bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Safety Profiles of Oncology Biosimilars vs. Originators in Europe: An Analysis of the EudraVigilance Database
Authors: Nikitina Victoria , Santi Laurini Greta , Montanaro Nicola , Motola Domenico
Published: July 2023

In the last decades, the clinical management of oncology patients has been transformed by the introduction of biologics. The high costs associated with the development and production of biologics limit patient access to these therapies. The expiration of exclusive patents for biologics has led to the development and market introduction of biosimilars, offering the reduction of costs for cancer treatments. Biosimilars are highly similar to the reference products in terms of structure, biological activity, efficacy, safety, and immunogenicity. Therefore, the monitoring of biosimilars’ safety in real-world clinical practice though pharmacovigilance is essential. This study aimed to analyze the post-marketing pharmacovigilance data of biosimilar monoclonal antibodies used in oncology and compare them with respective reference products. Data of a 2-year period (1 January 2021–31 December 2022) were retrieved from EudraVigilance, and descriptive and comparative analysis were performed using the Reporting Odds Ratio to evaluate the distribution of medicine-reaction pairs related to biosimilars of three antitumor biological products and their corresponding reference products: bevacizumab, rituximab, and trastuzumab. The results showed that most frequently reported ADRs for biosimilars were non-serious and consistent with the safety profiles of reference products. These findings provide reassurance regarding safety equivalence of biosimilars and support their use as valid alternatives to originator biologics.
Role of Transcription Factor BEND3 and Its Potential Effect on Cancer Progression
Authors: Naiyer Sarah , Dwivedi Lalita , Singh Nishant , Phulera Swastik , Mohan Vijay , Kamran Mohammad
Published: July 2023

BEND3 is a transcription factor that plays a critical role in the regulation of gene expression in mammals. While there is limited research on the role of BEND3 as a tumor suppressor or an oncogene and its potential role in cancer therapy is still emerging, several studies suggest that it may be involved in both the processes. Its interaction and regulation with multiple other factors via p21 have already been reported to play a significant role in cancer development, which serves as an indication of its potential role in oncogenesis. Its interaction with chromatin modifiers such as NuRD and NoRC and its role in the recruitment of polycomb repressive complex 2 (PRC2) are some of the additional events indicative of its potential role in cancer development. Moreover, a few recent studies indicate BEND3 as a potential target for cancer therapy. Since the specific mechanisms by which BEND3 may contribute to cancer progression are not yet fully elucidated, in this review, we have discussed the possible pathways BEND3 may take to serve as an oncogenic driver or suppressor.
Tailoring Morphology in Hydrothermally Synthesized CdS/ZnS Nanocomposites for Extraordinary Photocatalytic H2 Generation via Type-II Heterojunction
Authors: Huang Mianli , Yu Maoqing , Si Ruiru , Zhao Xiaojing , Chen Shuqin , Liu Kewei , Pan Xiaoyang
Published: July 2023

CdS@ZnS core shell nanocomposites were prepared by a one-pot hydrothermal route. The morphology of the composite was tuned by simply changing the Zn2+ precursor concentration. To characterize the samples prepared, various techniques were employed, including XRD, FESEM, TEM, XPS and UV-vis DRS. The band gaps of CdS and ZnS were measured to be 2.26 and 3.32 eV, respectively. Compared with pure CdS, the CdS@ZnS samples exhibited a slight blue shift, which indicated an increased band gap of 2.29 eV. The CdS@ZnS core shell composites exhibited efficient photocatalytic performance for H2 generation under simulated sunlight illumination in contrast to pure CdS and ZnS. Additionally, an optimized H2 generation rate (14.44 mmol·h−1·g−1cat) was acquired at CdS@ZnS-2, which was approximately 4.6 times greater than that of pure CdS (3.12 mmol·h−1·g−1cat). Moreover, CdS@ZnS heterojunction also showed good photocatalytic stability. The process of charge separation over the photocatalysts was investigated using photoelectrochemical analysis. The findings indicate that the CdS@ZnS nanocomposite has efficient charge separation efficiency. The higher H2 generation activity and stability for CdS@ZnS photocatalysts can be attributed to the intimate interface in the CdS@ZnS core–shell structure, which promoted the light absorption intensity and photoinduced charge separation efficiency. It is expected that this study will offer valuable insights into the development of efficient core shell composite photocatalysts.
“Heaven” of Data Deficient Species: The Conservation Status of the Endemic Amphibian Fauna of Vietnam
Authors: Nesi Priscilla , Luiselli Luca Maria , Vignoli Leonardo
Published: July 2023

Predicting the true status of Data Deficient (DD) species is a prominent theme in recent conservation biology, but there still is much debate regarding the conservation approach that should be used for DD taxa and no definitive conclusions are yet available. We review and analyse the current data available on the conservation status of amphibians in Vietnam, with an emphasis on the DD species. We also compare Vietnamese DD frequency of occurrence with other regions of the world, examine the extent of the range of taxa divided by Red List status, and explore the protection attributes of the taxa based on their inclusion within protected areas of Vietnam. We documented that the analysis of amphibians in Southeast Asia, and especially in Vietnam, substantially agrees with patterns highlighted by previous global research, and confirms the risk that several DD species may silently go extinct without their actual risk ever being recognized. Importantly, our study showed that fine-scale analyses are essential to highlight the potential drivers of extinction risk for the DD species of amphibians. A crucial next step for conservation policies in Vietnam (and in surrounding countries) is developing and implementing species-specific studies targeted at addressing each species’ drivers of extinction and determining science-based strategies for minimizing their extinction risk.
Dynamic Pricing Based on Demand Response Using Actor–Critic Agent Reinforcement Learning
Authors: Ismail Ahmed , Baysal Mustafa
Published: July 2023

