silenced HT22 cells. A significantly increased OCR was found in Rlip-overexpressed HT22 cells and in all groups of cells that overexpress Rlip cDNA. Mitochondrial function was defective in mTau-HT22 cells, RNA silenced Rlip in HT22 cells, and was further defective in mTau-HT22 + Rlip RNA-silenced HT22 cells; however, it was rescued in Rlip overexpressed in all groups of HT22 cells. Synaptic and mitophagy proteins were decreased in mTau-HT22 cells, and further reductions were found in RNA-silenced mTau-HT22 cells. However, these were increased in mTau + Rlip-overexpressed HT22 cells. An increased number of mitochondria and decreased mitochondrial length were found in mTau-HT22 cells. These were rescued in Rlip-overexpressed mTau-HT22 cells. These observations strongly suggest that Rlip deficiency causes oxidative stress/mitochondrial dysfunction and Rlip overexpression reverses these defects. Overall, our findings revealed that Rlip is a promising new target for aging, AD, and other tauopathies/neurological diseases.
Recyclable Multifunctional Magnetic Fe3O4@SiO2@Au Core/Shell Nanoparticles for SERS Detection of Hg (II)
Authors: Liu Chao , Wang Hui , Xu Shengmin , Li Hongbao , Lu Yilin , Zhu Chuhong
Published: June 2023

Mercury ions can be enriched along the food chain and even low concentrations of mercury ions can seriously affect human health and the environment. Therefore, rapid, sensitive, and highly selective detection of mercury ions is of great significance. In this work, we synthesized Fe3O4@SiO2@Au three-layer core/shell nanoparticles, and then modified 4-MPy (4-mercaptopyridine) to form a SERS sensor. Mercury ions in water can be easily captured by 4-MPy which were used as the reporter molecules, and the concentration of mercury ions can be evaluated based on the spectral changes (intensification and reduction of peaks) from 4-MPy. After the mercury ion was combined with the pyridine ring, the peak intensity at 1093 cm−1 increased with the concentration of mercury ion in the range of 10 ppm–1 ppb, while the Raman intensity ratio I (416 cm−1)/I (436 cm−1) decreased with the increase of mercury ion concentration. This magnetically separatable and recyclable SERS sensor demonstrates good stability, accuracy, and anti-interference ability and shows the potential to detect actual samples. Furthermore, we demonstrate that the probe is applicable for Hg2+ imaging in macrophage cells.
Cymbopogon citratus Essential Oil: Extraction, GC–MS, Phytochemical Analysis, Antioxidant Activity, and In Silico Molecular Docking for Protein Targets Related to CNS
Authors: Cortes-Torres Ana G. , López-Castillo Guiee N. , Marín-Torres Josefina L. , Portillo-Reyes Roberto , Luna Felix , Baca Beatriz E. , Sandoval-Ramírez Jesús , Carrasco-Carballo Alan
Published: June 2023

This study analyzed the chemical composition of Cymbopogon citratus essential oil from Puebla, México, assessed its antioxidant activity, and evaluated in silico protein–compound interactions related to central nervous system (CNS) physiology. GC–MS analysis identified myrcene (8.76%), Z-geranial (27.58%), and E-geranial (38.62%) as the main components, with 45 other compounds present, which depends on the region and growing conditions. DPPH and Folin–Ciocalteu assays using the leaves extract show a promising antioxidant effect (EC50 = 48.5 µL EO/mL), reducing reactive oxygen species. The bioinformatic tool SwissTargetPrediction (STP) shows 10 proteins as potential targets associated with CNS physiology. Moreover, protein–protein interaction diagrams suggest that muscarinic and dopamine receptors are related to each other through a third party. Molecular docking reveals that Z-geranial has higher binding energy than M1 commercial blocker and blocks M2, but not M4 muscarinic acetylcholine receptors, whereas β-pinene and myrcene block M1, M2, and M4 receptors. These actions may positively affect cardiovascular activity, memory, Alzheimer’s disease, and schizophrenia. This study highlights the significance of understanding natural product interactions with physiological systems to uncover potential therapeutic agents and advanced knowledge on their benefits for human health.
Flexural Strength and Vickers Microhardness of Graphene-Doped SnO2 Thin-Film-Coated Polymethylmethacrylate after Thermocycling
Authors: Akay Canan , Çakmak Gülce , Donmez Mustafa Borga , Abou-Ayash Samir , Mumcu Emre , Pat Suat , Yilmaz Burak
Published: June 2023

