bluuebunny/crossref_metadata_2025 huggingface dataset:
Hospitals’ Collaborations Strengthen Pandemic Preparedness: Lessons Learnt from COVID-19
Authors: Sakr Carine J. , Assaf Sara A. , Fakih Lina , Dakroub Saada , Rahme Diana , Musharrafieh Umayya , Khater Beatrice , Naous Jihane , Romani Maya , Tannous Joseph , Zahreddine Nada , Fakhreddine Mohammad , Itani Mira , Zalaquett Nader , Honein Gladys
Published: January 2024

Background: The COVID-19 pandemic strained healthcare systems around the world. This study aims to understand the preparedness of private remote hospitals in Lebanon to respond to the pandemic and evaluate the impact of inter-hospital collaborations on the hospitals’ readiness. Methods: A multi-centered study was conducted between August 2020 and June 2021 in ten Lebanese private remote hospitals based on a mixed-methods embedded approach where the quantitative supported the qualitative. Through the AUB-USAID (American University of Beirut-United States Agency for International Development) COVID-19 project, these hospitals received personal protective equipment and medical equipment in addition to COVID-19-related training using the Train-the-Trainer model. The quantitative part used knowledge and evaluation questionnaires and a pre–post-intervention hospital preparedness checklist. The qualitative approach adopted semi-structured interviews with a purposive sample from key hospital personnel. Quantitative data were analyzed using SPSS version 27, and a p-value of <0.05 was considered to be statistically significant. For the qualitative data, a thematic analysis was performed by adopting the six-phase process described by Braun and Clarke. Results: Of the 393 healthcare workers who attended the training and completed the evaluation questionnaire, 326 completed the pre- and post-training knowledge questionnaire. A significant improvement was observed in mean knowledge scores following training for infection control, nursing, and polymerase chain reaction sampling staff (p-value < 0.001, p-value < 0.001, and p-value = 0.006, respectively), but not for housekeeping staff. More than 93% of the participants showed high trainer and content evaluation scores. As for the hospitals’ preparedness assessments, there was a clear improvement in the pre- and post-assessment scores for each hospital, and there was a significant difference in the mean of the total scores of partner hospitals pre- and post-USAID-AUB project (p-value = 0.005). These findings were supported by the qualitative analysis, where nine hospitals expressed the positive impact of the USAID-AUB intervention in improving their preparedness to respond to the COVID-19 pandemic at a critical time when it was highly needed. Despite the intervention, persistent challenges remained. Conclusions: A timely and proactive collaborative program between academic/tertiary care centers and remote community hospitals that includes sharing supplies and expertise is feasible and highly effective during public health emergencies.
A Community-Based Intervention to Enhance Subjective Well-Being in Older Adults: Study Design and Baseline Participant Profiles
Authors: Nakada Tsubasa , Kozawa Takako , Seino Satoshi , Murota Shinichi , Eto Miki , Shimasawa Junko , Shimizu Yumiko , Tsurugano Shinobu , Katsukawa Fuminori , Sakamoto Kazunori , Washizaki Hironori , Ishigaki Yo , Sakamoto Maki , Takadama Keiki , Yanai Keiji , Matsuo Osamu , Kameue Chiyoko , Suzuki Hitomi , Kurotani Kayo , Ohkawara Kazunori
Published: January 2024

Promoting subjective well-being is a crucial challenge in aging societies. In 2022, we launched a community-based intervention trial (the Chofu-Digital-Choju Movement). This initiative centered on fostering in-person and online social connections to enhance the subjective well-being of older adults. This paper describes the study design and baseline survey. This quasi-experimental study involved community-dwelling older adults aged 65–84 years in Chofu City, Tokyo, Japan. A self-administered questionnaire was distributed to 3742 residents (1681 men and 2061 women), and a baseline survey was conducted in January 2022. We assessed subjective well-being (primary outcome); psychosocial, physical, and dietary factors; and the use of information and communication technology variables (secondary outcomes) among the participants. After the intervention involving online classes, community hubs, and community events, a 2-year follow-up survey will be conducted to evaluate the effects of the intervention, comparing the intervention group (participants) with the control group (non-participants). We received 2503 questionnaires (66.9% response rate); of these, the analysis included 2343 questionnaires (62.6% valid response rate; mean age, 74.4 (standard deviation, 5.4) years; 43.7% male). The mean subjective well-being score was 7.2 (standard deviation, 1.9). This study will contribute to the development of a prototype subjective well-being strategy for older adults.
Developing EST-SSR Markers for Identifying and Evaluating Asparagus Germplasm Resources Based on Transcriptome Sequences
Authors: Liu Dan , Yan Feili , Liu Changmei , Chen Aimeng , Wu Jiahui , Yu Ma , Lyu Xiangyang
Published: January 2024