Eco-friendly technologies for sustainable energy development require the efficient utilization of energy resources. Real-time pricing (RTP), also known as dynamic pricing, offers advantages over other pricing systems by enabling demand response (DR) actions. However, existing methods for determining and controlling DR have limitations in managing an increasing demand and predicting future pricing. This paper presents a novel approach to address the limitations of existing methods for determining and controlling demand response (DR) in the context of dynamic pricing systems for sustainable energy development. By leveraging actor–critic agent reinforcement learning (RL) techniques, a dynamic pricing DR model is proposed for efficient energy management. The model’s learning framework was trained using DR and real-time pricing data extracted from the Australian Energy Market Operator (AEMO) spanning a period of 17 years. The efficacy of the RL-based dynamic pricing approach was evaluated through two predicting cases: actual-predicted demand and actual-predicted price. Initially, long short-term memory (LSTM) models were employed to predict price and demand, and the results were subsequently enhanced using the deep RL model. Remarkably, the proposed approach achieved an impressive accuracy of 99% for every 30 min future price prediction. The results demonstrated the efficiency of the proposed RL-based model in accurately predicting both demand and price for effective energy management.
Short-Term Wind Power Prediction Based on CEEMDAN-SE and Bidirectional LSTM Neural Network with Markov Chain
Authors: Liu Yi , He Jun , Wang Yu , Liu Zong , He Lixun , Wang Yanyang
Published: July 2023

Accurate wind power data prediction is crucial to increase wind energy usage since wind power data are characterized by uncertainty and randomness, which present significant obstacles to the scheduling of power grids. This paper proposes a hybrid model for wind power prediction based on complementary ensemble empirical mode decomposition with adaptive noise (CEEMDAN), sample entropy (SE), bidirectional long short-term memory network (BiLSTM), and Markov chain (MC). First, CEEMDAN is used to decompose the wind power series into a series of subsequences at various frequencies, and then SE is employed to reconstruct the wind power series subsequences to reduce the model’s complexity. Second, the long short-term memory (LSTM) network is optimized, the BiLSTM neural network prediction method is used to predict each reconstruction component, and the results of the different component predictions are superimposed to acquire the total prediction results. Finally, MC is used to correct the model’s total prediction results to increase the accuracy of the predictions. Experimental validation with measured data from wind farms in a region of Xinjiang, and computational results demonstrate that the proposed model can better fit wind power data than other prediction models and has greater prediction accuracy and generalizability for enhancing wind power prediction performance.
Application of Artificial Intelligence in Power System Monitoring and Fault Diagnosis
Authors: Wang Guang , Xie Jiale , Wang Shunli
Published: July 2023

Emerging technologies such as artificial intelligence (AI), big data analytics, and deep learning have gained widespread attention in recent years and have demonstrated great potential for application in many industrial fields [...]
Application and Optimization of CCUS Technology in Shale Gas Production and Storage
Authors: Liu Jun , Feng Gan , Zhao Peng
Published: July 2023

Global climate change is a crucial issue confronting the international community [...]
Effects of 10 Dwarfing Interstocks on Cold Resistance of ‘Tianhong 2’ Apple
Authors: Jing Junli , Liu Mingxiao , Yin Baoying , Liang Bowen , Li Zhongyong , Zhang Xueying , Xu Jizhong , Zhou Shasha
Published: July 2023

The lack of dwarf stock with good cold resistance has affected the production of apples in northern China. Annual dormant branches of ‘Tianhong 2’ apple were grafted on 10 different dwarf interstocks (the rootstocks were the seedlings of Malus hupehensis var. Pingyiensis) as test materials. Among these 10 interstocks, Huang 6, 244, NO.1, 53, 24-5, ZC9-3, Jizhen 1 were newly developed by us (Apple Research Group of Hebei Agricultural University), and three interstocks with different degrees of cold resistance (GM256–with strongest cold resistance, SH40–with stronger cold resistance, M9–with poor cold resistance) were used as controls. The semi-lethal temperature (LT50) and related physiological indexes of the branches in the overwintering process were studied. Based on the comprehensive physiological indexes, the effects of 10 interstocks on cold resistance of the ‘Tianhong 2’ apple were analyzed. The results showed that the effects of 10 kinds of interstocks on the cold resistance of ‘Tianhong 2’ apple were quite different. The order of effects on cold resistance from strong to weak was as follow: GM256 > Huang 6 > 244 >NO.1> 53 > 24-5 > ZC9-3 >Jizhen 1 > SH40 > M9. The purpose of this study was to screen out the interstocks with strong cold resistance, in order to provide some basis for the selection and utilization of interstocks with strong cold resistance in apple cultivation to further promote the development of the apple industry in China.
Comment on Peycheva et al. Trace Elements and Omega-3 Fatty Acids of Wild and Farmed Mussels (Mytilus galloprovincialis) Consumed in Bulgaria: Human Health Risks. Int. J. Environ. Res. Public Health 2021, 18, 10023
Authors: Yap Chee Kong , Ong Meng Chuan
Published: July 2023

