bluuebunny/crossref_metadata_2025 huggingface dataset:
The origin and the genetic regulation of the self-compatibility mechanism in clementine (Citrus clementina Hort. ex Tan.)
Authors: Bennici Stefania , Poles Lara , Di Guardo Mario , Percival-Alwyn Lawrence , Caccamo Mario , Licciardello Concetta , Gentile Alessandra , Distefano Gaetano , La Malfa Stefano
Published: March 2024

Self-incompatibility (SI) is a genetic mechanism common in flowering plants to prevent self-fertilization. Among citrus species, several pummelo, mandarin, and mandarin-like accessions show SI behavior. In these species, SI is coupled with a variable degree of parthenocarpy ensuring the production of seedless fruits, a trait that is highly appreciated by consumers. In Citrus, recent evidences have shown the presence of a gametophytic SI system based on S-ribonucleases (S-RNases) ability to impair self-pollen tube growth in the upper/middle part of the style. In the present study, we combined PCR analysis and next-generation sequencing technologies, to define the presence of S7- and S11-Rnases in the S-genotype of the Citrus clementina (Hort. ex Tan.), the self-incompatible ‘Comune’ clementine and its self-compatible natural mutant ‘Monreal’. The reference genome of ‘Monreal’ clementine is presented for the first time, providing more robust results on the genetic sequence of the newly discovered S7-RNase. SNP discovery analysis coupled with the annotation of the variants detected enabled the identification of 7,781 SNPs effecting 5,661 genes in ‘Monreal’ compared to the reference genome of C. clementina. Transcriptome analysis of unpollinated pistils at the mature stage from both clementine genotypes revealed the lack of expression of S7-RNase in ‘Monreal’ suggesting its involvement in the loss of the SI response. RNA-seq analysis followed by gene ontology studies enabled the identification of 2,680 differentially expressed genes (DEGs), a significant number of those is involved in oxidoreductase and transmembrane transport activity. Merging of DNA sequencing and RNA data led to the identification of 164 DEGs characterized by the presence of at least one SNP predicted to induce mutations with a high effect on their amino acid sequence. Among them, four candidate genes referring to two Agamous-like MADS-box proteins, to MYB111 and to MLO-like protein 12 were validated. Moreover, the transcription factor MYB111 appeared to contain a binding site for the 2.0-kb upstream sequences of the S7- and S11-RNase genes. These results provide useful information about the genetic bases of SI indicating that SNPs present in their sequence could be responsible for the differential expression and the regulation of S7-RNase and consequently of the SI mechanism.
Assessing nature exposure: a study on the reliability and validity of a Portuguese version of the nature exposure scale
Authors: Picanço Ana , Arroz Ana Moura , Tsafack Noelline , Sánchez Ana Fuentes , Pereira Enésima , De Benedictis Marta , Amorim Isabel R. , da Luz Melo Maria , Gabriel Rosalina
Published: March 2024

Introduction

Engaging with nature has been widely acknowledged for its positive impact on well-being. Traditionally, assessments of nature exposure focus on estimating green space exposure and outdoor time. However, the Nature Exposure Scale (NES) offers a unique approach by evaluating the quality of nature experiences, encompassing both deliberate and spontaneous encounters.

Methods

This study aimed to assess the validity and reliability of the NES in the context of Portugal. Exploratory Factor Analysis (PCA) and Confirmatory Factor Analysis (CFA) were employed to examine the underlying structure of the scale. Additionally, reliability assessments, along with tests of convergent and divergent validity, were conducted. Data were collected from a sample of 558 adults and 241 adolescents between 2016 and 2018.

Results

The findings revealed strong internal consistency of the NES, supported by acceptable correlation values and robust factor loadings within a unidimensional model. The scale effectively predicted variations in nature exposure across diverse professional activities.

Discussion

In summary, the 4-item NES emerged as a reliable tool for assessing nature exposure in various settings, effectively bridging a gap in the Portuguese context. The scale demonstrated potential for cross-cultural research and was particularly adept at predicting nature exposure in different professional contexts. The results suggest that the NES can enhance our understanding of the impact of nature on well-being in diverse cultural settings.