Radix asparagi is the dried root tuber of the Liliaceae plant Asparagus cochinchinensis (Lour.) Merr., which is a major Chinese medicinal herb with high medicinal and edible value in China. The planting area of A. cochinchinensis is extensive, and there is blind introduction in various regions, leading to confusion the origin of Radix asparagi and impure germplasm. This study conducted morphological and karyotype analyses on cultivated Asparagus resources from seven main production areas in China and developed SSR molecular markers suitable for the identification of Asparagus germplasm resources based on the transcriptome sequencing results. The morphological results indicate that in addition to A. cochinchinensis (Lour.) Merr., recorded in the Pharmacopoeia of the People’s Republic of China, there are also A. taliensis Wang et Tang and A. lycopodineus (Baker) Wang et Tang cultivated in China. All the tested Asparagus resources were diploid and had 20 chromosomes. A total of 8841 single genes containing SSR loci were identified using transcriptome sequencing of Neijiang Asparagus, including 761 SSR loci with trinucleotide repeat units. One hundred pairs of SSR primers were randomly designed from the trinucleotide repeat loci for PCR and polymorphism verification, and ten pairs were selected for identification of Asparagus germplasm resources. The genetic diversity results of ten pairs of primers in seven Asparagus-producing regions were consistent with the morphological identification. This study provides technical support for the comprehensive evaluation and utilization of Asparagus germplasm resources.
Melatonin Application Induced Physiological and Molecular Changes in Carnation (Dianthus caryophyllus L.) under Heat Stress
Authors: Elmongy Mohamed S. , Abd El-Baset Mohaned M.
Published: January 2024

Carnation is one of the most important ornamental plants worldwide; however, heat stress is a problem, which affects carnation cultivation. The harmful effects of heat stress include impaired vegetative development and reduced floral induction. In this study, to enhance carnation growth under conditions of heat stress, various concentrations of melatonin were added to in vitro culture media. The mechanism by which melatonin reduced heat stress damage was then studied by taking measurements of morphological parameters, levels of reactive oxygen species (ROS), antioxidant enzymes, and malondialdehyde (MDA), as well as differential gene expression, in carnation plants during in vitro culture. These data revealed that untreated carnation plants were more harmed by conditions of heat stress than plants treated with melatonin. Melatonin at concentrations of 5 and 10 mM increased chlorophyll content, fresh weight, and plant height to a greater extent than other concentrations. Melatonin may, thus, be used to alleviate damage to carnations caused by heat stress. The application of melatonin was also found to reduce oxidative damage and enhance antioxidant defense mechanisms. In addition, the expression of heat-related genes was found to be upregulated; in melatonin-treated plants, an upregulation was recorded in the expression of GAPDH, DcPOD1, DcPOD2, DcPOD3, Gols1, MBF1c, HSF30, HSP101, HSP70, and sHSP (MT) genes. In short, we found that melatonin treatment increased heat tolerance in carnation plants. The data presented here may serve as a reference for those seeking to enhance the growth of plants in conditions of heat stress.
Development of an Evaluation Index for Forest Therapy Environments
Authors: Kang Jaewoo , Choi Jeongho , Lee Kyoungmin
Published: January 2024

Most research on forest therapy has examined the therapeutic effects of forest activity development. There has been insufficient research identifying and evaluating the forest therapy environment. This study aimed to derive a representative forest therapy environment from each of the four evaluation sites, comprising national luxury forests; Scopus, PubMed, Medline, Web of Science, RISS, and DBpia were searched, and 13 studies evaluating forest therapy environments were analyzed and synthesized. After conducting a Conformity Evaluation, one layer of items, comprising anions with low conformity scores, was excluded, and six field measurements, phytoncide, oxygen, illuminance, UV-rays, sound, and anion, were added to increase objectivity. Finally, five forest therapy environment categories and 25 detailed items were derived. Analytic Hierarchy Process-based importance was evaluated to calculate the weight between the final evaluation items. According to the site evaluations, the categories of landscape, forest air, sunlight, sound, and anions appeared, in that order. This study is significant as it developed evaluation items and rating criteria for forest therapy environments, applied these in the field, and derived representative forest therapy environments for each location. This study developed indicators, provided basic data for establishing a therapy environment management plan, and there recommendations were made for an environment suitable for visitors and customizing forest welfare and therapy services.
Parasitosis in Pet Dogs from Rondônia, Amazon Biome, and Human Perception of Zoonoses
Authors: Mendonça Talita Oliveira , Perin Patricia Parreira , Zanini Dayane da Silva , de Souza Hortência Laporti , Pires Paulo Henrique Kanopp , Muniz Igor Mansur , Tebaldi José Hairton , Mathias Luís Antonio , Bürger Karina Paes , Lux-Hoppe Estevam G.
Published: January 2024

Zoonotic parasitic diseases in dogs are particularly concerning in regions with low human development indices due to inadequate sanitary services and insufficient environmental and health education. This study aimed to assess the parasitological status of dogs living in households and evaluate their owners’ knowledge about zoonoses. A total of 183 dogs from Rolim de Moura, Rondônia State, were screened for the presence of ectoparasites, and 163 fecal samples were collected for analysis. The results showed that 74.23% (112/163) of the animals had at least one species of endoparasite. The most identified pathogens were Ancylostoma spp. (68.71%, 112/163), Trichuris vulpis (11.66%, 19/163), Toxocara canis (6.75%, 11/163), Cystoisospora canis (4.91%, 8/163), Dipylidium caninum (1.23%, 2/163), and Hammondia/Neospora (0.61%, 1/163). Ectoparasites were observed in 43.17% (79/183) of the evaluated animals, with Rhipicephalus sanguineus found in 31.15% (57/183) and Ctenocephalides felis felis in 20.77% (38/183). Only 11.48% (7/61) of the owners were familiar with the term “Zoonoses.” However, a significant majority (83.61%, 51/61) believed that dogs can transmit diseases to humans. Our findings highlight the prevalence of parasites in the studied area and associated risk factors, underscoring the urgent need for educational interventions to raise awareness about these diseases and their risks to human health.
Potential Migration and Health Risks of Heavy Metals and Metalloids in Take-Out Food Containers in South Korea
Authors: Han Yujin , Ryu Keunyoung , Song Nanju , Seo Jinjong , Kang Insook , Chung Hyun-Jung , Park Ran
Published: January 2024