First of all, the interesting paper by Peycheva et al. [...]
Exploring Bracing Adherence in Ponseti Treatment of Clubfoot: A Comparative Study of Factors and Outcomes in Uganda
Authors: Dreise Marieke , Elkins Catherine , Muhumuza Moses Fisha , Musoke Henry , Smythe Tracey
Published: July 2023

The Ponseti method of clubfoot treatment involves two phases: initial correction, usually including tenotomy; and bracing, to maintain correction and prevent relapse. Bracing should last up to four years, but in Uganda, approximately 21% of patients drop from clinical oversight within the first two years of using the brace. Our study compared 97 adherent and 66 non-adherent cases to assess the influential factors and effects on functional outcomes. We analyzed qualitative and quantitative data from clinical records, in-person caregiver interviews, and assessments of foot correction and functionality. Children who underwent tenotomy had 74% higher odds of adherence to bracing compared to those who did not undergo tenotomy. Conversely, children from rural households whose caregivers reported longer travel times to the clinic were more likely to be non-adherent to bracing (AOR 1.60 (95% CI: 1.11–2.30)) compared to those without these factors. Adhering to bracing for a minimum of two years was associated with improved outcomes, as non-adherent patients experienced 2.6 times the odds of deformity recurrence compared to adherent patients. Respondents reported transportation/cost issues, family disruptions, and lack of understanding about the treatment method or importance of bracing. These findings highlight the need to address barriers to adherence, including reducing travel/waiting time, providing ongoing education for caregivers on bracing protocol, and additional support targeting transportation barriers and household complexities.
Context-Aware Medical Systems within Healthcare Environments: A Systematic Scoping Review to Identify Subdomains and Significant Medical Contexts
Authors: Zon Michael , Ganesh Guha , Deen M. Jamal , Fang Qiyin
Published: July 2023

Context awareness is a field in pervasive computing, which has begun to impact medical systems via an increasing number of healthcare applications that are starting to use context awareness. The present work seeks to determine which contexts are important for medical applications and which domains of context-aware applications exist in healthcare. A systematic scoping review of context-aware medical systems currently used by patients or healthcare providers (inclusion criteria) was conducted between April 2021 and June 2023. A search strategy was designed and applied to Pub Med, EBSCO, IEEE Explore, Wiley, Science Direct, Springer Link, and ACM, articles from the databases were then filtered based on their abstract, and relevant articles were screened using a questionnaire applied to their full texts prior to data extraction. Applications were grouped into context-aware healthcare application domains based on past reviews and screening results. A total of 25 articles passed all screening levels and underwent data extraction. The most common contexts used were user location (8 out of 25 studies), demographic information (6 out of 25 studies), movement status/activity level (7 out of 25 studies), time of day (5 out of 25 studies), phone usage patterns (5 out of 25 studies), lab/vitals (7 out of 25 studies), and patient history data (8 out of 23 studies). Through a systematic review process, the current study determined the key contexts within context-aware healthcare applications that have reached healthcare providers and patients. The present work has illuminated many of the early successful context-aware healthcare applications. Additionally, the primary contexts leveraged by these systems have been identified, allowing future systems to focus on prioritizing the integration of these key contexts.
Perspectives of and Experience toward the Abuse of Antidiarrheal Drug (Loperamide) among Community Pharmacists: A Cross-Sectional Study
Authors: Barakat Muna , Akour Amal , Malaeb Diana , Cherri Sarah , Al.Safadi Wala’a , Al.Safadi Ala’a , Wazaify Mayyada
Published: July 2023

This study aimed to assess the ability of community pharmacists to recognize cases of loperamide abuse at the point of sale, their perspective of and experience toward potential abuse cases. Methods: A cross-sectional study was conducted in Jordan, using a self-administered online questionnaire. The questionnaire consisted of three main parts: demographics, the experience of pharmacists with abusers’ behavior, as well as their perspectives toward loperamide abuse. Results: A total of 250 community pharmacists completed the survey, 54% (135) of which were female. Almost one-third (33.2%; 83) of the participants reported exposure to suspected cases of loperamide abuse during the last six months. Pharmacists declared that most of the suspected loperamide abusers were male (60.2%), of middle–low socioeconomic status (69.9%), and between 20 and 30 years of age (57.8%). The largest quantity (packs) of loperamide requested by a single patient was around 33.2 ± 14.9 at once. As reported by pharmacists, the suspected reasons behind loperamide abuse included 50% seeking euphoria, 17% relieving anxiety, and 33% controlling addiction (weaning off other opioids). The multivariate logistic regression analysis demonstrated a significant correlation between the male sex (OR = 1.2, 95% CI 0.12–1.59), pharmacy location in the center of Jordan (OR = 21.2, 95% CI 2.45–183.59), late-night working shift (Shift C, OR = 1.29, 95% CI 0.12–2.08), and abuse to loperamide during the last six months. Conclusions: This study sheds light on loperamide abuse potentials, which could be influenced by different sociodemographic characteristics. Accordingly, close monitoring and thorough tackling of the abuse practices are mandated through an increase in educational and awareness campaigns about proper medication use.
Can a Clinic-Based Community Health Worker Intervention Buffer the Negative Impact of the COVID-19 Pandemic on Health and Well-Being of Low-Income Families during Early Childhood
Authors: Salaguinto Taylor , Guzman Yasmin , Lowry Sarah J. , Liljenquist Kendra , LaFontaine Rachel , Ortiz Janette E. , Szilagyi Peter G. , Fiscella Kevin , Weaver Marcia R. , Coker Tumaini R.
Published: July 2023