Removable dental prostheses are commonly fabricated using polymethylmethacrylate, a material that does not have favorable mechanical properties and needs reinforcement with particles such as graphene. The aim of this study was to evaluate the flexural strength (FS) and Vickers microhardness of a heat-polymerized polymethylmethacrylate coated with graphene-doped stannic oxide (SnO2) thin films using a thermionic vacuum arc method after thermocycling. Forty bar-shaped specimens (65 × 10 × 3 mm) were fabricated using a heat-polymerized denture base resin and divided into four groups according to the graphene-doped SnO2 thin film surface coating performed: No-coat (uncoated), Coat-15 s (coating duration of 15 s), Coat-20 s (coating duration of 20 s), and Coat-30 s (coating duration of 30 s) (n = 10). The thermionic vacuum arc method was used to coat both surfaces of the specimens of each test group with varying durations, and surface coating was verified using Fourier Transform Infrared Spectroscopy. Specimens were subjected to 10,000 cycles of thermocycling. Atomic force microscopy was used to evaluate the surfaces of all specimens before and after thermocycling. Microhardness values were measured five times and averaged. Then, each specimen was subjected to a three-point bending test, and FS values were calculated. Data were analyzed using one-way analysis of variance and Bonferroni tests (α = 0.05). Differences among test groups were nonsignificant when FS data were considered (p = 0.605). However, significant differences were observed among test groups when Vickers microhardness data were considered (p < 0.001). Coat-30 s had the highest hardness (p ≤ 0.003), while the difference among remaining groups were nonsignificant (p ≥ 0.166). Graphene-doped SnO2 thin film surface coatings did not significantly affect the FS of tested heat-polymerized denture base resin but increased the Vickers microhardness when the coating duration was 30 s.
Alginate-Chitosan Microgel Particles, Water–Oil Interfacial Layers, and Emulsion Stabilization
Authors: Charisis Aggelos , Kalogianni Eleni P.
Published: June 2023

In this work, alginate-chitosan microgel particles were formed at different pH levels with the aim of using them as viscoelastic interfacial layers, which confer emulsion stability to food systems. The particles’ size and structural characteristics were determined using laser diffraction, confocal laser microscopy (CLSM), and time-domain nuclear magnetic resonance (TD-NMR). The pH affected the microgel characteristics, with larger particles formed at lower pH levels. T2 relaxation measurements with TD-NMR did not reveal differences in the mobility within the particles for the different pH levels, which could have been related to the more or less swollen structure. The rate of adsorption of the particles at the sunflower oil–water interface differed between particles formed at different pH levels, but the equilibrium interfacial tension of all systems was similar. Higher interfacial dilatational viscoelasticity was obtained for the systems at lower pH (3, 4, 5), with G’ reaching 13.6 mN/m (0.1 Hz) at pH 3. The interfacial rheological regime transitioned from a linear elastic regime at lower pH to a linear but more viscoelastic one at higher pH. The thicker, highly elastic interfacial layer at low pH, in combination with the higher charges expected at lower pH, was related to its performance during emulsification and the performance of the emulsion during storage. As revealed by laser diffraction and CLSM, the droplet sizes of emulsions formed at pH 6 and 7 were significantly larger and increased in size during 1 week of storage. CLSM examination of the emulsions revealed bridging flocculation with the higher pH. Nevertheless, all emulsions formed with microgel systems presented macroscopic volumetric stability for periods exceeding 1 week at 25 °C. A potential application of the present systems could be in the formation of stable, low-fat dressings without the addition of any emulsifier, allowing, at the same time, the release of the bioactive compounds for which such particles are known.