The consumption of take-out food has increased worldwide; consequently, people are increasingly being exposed to chemicals from food containers. However, research on the migration of metals from containers to food is limited, and therefore, information required to determine the health risks is lacking. Herein, the amount of transfer of nine metals and metalloids (Pb, Sb, Cd, Ge, Co, Mn, Sn, As, and Hg) from food containers to food in South Korea was assessed from take-out food containers classified into paper and plastic container groups. The sample containers were eluted over time by either warming with 4% acetic acid at 70 °C or cooling with 4% acetic acid at 100 °C /deionized water at 25 °C. It was analyzed using an inductively coupled plasma mass spectrometer and a direct mercury analyzer. The reliability of the quantitative results was verified by calculating the linearity, limit of detection, and limit of quantification. We found that the amount of metals and metalloids (Pb, Sb, Cd, and Co) eluting over time was highly significant in the plastic group. Regardless of the food simulant and elution time, the amount of Sb transferred from the food containers to food was substantially higher in the plastic (average concentration: 0.488–1.194 μg/L) than in the paper group (average concentration: 0.001–0.03 μg/L). Fortunately, all food containers were distributed at levels safe for human health (hazard index: 0.000–64.756%). However, caution is needed when warm food is added to food containers. Overall, our results provide baseline data for the management and use of take-out containers.
The Silencing of GhPIP5K2 and GhPIP5K22 Weakens Abiotic Stress Tolerance in Upland Cotton (Gossypium hirsutum)
Authors: Ling Pingjie , Ju Jisheng , Zhang Xueli , Wei Wei , Luo Jin , Li Ying , Hai Han , Shang Bowen , Cheng Hongbo , Wang Caixiang , Zhang Xianliang , Su Junji
Published: January 2024

Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks), essential enzymes in the phosphatidylinositol signaling pathway, are crucial for the abiotic stress responses and the overall growth and development of plants. However, the GhPIP5Ks had not been systematically studied, and their function in upland cotton was unknown. This study identified a total of 28 GhPIP5Ks, and determined their chromosomal locations, gene structures, protein motifs and cis-acting elements via bioinformatics analysis. A quantitative real-time PCR (qRT‒PCR) analysis showed that most GhPIP5Ks were upregulated under different stresses. A virus-induced gene silencing (VIGS) assay indicated that the superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities were significantly decreased, while malondialdehyde (MDA) content were significantly increased in GhPIP5K2- and GhPIP5K22-silenced upland cotton plants under abiotic stress. Furthermore, the expression of the stress marker genes GhHSFB2A, GhHSFB2B, GhDREB2A, GhDREB2C, GhRD20-1, GhRD29A, GhBIN2, GhCBL3, GhNHX1, GhPP2C, GhCBF1, GhSnRK2.6 and GhCIPK6 was significantly decreased in the silenced plants after exposure to stress. These results revealed that the silencing of GhPIP5K2 and GhPIP5K22 weakened the tolerance to abiotic stresses. These discoveries provide a foundation for further inquiry into the actions of the GhPIP5K gene family in regulating the response and resistance mechanisms of cotton to abiotic stresses.
Genome-Wide Comparative Analysis of SRCR Gene Superfamily in Invertebrates Reveals Massive and Independent Gene Expansions in the Sponge and Sea Urchin
Authors: Peng Zhangjie , Zhang Wei , Fu Hailun , Li Yuzhu , Zhang Chunyu , Li Jie , Chan Jiulin , Zhang Linlin
Published: January 2024

Without general adaptative immunity, invertebrates evolved a vast number of heterogeneous non-self recognition strategies. One of those well-known adaptations is the expansion of the immune receptor gene superfamily coding for scavenger receptor cysteine-rich domain containing proteins (SRCR) in a few invertebrates. Here, we investigated the evolutionary history of the SRCR gene superfamily (SRCR-SF) across 29 metazoan species with an emphasis on invertebrates. We analyzed their domain architectures, genome locations and phylogenetic distribution. Our analysis shows extensive genome-wide duplications of the SRCR-SFs in Amphimedon queenslandica and Strongylocentrotus purpuratus. Further molecular evolution study reveals various patterns of conserved cysteines in the sponge and sea urchin SRCR-SFs, indicating independent and convergent evolution of SRCR-SF expansion during invertebrate evolution. In the case of the sponge SRCR-SFs, a novel motif with seven conserved cysteines was identified. Exon–intron structure analysis suggests the rapid evolution of SRCR-SFs during gene duplications in both the sponge and the sea urchin. Our findings across nine representative metazoans also underscore a heightened expression of SRCR-SFs in immune-related tissues, notably the digestive glands. This observation indicates the potential role of SRCR-SFs in reinforcing distinct immune functions in these invertebrates. Collectively, our results reveal that gene duplication, motif structure variation, and exon–intron divergence might lead to the convergent evolution of SRCR-SF expansions in the genomes of the sponge and sea urchin. Our study also suggests that the utilization of SRCR-SF receptor duplication may be a general and basal strategy to increase immune diversity and tissue specificity for the invertebrates.
Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity
Authors: Eržen Stjepan , Tonin Gašper , Jurišić Eržen Dubravka , Klen Jasna
Published: January 2024

Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term—diabesity—has emerged. The gut–brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from β-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.
Mitochondrial Signaling, the Mechanisms of AKI-to-CKD Transition and Potential Treatment Targets
Authors: Chang Li-Yun , Chao Yu-Lin , Chiu Chien-Chih , Chen Phang-Lang , Lin Hugo Y.-H.
Published: January 2024

Acute kidney injury (AKI) is increasing in prevalence and causes a global health burden. AKI is associated with significant mortality and can subsequently develop into chronic kidney disease (CKD). The kidney is one of the most energy-demanding organs in the human body and has a role in active solute transport, maintenance of electrochemical gradients, and regulation of fluid balance. Renal proximal tubular cells (PTCs) are the primary segment to reabsorb and secrete various solutes and take part in AKI initiation. Mitochondria, which are enriched in PTCs, are the main source of adenosine triphosphate (ATP) in cells as generated through oxidative phosphorylation. Mitochondrial dysfunction may result in reactive oxygen species (ROS) production, impaired biogenesis, oxidative stress multiplication, and ultimately leading to cell death. Even though mitochondrial damage and malfunction have been observed in both human kidney disease and animal models of AKI and CKD, the mechanism of mitochondrial signaling in PTC for AKI-to-CKD transition remains unknown. We review the recent findings of the development of AKI-to-CKD transition with a focus on mitochondrial disorders in PTCs. We propose that mitochondrial signaling is a key mechanism of the progression of AKI to CKD and potential targeting for treatment.
The Shoot Apical Meristem: An Evolutionary Molding of Higher Plants
Authors: Kean-Galeno Tania , Lopez-Arredondo Damar , Herrera-Estrella Luis
Published: January 2024

The shoot apical meristem (SAM) gives rise to the aerial structure of plants by producing lateral organs and other meristems. The SAM is responsible for plant developmental patterns, thus determining plant morphology and, consequently, many agronomic traits such as the number and size of fruits and flowers and kernel yield. Our current understanding of SAM morphology and regulation is based on studies conducted mainly on some angiosperms, including economically important crops such as maize (Zea mays) and rice (Oryza sativa), and the model species Arabidopsis (Arabidopsis thaliana). However, studies in other plant species from the gymnosperms are scant, making difficult comparative analyses that help us understand SAM regulation in diverse plant species. This limitation prevents deciphering the mechanisms by which evolution gave rise to the multiple plant structures within the plant kingdom and determines the conserved mechanisms involved in SAM maintenance and operation. This review aims to integrate and analyze the current knowledge of SAM evolution by combining the morphological and molecular information recently reported from the plant kingdom.
Exploring the Molecular Aspects of Myeloproliferative Neoplasms Associated with Unusual Site Vein Thrombosis: Review of the Literature and Latest Insights
Authors: Morsia Erika , Torre Elena , Martini Francesco , Morè Sonia , Poloni Antonella , Olivieri Attilio , Rupoli Serena
Published: January 2024

Myeloproliferative neoplasms (MPNs) are the leading causes of unusual site thrombosis, affecting nearly 40% of individuals with conditions like Budd–Chiari syndrome or portal vein thrombosis. Diagnosing MPNs in these cases is challenging because common indicators, such as spleen enlargement and elevated blood cell counts, can be obscured by portal hypertension or bleeding issues. Recent advancements in diagnostic tools have enhanced the accuracy of MPN diagnosis and classification. While bone marrow biopsies remain significant diagnostic criteria, molecular markers now play a pivotal role in both diagnosis and prognosis assessment. Hence, it is essential to initiate the diagnostic process for splanchnic vein thrombosis with a JAK2 V617F mutation screening, but a comprehensive approach is necessary. A multidisciplinary strategy is vital to accurately determine the specific subtype of MPNs, recommend additional tests, and propose the most effective treatment plan. Establishing specialized care pathways for patients with splanchnic vein thrombosis and underlying MPNs is crucial to tailor management approaches that reduce the risk of hematological outcomes and hepatic complications.
Recent Achievements in the Development of Biomaterials Improved with Platelet Concentrates for Soft and Hard Tissue Engineering Applications
Authors: Grzelak Agnieszka , Hnydka Aleksandra , Higuchi Julia , Michalak Agnieszka , Tarczynska Marta , Gaweda Krzysztof , Klimek Katarzyna
Published: January 2024

Platelet concentrates such as platelet-rich plasma, platelet-rich fibrin or concentrated growth factors are cost-effective autologous preparations containing various growth factors, including platelet-derived growth factor, transforming growth factor β, insulin-like growth factor 1 and vascular endothelial growth factor. For this reason, they are often used in regenerative medicine to treat wounds, nerve damage as well as cartilage and bone defects. Unfortunately, after administration, these preparations release growth factors very quickly, which lose their activity rapidly. As a consequence, this results in the need to repeat the therapy, which is associated with additional pain and discomfort for the patient. Recent research shows that combining platelet concentrates with biomaterials overcomes this problem because growth factors are released in a more sustainable manner. Moreover, this concept fits into the latest trends in tissue engineering, which include biomaterials, bioactive factors and cells. Therefore, this review presents the latest literature reports on the properties of biomaterials enriched with platelet concentrates for applications in skin, nerve, cartilage and bone tissue engineering.
Development of Novel Bioluminescent Biosensors Monitoring the Conformation and Activity of the Merlin Tumour Suppressor
Authors: Pipchuk Alexander , Kelly Tynan , Carew Madeleine , Nicol Christopher , Yang Xiaolong
Published: January 2024