We examined changes in self-reported mental health, physical health, and emotional support among low-income parents with children ages 0–2 years old from pre-pandemic to pandemic periods and compared changes in parental health among parents who did versus did not have access to a clinic-based community health worker intervention supporting parents at early childhood preventive care visits. We utilized longitudinal parent survey data from pre-COVID-19 and COVID-19 time periods from both the intervention and control arms of an existing cohort of parents enrolled in a 10-clinic cluster randomized controlled trial (RCT). At enrollment (pre-pandemic) and 12-month follow-up (pandemic), participants reported on mental health, physical health, and emotional support using PROMIS measures (n = 401). During the pre-pandemic portion, control and intervention group parents had similar mean T-scores for mental health, physical health, and emotional support. At follow-up, mean T-scores for mental health, physical health, and emotional support decreased across both control and intervention groups, but intervention group parents had smaller declines in mental health T-scores (p = 0.005). Our findings indicate that low-income parents with young children suffered significant declines in mental and physical health and emotional support during the pandemic and that the decline in mental health may have been buffered by the community health worker intervention.
Values Clarification Exercises to Prepare Nursing Students for Artificial Intelligence Integration
Authors: De Gagne Jennie C.
Published: July 2023

Artificial intelligence (AI) is rapidly revolutionizing health care and education globally, including nursing practice and education. The responsible utilization of AI in a nursing context requires thoughtful consideration of its alignment with nursing values such as compassionate and patient-centered care provision, and respect for diverse perspectives. Values clarification, a vital teaching strategy in nursing education, can reinforce the foundational values and beliefs that guide nursing practice, thereby facilitating nurses’ critical evaluation of the ethical implications of AI implementation. The early introduction of values clarification into nursing education (a) provides students with a framework to prioritize and reflect on the impact of nursing values on their practice, (b) enables educators to make informed decisions and enhance teaching strategies, (c) contributes to the continual improvement of nursing education programs, and (d) fosters an ethical and values-driven approach to the integration of AI into nursing education and practice. This article examines the integration of values clarification into nursing education, offers strategies for nurse educators to integrate AI into their teaching toolkit effectively and ethically, and addresses concerns regarding potential misuses of AI.
Patients’ Perspectives on the Use of a Newly Developed “Patients’ Guide for Doctor’s Visit”: DocVISITguide
Authors: Jaks Rebecca , Guggiari Elena , De Gani Saskia Maria , Nicca Dunja
Published: July 2023

During doctor’s visits, fundamental decisions regarding a patient’s diagnosis and therapy are taken. However, consultations often take place within a limited time frame and are characterized by an asymmetric interaction. Therefore, patients’ questions can remain unanswered and concerns unspoken. A "Patients’ Guide for Doctor’s Visit" (DocVISITguide) was developed to prepare patients for their visits, supporting them to take an active role in the communication and leave the consultation well-informed. This paper describes the development of the DocVISITguide and its first small-scale evaluation based on a sequential explanatory mixed methods design from the patients’ perspective. For this purpose, a small sample of patients completed a pre- and post-questionnaire, and two in-depth interviews were conducted. Most participants found the DocVISITguide easy to understand. The guide helped them to take a closer look at their own health situation and be better prepared for the visit. More than three-quarters (82%) of the participants would probably use the guide again, and all (100%) would recommend it to family and friends. However, some patients felt unsure about using the guide within the consultation and showing it to their physician. To counteract this uncertainty, physicians should be actively involved in the use of such guides in the future.
Lipid Peroxidation as a Possible Factor Affecting Bone Resorption in Obese Subjects—Preliminary Research
Authors: Maciejewski Marcin , Siódmiak Joanna , Borkowski Bartłomiej , Lorkowski Matthias , Olszewska-Słonina Dorota M.
Published: July 2023

Oxidative stress, which promotes bone catabolism, also affects the quality of bone tissue. We aimed to assess the impact of metabolic disorders and oxidant–antioxidant imbalance associated with primary obesity on bone resorption and formation processes. Anthropometric parameters, metabolic variables, oxidative stress indicators (malondialdehyde, vitamins A and E, uric acid, superoxide dismutase, catalase, glutathione peroxidase, type 1 paraoxonase, iron-reducing plasma antioxidant power) and markers of bone turnover (type I procollagen N-terminal propeptide and the type I collagen C-terminal cross-linked telopeptide; P1NP and CTX) were assessed in 108 Polish participants. Under the influence of oxidative stress, both enzymatic and non-enzymatic defense mechanisms were stimulated in obese subjects, especially in women, who had increased lipid peroxidation and activity of catalase (particularly in first-degree obesity) and decreased vitamin E concentration. The process of lipid peroxidation, as well as the weakening of the bone formation, was strongly manifested in women at a BMI range of 35.0–39.9 kg/m2 but not at BMI > 40.0 kg/m2, but it had a comprehensive negative impact on bone turnover in obese men. Obesity and its degree of advancement significantly affected the decrease in the concentration of the marker of bone formation—P1NP—only in the plasma of women. Excessive body weight had no effect on the value of the bone resorption marker in plasma, regardless of gender. Our results confirm the existence of the “obesity paradox” in the aspect of bone tissue metabolism and suggest that a specific body weight threshold changed the molecular response of the tissue.
The Sigma-1 Receptor Is a Novel Target for Improving Cold Preservation in Rodent Kidney Transplants
Authors: Hosszu Adam , Toth Akos R. , Lakat Tamas , Stepanova Ganna , Antal Zsuzsanna , Wagner Laszlo J. , Szabo Attila J. , Fekete Andrea
Published: July 2023