Conclusion

The study underscores the reliability of the NES in assessing nature exposure in Portugal, paving the way for further exploration in Portuguese-speaking regions. The scale holds promise for advancing research on the relationship between nature and well-being, contributing valuable insights across different cultural contexts.
Identification of dihydromyricetin as a natural DNA methylation inhibitor with rejuvenating activity in human skin
Authors: Falckenhayn Cassandra , Bienkowska Agata , Söhle Jörn , Wegner Katrin , Raddatz Guenter , Kristof Boris , Kuck Dirk , Siegner Ralf , Kaufmann Ronny , Korn Julia , Baumann Sascha , Lange Daniela , Schepky Andreas , Völzke Henry , Kaderali Lars , Winnefeld Marc , Lyko Frank , Grönniger Elke
Published: March 2024

Changes in DNA methylation patterning have been reported to be a key hallmark of aged human skin. The altered DNA methylation patterns are correlated with deregulated gene expression and impaired tissue functionality, leading to the well-known skin aging phenotype. Searching for small molecules, which correct the aged methylation pattern therefore represents a novel and attractive strategy for the identification of anti-aging compounds. DNMT1 maintains epigenetic information by copying methylation patterns from the parental (methylated) strand to the newly synthesized strand after DNA replication. We hypothesized that a modest inhibition of this process promotes the restoration of the ground-state epigenetic pattern, thereby inducing rejuvenating effects. In this study, we screened a library of 1800 natural substances and 640 FDA-approved drugs and identified the well-known antioxidant and anti-inflammatory molecule dihydromyricetin (DHM) as an inhibitor of the DNA methyltransferase DNMT1. DHM is the active ingredient of several plants with medicinal use and showed robust inhibition of DNMT1 in biochemical assays. We also analyzed the effect of DHM in cultivated keratinocytes by array-based methylation profiling and observed a moderate, but significant global hypomethylation effect upon treatment. To further characterize DHM-induced methylation changes, we used published DNA methylation clocks and newly established age predictors to demonstrate that the DHM-induced methylation change is associated with a reduction in the biological age of the cells. Further studies also revealed re-activation of age-dependently hypermethylated and silenced genes in vivo and a reduction in age-dependent epidermal thinning in a 3-dimensional skin model. Our findings thus establish DHM as an epigenetic inhibitor with rejuvenating effects for aged human skin.
Evidence that the loss of colonic anti-microbial peptides may promote dysbiotic Gram-negative inflammaging-associated bacteria in aging mice
Authors: Forsyth Christopher B. , Shaikh Maliha , Engen Phillip A. , Preuss Fabian , Naqib Ankur , Palmen Breanna A. , Green Stefan J. , Zhang Lijuan , Bogin Zlata R. , Lawrence Kristi , Sharma Deepak , Swanson Garth R. , Bishehsari Faraz , Voigt Robin M. , Keshavarzian Ali
Published: March 2024

Introduction: Aging studies in humans and mice have played a key role in understanding the intestinal microbiome and an increased abundance of “inflammaging” Gram-negative (Gn) bacteria. The mechanisms underlying this inflammatory profile in the aging microbiome are unknown. We tested the hypothesis that an aging-related decrease in colonic crypt epithelial cell anti-microbial peptide (AMP) gene expression could promote colonic microbiome inflammatory Gn dysbiosis and inflammaging.

Methods: As a model of aging, C57BL/6J mice fecal (colonic) microbiota (16S) and isolated colonic crypt epithelial cell gene expression (RNA-seq) were assessed at 2 months (mth) (human: 18 years old; yo), 15 mth (human: 50 yo), and 25 mth (human: 84 yo). Informatics examined aging-related microbial compositions, differential colonic crypt epithelial cell gene expressions, and correlations between colonic bacteria and colonic crypt epithelial cell gene expressions.

Results: Fecal microbiota exhibited significantly increased relative abundances of pro-inflammatory Gn bacteria with aging. Colonic crypt epithelial cell gene expression analysis showed significant age-related downregulation of key AMP genes that repress the growth of Gn bacteria. The aging-related decrease in AMP gene expressions is significantly correlated with an increased abundance in Gn bacteria (dysbiosis), loss of colonic barrier gene expression, and senescence- and inflammation-related gene expression.

Conclusion: This study supports the proposed model that aging-related loss of colonic crypt epithelial cell AMP gene expression promotes increased relative abundances of Gn inflammaging-associated bacteria and gene expression markers of colonic inflammaging. These data may support new targets for aging-related therapies based on intestinal genes and microbiomes.
The impact of the climate crisis on gender inequality. Looking to the frontlines in search of priorities for policy
Authors: Castelo Sofia , Antunes Lia , Ashrafuzzaman Md.
Published: March 2024