Solid tumours can universally evade contact inhibition of proliferation (CIP), a mechanism halting cell proliferation when cell–cell contact occurs. Merlin, an ERM-like protein, crucially regulates CIP and is frequently deactivated in various cancers, indicating its significance as a tumour suppressor in cancer biology. Despite extensive investigations into Merlin’s role in cancer, its lack of intrinsic catalytic activity and frequent conformation changes have made it notoriously challenging to study. To address this challenge, we harnessed innovative luciferase technologies to create and validate a NanoBiT split-luciferase biosensor system in which Merlin is cloned between two split components (LgBiT and SmBiT) of NanoLuc luciferase. This system enables precise quantification of Merlin’s conformation and activity both in vitro and within living cells. This biosensor significantly enhances the study of Merlin’s molecular functions, serving as a potent tool for exploring its contributions to CIP and tumorigenesis.
Effect of Selected Antioxidants on the In Vitro Aging of Human Fibroblasts
Authors: Bartosz Grzegorz , Pieńkowska Natalia , Sadowska-Bartosz Izabela
Published: January 2024

The modification of the replicative lifespan (RLS) of fibroblasts is of interest both from a knowledge point of view and for the attenuation of skin aging. The effect of six antioxidants at a concentration of 1 μM on the replicative lifespan of human dermal fibroblasts was studied. The nitroxide 4-hydroxy-TEMPO (TEMPOL), ergothioneine, and Trolox extended the replicative lifespan (RLS) (40 ± 1 population doublings (PD)) by 7 ± 2, 4 ± 1, and 3 ± 1 PD and lowered the expression of p21 at late passages. Coumaric acid, curcumin and resveratrol did not affect the RLS . The level of reactive oxygen species (ROS) was decreased or not affected by the antioxidants although TEMPOL and coumaric acid decreased the level of glutathione. Only ergothioneine and resveratrol decreased the level of protein carbonylation. The antioxidants that could prolong the RLS elevated the mitochondrial membrane potential. Protecting the activity of mitochondria seems to be important for maintaining the replicative capacity of fibroblasts.
Formulation Studies with Cyclodextrins for Novel Selenium NSAID Derivatives
Authors: Ramos-Inza Sandra , Morán-Serradilla Cristina , Gaviria-Soteras Leire , Sharma Arun K. , Plano Daniel , Sanmartín Carmen , Font María
Published: January 2024

Commercial cyclodextrins (CDs) are commonly used to form inclusion complexes (ICs) with different molecules in order to enhance their water solubility, stability, and bioavailability. Nowadays, there is strong, convincing evidence of the anticancer effect of selenium (Se)-containing compounds. However, pharmaceutical limitations, such as an unpleasant taste or poor aqueous solubility, impede their further evaluation and clinical use. In this work, we study the enhancement of solubility with CD complexes for a set of different nonsteroidal anti-inflammatory drug (NSAID) derivatives with Se as selenoester or diacyl diselenide chemical forms, with demonstrated antitumoral activity. The CD complexes were analyzed via nuclear magnetic resonance (NMR) spectroscopic techniques. In order to obtain additional data that could help explain the experimental results obtained, 3D models of the theoretical CD-compound complexes were constructed using molecular modeling techniques. Among all the compounds, I.3e and II.5 showed a remarkable increase in their water solubility, which could be ascribed to the formation of the most stable interactions with the CDs used, in agreement with the in silico studies performed. Thus, the preliminary results obtained in this work led us to confirm the selection of β and γ-CD as the most suitable for overcoming the pharmaceutical drawbacks of these Se derivatives.
A Clinical Case of Probable Sitosterolemia
Authors: Terasaki Michishige , Izumi Mikiko , Yamagishi Sho-ichi
Published: January 2024

Sitosterolemia is a rare genetic lipid disorder characterized by elevated plant sterols in the serum. A 24-year-old Japanese woman was referred to our hospital due to a high serum low-density lipoprotein cholesterol (LDL-C) level of 332 mg/dL. At first, she was suspected to suffer from familial hypercholesterolemia, and thus received lipid-lowering agents. Although her LDL-C level remained high (220 mg/dL) with diet therapy plus 10 mg/day rosuvastatin, it was drastically decreased to 46 mg/dL with the addition of 10 mg/day ezetimibe. Finally, her LDL-C level was well-controlled at about 70 mg/dL with 10 mg/day ezetimibe alone. Furthermore, while her serum sitosterol level was elevated at 10.5 μg/mL during the first visit to our hospital, it decreased to 3.6 μg/mL with the 10 mg/day ezetimibe treatment alone. These observations suggest that she might probably suffer from sitosterolemia. Therefore, targeted gene sequencing analysis was performed using custom panels focusing on the exome regions of 21 lipid-associated genes, including ABCG5, ABCG8, and familial hypercholesterolemia-causing genes (LDL receptor, LDLRAP1, PCSK9, and apolipoprotein B). We finally identified a heterozygous ABCG8 variant (NM_022437.2:c.1285A>G or NP_071882.1:p.Met429Val) in our patient. The same gene mutation was detected in her mother. We report here a rare case exhibiting probable sitosterolemia caused by a heterozygous Met429Val variant in the ABCG8 gene and additional unknown variants.
TRPV4 Channels Promote Pathological, but Not Physiological, Cardiac Remodeling through the Activation of Calcineurin/NFAT and TRPC6
Authors: Yáñez-Bisbe Laia , Moya Mar , Rodríguez-Sinovas Antonio , Ruiz-Meana Marisol , Inserte Javier , Tajes Marta , Batlle Montserrat , Guasch Eduard , Mas-Stachurska Aleksandra , Miró Elisabet , Rivas Nuria , Ferreira González Ignacio , Garcia-Elias Anna , Benito Begoña
Published: January 2024