Kidney transplantation is the preferred treatment for patients with end-stage kidney disease. Maintaining organ viability between donation and transplantation, as well as minimizing ischemic injury, are critically important for long-term graft function and survival. Moreover, the increasing shortage of transplantable organs is a considerable problem; thus, optimizing the condition of grafts is a pivotal task. Here, rodent models of kidney transplantation and cold storage were used to demonstrate that supplementation of a preservation solution with Sigma-1 receptor (S1R) agonist fluvoxamine (FLU) reduces cold and warm ischemic injury. Post-transplant kidney function was improved, histological injury was mitigated, and mRNA expression of two tubular injury markers—kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin—was robustly reduced. In addition, renal inflammation was diminished, as shown by reduced leukocyte infiltration and pro-inflammatory cytokine expression. In the cold ischemia model, FLU ameliorated structural injury profoundly after 2 h as well as 24 h. The reduced number of TUNEL-positive and Caspase 3-positive cells suggests the anti-apoptotic effect of FLU. None of these beneficial effects of FLU were observed in S1R−/− mice. Of note, organ damage in FLU-treated kidneys after 24 h of cold storage was similar to just 2 h without FLU. These results indicate that S1R agonists can prolong storage time and have great potential in improving organ preservation and in alleviating the problem of organ shortages.
Mechanism of Androgen-Independent Stromal Proliferation in Benign Prostatic Hyperplasia
Authors: Hata Junya , Harigane Yuki , Matsuoka Kanako , Akaihata Hidenori , Yaginuma Kei , Meguro Satoru , Hoshi Seiji , Sato Yuichi , Ogawa Soichiro , Uemura Motohide , Kojima Yoshiyuki
Published: July 2023

Benign prostatic hyperplasia (BPH) is a chronic proliferative disease showing stromal-dominant proliferation. However, the detailed proliferation mechanism has remained unclear. Although aging and androgen have been reported as definitive risk factors for BPH, recent studies have focused on the involvement of androgen-independent factors. Androgen-independent factors include ischemia, oxidative stress, metabolic syndrome, infection, autoimmune reactions, and inflammation, with inflammation in BPH tissues playing a central role in the BPH proliferative process. Inflammation in BPH tissues by various factors finally leads to tissue remodeling and stromal proliferation through the wound healing process of the prostate. To elucidate the proliferative mechanism of BPH, a study using whole-genome gene expression analysis in a stromal-dominant BPH rat model was performed and showed that immune response-related pathways and complement classical pathways are activated. Furthermore, expression analysis using this BPH rat model showed that the autoimmune reaction triggered complement pathway activation in the proliferative process of BPH. BPH is a multifactorial disease, and understanding the role of androgen-independent factors including immune responses contributes to elucidating the pathogenesis of BPH. Androgen-independent factors may lead to new therapeutic targets for BPH, and further development of this research is expected.
GSK3β Inhibition Ameliorates Atherosclerotic Calcification
Authors: Cai Xinjiang , Zhao Yan , Yang Yang , Wu Xiuju , Zhang Li , Ma Jocelyn A. , Ji Jaden , Boström Kristina I. , Yao Yucheng
Published: July 2023

Endothelial-mesenchymal transition (EndMT) drives endothelium to contribute to atherosclerotic calcification. In a previous study, we showed that glycogen synthase kinase-3β (GSK3β) inhibition induced β-catenin and reduced mothers against DPP homolog 1 (SMAD1) in order to redirect osteoblast-like cells towards endothelial lineage, thereby reducing vascular calcification in Matrix Gla Protein (Mgp) deficiency and diabetic Ins2Akita/wt mice. Here, we report that GSK3β inhibition or endothelial-specific deletion of GSK3β reduces atherosclerotic calcification. We also find that alterations in β-catenin and SMAD1 induced by GSK3β inhibition in the aortas of Apoe−/− mice are similar to Mgp−/− mice. Together, our results suggest that GSK3β inhibition reduces vascular calcification in atherosclerotic lesions through a similar mechanism to that in Mgp−/− mice.
Production of Plant-Derived Japanese Encephalitis Virus Multi-Epitope Peptide in Nicotiana benthamiana and Immunological Response in Mice
Authors: Jung Jae-Wan , Park Pil-Gu , Lee Won-Kyung , Shin Jun-Hye , Jang Mi-Hwa , Seo Eun-Hye , An Timothy , Kim Young Beom , Moon Myeong Hee , Choi Seuk-Keun , Yun Jee Sun , Hong Kee-Jong , Kim Seong-Ryong
Published: July 2023

The current production of the Japanese encephalitis virus (JEV) vaccine is based on animal cells, where various risk factors for human health should be resolved. This study used a transient expression system to express the chimeric protein composed of antigenic epitopes from the JEV envelope (E) protein in Nicotiana benthamiana. JEV multi-epitope peptide (MEP) sequences fused with FLAG-tag or 6× His-tag at the C- or N-terminus for the purification were introduced into plant expression vectors and used for transient expression. Among the constructs, vector pSK480, which expresses MEP fused with a FLAG-tag at the C-terminus, showed the highest level of expression and yield in purification. Optimization of transient expression procedures further improved the target protein yield. The purified MEP protein was applied to an ICR mouse and successfully induced an antibody against JEV, which demonstrates the potential of the plant-produced JEV MEP as an alternative vaccine candidate.
Titanium Particles Modulate Lymphocyte and Macrophage Polarization in Peri-Implant Gingival Tissues
Authors: Kheder Waad , Bouzid Amal , Venkatachalam Thenmozhi , Talaat Iman M. , Elemam Noha Mousaad , Raju Tom Kalathil , Sheela Soumya , Jayakumar Manju Nidagodu , Maghazachi Azzam A. , Samsudin Abdul Rani , Hamoudi Rifat
Published: July 2023

Titanium dental implants are one of the modalities to replace missing teeth. The release of titanium particles from the implant’s surface may modulate the immune cells, resulting in implant failure. However, little is known about the immune microenvironment that plays a role in peri-implant inflammation as a consequence of titanium particles. In this study, the peri-implant gingival tissues were collected from patients with failed implants, successful implants and no implants, and then a whole transcriptome analysis was performed. The gene set enrichment analysis confirmed that macrophage M1/M2 polarization and lymphocyte proliferation were differentially expressed between the study groups. The functional clustering and pathway analysis of the differentially expressed genes between the failed implants and successful implants versus no implants revealed that the immune response pathways were the most common in both comparisons, implying the critical role of infiltrating immune cells in the peri-implant tissues. The H&E and IHC staining confirmed the presence of titanium particles and immune cells in the tissue samples, with an increase in the infiltration of lymphocytes and macrophages in the failed implant samples. The in vitro validation showed a significant increase in the level of IL-1β, IL-8 and IL-18 expression by macrophages. Our findings showed evidence that titanium particles modulate lymphocyte and macrophage polarization in peri-implant gingival tissues, which can help in the understanding of the imbalance in osteoblast–osteoclast activity and failure of dental implant osseointegration.
Sigma-1 Receptor Agonist Fluvoxamine Ameliorates Fibrotic Response of Trabecular Meshwork Cells
Authors: Hodrea Judit , Tran Minh Ngoc , Besztercei Balazs , Medveczki Timea , Szabo Attila J. , Őrfi Laszlo , Kovacs Illes , Fekete Andrea
Published: July 2023

Primary open-angle glaucoma remains a global issue, lacking a definitive treatment. Increased intraocular pressure (IOP) is considered the primary risk factor of the disease and it can be caused by fibrotic-like changes in the trabecular meshwork (TM) such as increased tissue stiffness and outflow resistance. Previously, we demonstrated that the sigma-1 receptor (S1R) agonist fluvoxamine (FLU) has anti-fibrotic properties in the kidney and lung. In this study, the localization of the S1R in TM cells was determined, and the anti-fibrotic efficacy of FLU was examined in both mouse and human TM cells. Treatment with FLU reduced the F-actin rearrangement, inhibited cell proliferation and migration induced by the platelet-derived growth factor and decreased the levels of fibrotic proteins. The protective role of the S1R in fibrosis was confirmed by a more pronounced increase in alpha smooth muscle actin and F-actin bundle and clump formation in primary mouse S1R knockout TM cells. Furthermore, FLU demonstrated its protective effects by increasing the production of nitric oxide and facilitating the degradation of the extracellular matrix through the elevation of cathepsin K. These findings suggest that the S1R could be a novel target for the development of anti-fibrotic drugs and offer a new therapeutic approach for glaucoma.
The Protective Potential of Aronia melanocarpa L. Berry Extract against Cadmium-Induced Kidney Damage: A Study in an Animal Model of Human Environmental Exposure to This Toxic Element
Authors: Smereczański Nazar M. , Brzóska Małgorzata M. , Rogalska Joanna , Hutsch Tomasz
Published: July 2023