TRPV4 channels, which respond to mechanical activation by permeating Ca2+ into the cell, may play a pivotal role in cardiac remodeling during cardiac overload. Our study aimed to investigate TRPV4 involvement in pathological and physiological remodeling through Ca2+-dependent signaling. TRPV4 expression was assessed in heart failure (HF) models, induced by isoproterenol infusion or transverse aortic constriction, and in exercise-induced adaptive remodeling models. The impact of genetic TRPV4 inhibition on HF was studied by echocardiography, histology, gene and protein analysis, arrhythmia inducibility, Ca2+ dynamics, calcineurin (CN) activity, and NFAT nuclear translocation. TRPV4 expression exclusively increased in HF models, strongly correlating with fibrosis. Isoproterenol-administered transgenic TRPV4−/− mice did not exhibit HF features. Cardiac fibroblasts (CFb) from TRPV4+/+ animals, compared to TRPV4−/−, displayed significant TRPV4 overexpression, elevated Ca2+ influx, and enhanced CN/NFATc3 pathway activation. TRPC6 expression paralleled that of TRPV4 in all models, with no increase in TRPV4−/− mice. In cultured CFb, the activation of TRPV4 by GSK1016790A increased TRPC6 expression, which led to enhanced CN/NFATc3 activation through synergistic action of both channels. In conclusion, TRPV4 channels contribute to pathological remodeling by promoting fibrosis and inducing TRPC6 upregulation through the activation of Ca2+-dependent CN/NFATc3 signaling. These results pose TRPV4 as a primary mediator of the pathological response.
Impact of Heavy Metals on Cold Acclimation of Salix viminalis Roots
Authors: Ambroise Valentin , Legay Sylvain , Jozefczak Marijke , Leclercq Céline C. , Planchon Sebastien , Hausman Jean-Francois , Renaut Jenny , Cuypers Ann , Sergeant Kjell
Published: January 2024

In nature, plants are exposed to a range of climatic conditions. Those negatively impacting plant growth and survival are called abiotic stresses. Although abiotic stresses have been extensively studied separately, little is known about their interactions. Here, we investigate the impact of long-term mild metal exposure on the cold acclimation of Salix viminalis roots using physiological, transcriptomic, and proteomic approaches. We found that, while metal exposure significantly affected plant morphology and physiology, it did not impede cold acclimation. Cold acclimation alone increased glutathione content and glutathione reductase activity. It also resulted in the increase in transcripts and proteins belonging to the heat-shock proteins and related to the energy metabolism. Exposure to metals decreased antioxidant capacity but increased catalase and superoxide dismutase activity. It also resulted in the overexpression of transcripts and proteins related to metal homeostasis, protein folding, and the antioxidant machinery. The simultaneous exposure to both stressors resulted in effects that were not the simple addition of the effects of both stressors taken separately. At the antioxidant level, the response to both stressors was like the response to metals alone. While this should have led to a reduction of frost tolerance, this was not observed. The impact of the simultaneous exposure to metals and cold acclimation on the transcriptome was unique, while at the proteomic level the cold acclimation component seemed to be dominant. Some genes and proteins displayed positive interaction patterns. These genes and proteins were related to the mitigation and reparation of oxidative damage, sugar catabolism, and the production of lignans, trehalose, and raffinose. Interestingly, none of these genes and proteins belonged to the traditional ROS homeostasis system. These results highlight the importance of the under-studied role of lignans and the ROS damage repair and removal system in plants simultaneously exposed to multiple stressors.
Grid-Based Structural and Dimensional Skin Cancer Classification with Self-Featured Optimized Explainable Deep Convolutional Neural Networks
Authors: Behara Kavita , Bhero Ernest , Agee John Terhile
Published: January 2024

Skin cancer is a severe and potentially lethal disease, and early detection is critical for successful treatment. Traditional procedures for diagnosing skin cancer are expensive, time-intensive, and necessitate the expertise of a medical practitioner. In recent years, many researchers have developed artificial intelligence (AI) tools, including shallow and deep machine learning-based approaches, to diagnose skin cancer. However, AI-based skin cancer diagnosis faces challenges in complexity, low reproducibility, and explainability. To address these problems, we propose a novel Grid-Based Structural and Dimensional Explainable Deep Convolutional Neural Network for accurate and interpretable skin cancer classification. This model employs adaptive thresholding for extracting the region of interest (ROI), using its dynamic capabilities to enhance the accuracy of identifying cancerous regions. The VGG-16 architecture extracts the hierarchical characteristics of skin lesion images, leveraging its recognized capabilities for deep feature extraction. Our proposed model leverages a grid structure to capture spatial relationships within lesions, while the dimensional features extract relevant information from various image channels. An Adaptive Intelligent Coney Optimization (AICO) algorithm is employed for self-feature selected optimization and fine-tuning the hyperparameters, which dynamically adapts the model architecture to optimize feature extraction and classification. The model was trained and tested using the ISIC dataset of 10,015 dermascope images and the MNIST dataset of 2357 images of malignant and benign oncological diseases. The experimental results demonstrated that the model achieved accuracy and CSI values of 0.96 and 0.97 for TP 80 using the ISIC dataset, which is 17.70% and 16.49% more than lightweight CNN, 20.83% and 19.59% more than DenseNet, 18.75% and 17.53% more than CNN, 6.25% and 6.18% more than Efficient Net-B0, 5.21% and 5.15% over ECNN, 2.08% and 2.06% over COA-CAN, and 5.21% and 5.15% more than ARO-ECNN. Additionally, the AICO self-feature selected ECNN model exhibited minimal FPR and FNR of 0.03 and 0.02, respectively. The model attained a loss of 0.09 for ISIC and 0.18 for the MNIST dataset, indicating that the model proposed in this research outperforms existing techniques. The proposed model improves accuracy, interpretability, and robustness for skin cancer classification, ultimately aiding clinicians in early diagnosis and treatment.
Improved Efficacy of Delayed Treatment with Human Bone Marrow-Derived Stromal Cells Evaluated in Rats with Spinal Cord Injury
Authors: Aguado-Garrido Marta , García-Rama Concepción , Romero-Ramírez Lorenzo , Buzoianu-Anguiano Vinnitsa , Pérez-Rizo Enrique , Kramer Boris W. , Mey Jörg
Published: January 2024