The impact of cadmium (Cd) on the function and structure of the kidney and the potential protective effect of an extract from Aronia melanocarpa L. berries were investigated in a rat model of low- and moderate-level environmental exposure to this heavy metal (1 and 5 mg Cd/kg feed for up to 24 months). The sensitive biomarkers of Cd-induced damage to the kidney tubules (N-acetyl-β-D-glucosaminidase (NAG), alkaline phosphatase (ALP), β2-microglobulin (β2-MG), and kidney injury molecule-1 (KIM-1) in the urine), clinically relevant early markers of glomerular damage (albumin in the urine and creatinine clearance), and other markers of the general functional status of this organ (urea, uric acid, and total protein in the serum and/or urine) and Cd concentration in the urine, were evaluated. The morphological structure of the kidney and inflammatory markers (chemerin, macrophage inflammatory protein 1 alpha (MIP1a), and Bcl2-associated X protein (Bax)) were also estimated. Low-level and moderate exposure to Cd led to damage to the function and structure of the kidney tubules and glomeruli. The co-administration of A. melanocarpa berry extract significantly protected against the injurious impact of this toxic element. In conclusion, even low-level, long-term exposure to Cd poses a risk of kidney damage, whereas an intake of Aronia berry products may effectively protect from this outcome.
Anti-Fibrotic and Anti-Inflammatory Role of NO-Sensitive Guanylyl Cyclase in Murine Lung
Authors: Englert Nils , Burkard Philipp , Aue Annemarie , Rosenwald Andreas , Nieswandt Bernhard , Friebe Andreas
Published: July 2023

Pulmonary fibrosis is a chronic and progressive disease with limited therapeutic options. Nitric oxide (NO) is suggested to reduce the progression of pulmonary fibrosis via NO-sensitive guanylyl cyclase (NO-GC). The exact effects of NO-GC during pulmonary fibrosis are still elusive. Here, we used a NO-GC knockout mouse (GCKO) and examined fibrosis and inflammation after bleomycin treatment. Compared to wildtype (WT), GCKO mice showed an increased fibrotic reaction, as myofibroblast occurrence (p = 0.0007), collagen content (p = 0.0006), and mortality (p = 0.0009) were significantly increased. After fibrosis induction, lymphocyte accumulations were observed in the lungs of GCKO but not in WT littermates. In addition, the total number of immune cells, specifically lymphocytes (p = <0.0001) and neutrophils (p = 0.0047), were significantly higher in the bronchoalveolar lavage fluid (BALF) of GCKO animals compared to WT, indicating an increased inflammatory response in the absence of NO-GC. The pronounced fibrotic response in GCKO mice was paralleled by significantly increased levels of transforming growth factor β (TGFβ) in BALF (p = 0.0207), which correlated with the total number of immune cells. Taken together, our data show the effect of NO-GC deletion in the pathology of lung fibrosis and the effect on immune cells in BALF. In summary, our results show that NO-GC has anti-inflammatory and anti-fibrotic properties in the murine lung, very likely by attenuating TGFβ-mediated effects.
Transcriptome Dynamics during Spike Differentiation of Wheat Reveal Amazing Changes in Cell Wall Metabolic Regulators
Authors: Han Junjie , Liu Yichen , Shen Yiting , Zhang Donghai , Li Weihua
Published: July 2023

Coordinated cell proliferation and differentiation result in the complex structure of the inflorescence in wheat. It exhibits unique differentiation patterns and structural changes at different stages, which have attracted the attention of botanists studying the dynamic regulation of its genes. Our research aims to understand the molecular mechanisms underlying the regulation of spike development genes at different growth stages. We conducted RNA-Seq and qRT-PCR evaluations on spikes at three stages. Our findings revealed that genes associated with the cell wall and carbohydrate metabolism showed high expression levels between any two stages throughout the entire process, suggesting their regulatory role in early spike development. Furthermore, through transgenic experiments, we elucidated the role of the cell wall regulator gene in spike development regulation. These research results contribute to identifying essential genes associated with the morphology and development of wheat spike tissue.
Lignin, the Lignification Process, and Advanced, Lignin-Based Materials
Authors: Balk Maria , Sofia Pietro , Neffe Axel T. , Tirelli Nicola
Published: July 2023

At a time when environmental considerations are increasingly pushing for the application of circular economy concepts in materials science, lignin stands out as an under-used but promising and environmentally benign building block. This review focuses (A) on understanding what we mean with lignin, i.e., where it can be found and how it is produced in plants, devoting particular attention to the identity of lignols (including ferulates that are instrumental for integrating lignin with cell wall polysaccharides) and to the details of their coupling reactions and (B) on providing an overview how lignin can actually be employed as a component of materials in healthcare and energy applications, finally paying specific attention to the use of lignin in the development of organic shape-memory materials.
Implications of the Cultivation of Rosemary and Thyme (Lamiaceae) in Plant Communities for the Development of Antioxidant Therapies
Authors: Luță Emanuela-Alice , Biță Andrei , Moroșan Alina , Mihaiescu Dan Eduard , Mihai Dragoș Paul , Popescu Liliana , Bejenaru Ludovic Everard , Bejenaru Cornelia , Popovici Violeta , Olaru Octavian Tudorel , Gîrd Cerasela Elena
Published: July 2023