The treatment of spinal cord injury (SCI) with uncultivated human bone marrow-derived stromal cells (bmSCs) prepared by negative selection has been proposed to be therapeutically superior to treatment with stem cells that were expanded in vitro. To explore their use in clinical trials, we studied the functional effects of delayed application at 7 days after SCI by testing different doses of bmSCs. Spinal cord contusion injury was induced in adult male Wistar rats at the thoracic level T9. Human bmSCs were prepared by negative selection without expansion in vitro (NeuroCellsTM). Treatment consisted of one 150 µL injection into the cisterna magna containing 0.5 or 2.5 million fresh bmSCs or 2.5 million bmSCs. The recovery of motor functions was evaluated during a surveillance period of six weeks (6 W), during which spinal cords were assessed histologically. Treatment resulted in a significant, dose-dependent therapeutic effect on the recovery of motor performance. The histological analysis revealed a lower degree of axonal degeneration and better survival of neurons and oligodendrocytes in bmSCs treated rats. Our results support delayed intrathecal application of bmSCs prepared by negative selection without expansion in vitro as a treatment of SCI.
Hydrophilic Reduction-Resistant Spin Labels of Pyrrolidine and Pyrroline Series from 3,4-Bis-hydroxymethyl-2,2,5,5-tetraethylpyrrolidine-1-oxyl
Authors: Usatov Mikhail S. , Dobrynin Sergey A. , Polienko Yuliya F. , Morozov Denis A. , Glazachev Yurii I. , An’kov Sergey V. , Tolstikova Tatiana G. , Gatilov Yuri V. , Bagryanskaya Irina Yu. , Raizvikh Arthur E. , Bagryanskaya Elena G. , Kirilyuk Igor A.
Published: January 2024

Highly resistant to reduction nitroxides open new opportunities for structural studies of biological macromolecules in their native environment inside living cells and for functional imaging of pH and thiols, enzymatic activity and redox status in living animals. 3,4-Disubstituted nitroxides of 2,2,5,5-tetraethylpyrrolidine and pyrroline series with a functional group for binding to biomolecules and a polar moiety for higher solubility in water and for more rigid attachment via additional coordination to polar sites were designed and synthesized. The EPR spectra, lipophilicities, kinetics of the reduction in ascorbate-containing systems and the decay rates in liver homogenates were measured. The EPR spectra of all 3,4-disubstituted pyrrolidine nitroxides showed additional large splitting on methylene hydrogens of the ethyl groups, while the spectra of similar pyrroline nitroxides were represented with a simple triplet with narrow lines and hyperfine structure of the nitrogen manifolds resolved in oxygen-free conditions. Both pyrrolidine and pyrroline nitroxides demonstrated low rates of reduction with ascorbate, pyrrolidines being a bit more stable than similar pyrrolines. The decay of positively charged nitroxides in the rat liver homogenate was faster than that of neutral and negatively charged radicals, with lipophilicity, rate of reduction with ascorbate and the ring type playing minor role. The EPR spectra of N,N-dimethyl-3,4-bis-(aminomethyl)-2,2,5,5-tetraethylpyrrolidine-1-oxyl showed dependence on pH with pKa = 3, ΔaN = 0.055 mT and ΔaH = 0.075 mT.
Thermodynamic Characteristics and Selectivity of the Liquid-Phase Adsorption of Aromatic Compounds on Hypercrosslinked Polystyrene Networks with Ultimate-High Crosslinking Densities by Data of Liquid Chromatography
Authors: Saifutdinov Bulat R. , Buryak Aleksey K.
Published: January 2024