Oxidative stress is the most critical factor in multiple functional disorders’ development, and natural antioxidants could protect the human body against it. Our study aims to investigate the polyphenol content of four extracts of two medicinal plants (Rosmarinus officinalis L. and Thymus vulgaris L.) and analyze the correlation with their antioxidant activity. The research was carried out on extracts of rosemary and thyme obtained from species cultivated together in plant communities. Both were compared with extracts from species cultivated in individual crops (control crops). Their polyphenols were determined by spectrophotometric methods (dosage of flavones, phenol carboxylic acids, and total polyphenols) and chromatography (UHPLC–MS and FT–ICR MS). Triterpenic acids were also quantified, having a higher concentration in the thyme extract from the culture. The antioxidant activity of the dry extracts was evaluated in vitro (DPPH, ABTS, and FRAP) and in silico (prediction of interactions with BACH1/BACH2 transcription factors). The concentrations of polyphenols are higher in the extracts obtained from the sources collected from the common crops. These observations were also validated following the chromatographic analysis for some compounds. Statistically significant differences in the increase in the antioxidant effect were observed for the extracts from the common batches compared to those from the individual ones. Following the Pearson analysis, the IC50 values for each plant extract were strongly correlated with the concentration of active phytoconstituents. Molecular docking studies revealed that quercetin could bind to BTB domains of BACH1 and BACH2 transcription factors, likely translating into increased antioxidant enzyme expression. Future studies must validate the in silico findings and further investigate phytosociological cultivation’s effects.
Calcium-Sensing Receptor Expression in Breast Cancer
Authors: Busic-Pavlek Iva , Dumic-Cule Ivo , Kovacevic Lucija , Milosevic Milan , Delimar Petra , Korsa Lea , Marusic Zlatko , Prutki Maja
Published: July 2023

The calcium-sensing receptor (CaSR) plays a crucial role in maintaining the balance of calcium in the body. Altered signaling through the CaSR has been linked to the development of various tumors, such as colorectal and breast tumors. This retrospective study enrolled 79 patients who underwent surgical removal of invasive breast carcinoma of no special type (NST) to explore the expression of the CaSR in breast cancer. The patients were categorized based on age, tumor size, hormone receptor status, HER2 status, Ki-67 proliferation index, tumor grade, and TNM staging. Immunohistochemistry was conducted on core needle biopsy samples to assess CaSR expression. The results revealed a positive correlation between CaSR expression and tumor size, regardless of the tumor surrogate subtype (p = 0.001). The expression of ER exhibited a negative correlation with CaSR expression (p = 0.033). In contrast, a positive correlation was observed between CaSR expression and the presence of HER2 receptors (p = 0.002). Increased CaSR expression was significantly associated with lymph node involvement and the presence of distant metastasis (p = 0.001 and p = 0.038, respectively). CaSR values were significantly higher in the patients with increased Ki-67 (p = 0.042). Collectively, higher CaSR expression in breast cancer could suggest a poor prognosis and treatment outcome regardless of the breast cancer subtype.
Bacterial Biofilm Formation on Biomaterials and Approaches to Its Treatment and Prevention
Authors: Li Panxin , Yin Rui , Cheng Juanli , Lin Jinshui
Published: July 2023

Bacterial biofilms can cause widespread infection. In addition to causing urinary tract infections and pulmonary infections in patients with cystic fibrosis, biofilms can help microorganisms adhere to the surfaces of various medical devices, causing biofilm-associated infections on the surfaces of biomaterials such as venous ducts, joint prostheses, mechanical heart valves, and catheters. Biofilms provide a protective barrier for bacteria and provide resistance to antimicrobial agents, which increases the morbidity and mortality of patients. This review summarizes biofilm formation processes and resistance mechanisms, as well as the main features of clinically persistent infections caused by biofilms. Considering the various infections caused by clinical medical devices, we introduce two main methods to prevent and treat biomaterial-related biofilm infection: antibacterial coatings and the surface modification of biomaterials. Antibacterial coatings depend on the covalent immobilization of antimicrobial agents on the coating surface and drug release to prevent and combat infection, while the surface modification of biomaterials affects the adhesion behavior of cells on the surfaces of implants and the subsequent biofilm formation process by altering the physical and chemical properties of the implant material surface. The advantages of each strategy in terms of their antibacterial effect, biocompatibility, limitations, and application prospects are analyzed, providing ideas and research directions for the development of novel biofilm infection strategies related to therapeutic materials.
Impact of Semiochemicals Binding to Fel d 1 on Its 3D Conformation and Predicted B-Cell Epitopes Using Computational Approaches
Authors: Durairaj Rajesh , Pageat Patrick , Bienboire-Frosini Cécile
Published: July 2023

The major cat allergen Fel d 1 is a tetrameric glycoprotein from the secretoglobin superfamily. Fel d 1’s biological role is unknown, but it has been previously shown that it participates in semiochemical binding/transportation. Fel d 1 has linear epitopes, but its conformational epitope sites remain unclear. In this study, we predicted the B-cell epitopes of Fel d 1 and explored semiochemical dynamics with epitopes using bioinformatics tools. The epitope residues were tabulated for chains 1 and 2 and the heterodimers of Fel d 1. The residual interactions of Fel d 1 with IgE were evaluated, and the prominent epitope sites were predicted. The molecular dynamics simulation (MDS) of Fel d 1 was performed with seven reported semiochemicals to evaluate the Fel d 1–ligand complex stability and decipher the semiochemical effect on Fel d 1 conformational epitopes. Fel d 1–lauric acid, Fel d 1–oleic acid, and Fel d 1–progesterone showed more stability and less fluctuation than other compounds. Fel d 1–linoleic acid and Fel d 1–pregnenolone displayed the most unstable complex with fluctuations. The effects of conformational changes on epitopes are discussed. All the ligand complexes drive substantial fluctuation towards the functionally exposed IgE-binding epitopes. Fel d 1 could be examined for its ligand-binding and conformational changes caused by mutations of B-cell epitopes.