This study delves into the thermodynamics of liquid-phase adsorption on hypercrosslinked polystyrene networks (HPSNs), widely recognized for their distinct structure and properties. Despite the considerable progress in HPSN synthesis and characterization, gaps persist regarding the chromatographic retention mechanism, thermodynamics of adsorption, and their impact on the adsorption selectivity, especially in the case of networks with ultra-high crosslinking densities (up to 500%). Utilizing high-performance liquid chromatography (HPLC), we have explored, for the first time, the thermodynamic intricacies of liquid-phase adsorption onto HPSNs crosslinked in the entire range of the crosslinking degree from 100 to 500%. Our findings reveal the dependences of thermodynamic characteristics and selectivity of adsorption on the crosslinking degree, textural features, and liquid-phase composition in the region of extremely low adsorbent surface coverages (Henry’s range). We have detected that, in the case of HPSNs, the dependence of the thermodynamic characteristics of adsorption on the liquid-phase composition is different than for classical HPLC stationary phases. Moreover, we scrutinize the impact of the molecular structure of the studied aromatic compounds on the thermodynamic characteristics and selectivity of the liquid-phase adsorption on HPSNs. Investigating liquid-phase adsorption selectivity, we demonstrate the pivotal role of π-π interactions in separating aromatic compounds on HPSNs. Eventually, we unveil that the thermodynamic characteristics of adsorption peculiarly depend on the crosslinking degree due to the profound impact of the crosslinking on the electronic density in benzene rings in HPSNs, whereas the separation throughput peaks for the polymer with a 500% crosslinking degree, attributed to its exceptionally rigid network structure, moderate swelling and micropore volume, and minimum specific surface area.
Bioinformatics and Experimental Validation for Identifying Biomarkers Associated with AMG510 (Sotorasib) Resistance in KRASG12C-Mutated Lung Adenocarcinoma
Authors: Lin Peng , Cheng Wei , Qi Xin , Zhang Pinglu , Xiong Jianshe , Li Jing
Published: January 2024

The Kirsten rat sarcoma viral oncogene homolog (KRAS)G12C mutation is prevalent in lung adenocarcinoma (LUAD), driving tumor progression and indicating a poor prognosis. While the FDA-approved AMG510 (Sotorasib) initially demonstrated efficacy in treating KRASG12C-mutated LUAD, resistance emerged within months. Data from AMG510 treatment-resistant LUAD (GSE204753) and single-cell datasets (GSE149655) were analyzed. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were used to explore enriched signaling pathways, nomogram models were constructed, and transcription factors predicting resistance biomarkers were predicted. CIBERSORT identified immune cell subpopulations, and their association with resistance biomarkers was assessed through single-cell analysis. AMG510-resistant LUAD cells (H358-AR) were constructed, and proliferative changes were evaluated using a CCK-8 assay. Key molecules for AMG510 resistance, including SLC2A1, TLE1, FAM83A, HMGA2, FBXO44, and MTRNR2L12, were recognized. These molecules impacted multiple signaling pathways and the tumor microenvironment and were co-regulated by various transcription factors. Single-cell analysis revealed a dampening effect on immune cell function, with associations with programmed cell death ligand 1 (PDL1) expression, cytokine factors, and failure factors. The findings indicate that these newly identified biomarkers are linked to the abnormal expression of PDL1 and have the potential to induce resistance through immunosuppression. These results highlight the need for further research and therapeutic intervention to address this issue effectively.
Orchestrating Cellular Balance: ncRNAs and RNA Interactions at the Dominant of Autophagy Regulation in Cancer
Authors: Yang Xueni , Xiong Shizheng , Zhao Xinmiao , Jin Jiaming , Yang Xinbing , Du Yajing , Zhao Linjie , He Zhiheng , Gong Chengjun , Guo Li , Liang Tingming
Published: January 2024

Autophagy, a complex and highly regulated cellular process, is critical for the maintenance of cellular homeostasis by lysosomal degradation of cellular debris, intracellular pathogens, and dysfunctional organelles. It has become an interesting and attractive topic in cancer because of its dual role as a tumor suppressor and cell survival mechanism. As a highly conserved pathway, autophagy is strictly regulated by diverse non-coding RNAs (ncRNAs), ranging from short and flexible miRNAs to lncRNAs and even circRNAs, which largely contribute to autophagy regulatory networks via complex RNA interactions. The potential roles of RNA interactions during autophagy, especially in cancer procession and further anticancer treatment, will aid our understanding of related RNAs in autophagy in tumorigenesis and cancer treatment. Herein, we mainly summarized autophagy-related mRNAs and ncRNAs, also providing RNA–RNA interactions and their potential roles in cancer prognosis, which may deepen our understanding of the relationships between various RNAs during autophagy and provide new insights into autophagy-related therapeutic strategies in personalized medicine.
Vinorelbine Improves the Efficacy of Sorafenib against Hepatocellular Carcinoma: A Promising Therapeutic Approach
Authors: Ng Wai Har , Soo Khee Chee , Huynh Hung
Published: January 2024

Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Despite the widespread adoption of sorafenib as the standard HCC treatment, its efficacy is constrained, frequently encountering resistance. To augment the effectiveness of sorafenib, this study investigated the synergy of sorafenib and vinorelbine using 22 HCC patient-derived xenograft (PDX) models. In this study, mice bearing HCC tumors were treated with the vehicle, sorafenib (15 mg/kg), vinorelbine (3 mg/kg), and sorafenib–vinorelbine combination (Sora/Vino). Rigorous monitoring of the tumor growth and side effects coupled with comprehensive histological and molecular analyses was conducted. The overall survival (OS) of mice bearing HCC orthotopic tumors was also assessed. Our data showed a notable 86.4% response rate to Sora/Vino, surpassing rates of 31.8% for sorafenib and 9.1% for vinorelbine monotherapies. Sora/Vino significantly inhibited tumor growth, prolonged OS of mice bearing HCC orthotopic tumors (p < 0.01), attenuated tumor cell proliferation and angiogenesis, and enhanced necrosis and apoptosis. The combination therapy effectively suppressed the focal adhesion kinase (FAK) pathway, which is a pivotal player in cell proliferation, tumor angiogenesis, survival, and metastasis. The noteworthy antitumor activity in 22 HCC PDX models positions Sora/Vino as a promising candidate for early-phase clinical trials, leveraging the established use of sorafenib and vinorelbine in HCC and other cancers.