The climate crisis disproportionately impacts women and girls all over the world. To understand what the priorities in terms of policy are, an examination is conducted on the impacts taking place in South Asia (focusing on the countries of Bangladesh, India, and Pakistan), an area of the globe that is highly vulnerable to climate change and is characterized by having strong patriarchal values. Gender stereotypes and roles in the region heighten women and girls' vulnerability to climate impacts, both in general and in situations of crisis resulting from extreme weather events. Deepening the understanding of the climate crisis' impact on gender in South Asia, a region at the frontline of these effects, can assist in reaching a baseline understanding of the challenge from a global perspective. Methodologically, we reviewed an extensive body of literature, both specialty books and scientific articles, recent institutional reports as well as news or journalistic reports from reliable international press. In this research, the argument is made that today, climate action and urban development cannot be considered separately from women's rights. Extensive scientific data and research support the integration of a gender perspective in urban adaptation standard practices, and priorities in terms of policy to safeguard women and girls are identified accordingly. The allocation of half of climate funds, including those of loss and damage, directly to women or women-led organizations is identified as being particularly relevant. Bold and ambitious policymaking is urgently needed to build capacity to face the multiple crises unfolding.
Bandage contact lens for in-game corneal abrasion can allow immediate return to play
Authors: Kubba Rohan , Kandavel Ganesha R. , Scott Joshua , Roldan Cesar , Jackson Hayden
Published: March 2024

While the prevailing treatment for corneal abrasions outside the athletic sphere is the application of a bandage contact lens (BCL), which lessens pain and allows for the maintenance of binocular vision, this is not the case during athletic play. This brief report highlights the advantage of BCLs in treating in-game corneal abrasions, ultimately allowing for an immediate return to play. Additionally, this report summarizes the mechanisms of bandage contact lenses, differentiates them from standard hydrogel contact lenses, and highlights the significant steps necessary to apply the bandage contact lens during an in-game corneal abrasion event. Overall, we link modern ophthalmology clinical practice and sports medicine, allowing for the attenuation of acutely-induced ocular pain to a manageable state.
A fusion protein of vimentin with Fc fragment inhibits Japanese encephalitis virus replication
Authors: Zhang Taoping , Chen Zhixin , Xie Lyu , Xu Ruixian , Chen Lu , Jia Ting , Shi Wengang , Wang Yongbo , Song Yuzhu , Han Qinqin , Xia Xueshan , Yuan Tao , Zhang Jinyang
Published: March 2024

Japanese encephalitis virus (JEV), a member of the Flaviviridae family and a flavivirus, is known to induce acute encephalitis. Vimentin protein has been identified as a potential receptor for JEV, engaging in interactions with the viral membrane protein. The Fc fragment, an integral constituent of immunoglobulins, plays a crucial role in antigen recognition by dendritic cells (DCs) or phagocytes, leading to subsequent antigen presentation, cytotoxicity, or phagocytosis. In this study, we fused the receptor of JEV vimentin with the Fc fragment of IgG and expressed the resulting vimentin-Fc fusion protein in Escherichia coli. Pull-down experiments demonstrated the binding ability of the vimentin-Fc fusion protein to JEV virion in vitro. Additionally, we conducted inhibition assays at the cellular level, revealing the ability of vimentin-Fc protein suppressing JEV replication, it may be a promising passive immunotherapy agent for JEV. These findings pave the way for potential therapeutic strategies against JEV.
Hypnotic Modulation of Autonomic Nervous System (ANS) Activity
Authors: De Benedittis Giuseppe
Published: March 2024

Hypnosis, a time-honored therapeutic approach, has gained widespread recognition for its effectiveness in addressing a range of psychological and somatic disorders. While its primary effects are mediated by central top–down mechanisms, hypnosis also exerts peripheral influence by modulating the autonomic nervous system (ANS). Psychophysiological measures, such as heart rate (HR) and its variability (HRV), electrodermal activity (EDA), respiratory rate (RR), and the analgesia nociceptive index (ANI), serve as reliable indicators of ANS activity. Studies have consistently demonstrated hypnosis’ ability to significantly impact ANS functions, lowering sympathetic activity and enhancing parasympathetic tone. This effect is particularly pronounced during relaxation procedures and is influenced by mediating factors like hypnotizability and task conditions. Despite methodological limitations, this review highlights the potential of enhanced ANS modulation through hypnosis, including its connections to the central nervous system (CNS), to optimize therapeutic outcomes in patients with psychosomatic disorders associated with ANS dysfunction.
Techno-Economic Comparison between Centralized and Distributed Energy Resource Systems: A Case Study of an Underground Transportation Infrastructure System in Changsha, China
Authors: Zhuang Ran , Wang Yuan
Published: March 2024

Due to their higher energy efficiency and better economic performance, distributed energy resource (DER) systems are expected to be one of the main energy supply forms in the future and have gained increasing attention in recent years. Thus, there is a need to boost our understanding of how to apply DER systems in different types of actual cases. This paper investigates a techno-economic analysis of a DER system applied in a real case in a hot-summer and cold-winter zone in China, where the climate is considered to be Cfa according to the Köppen–Geiger climate classification system. An urban underground transportation infrastructure system located in Changsha (China) was chosen to analyze the techno-economic performance of a natural-gas-fired DER system in comparison with a centralized energy system (CES). First, a scientific and reasonable application program of the natural-gas-fired DER system was developed by an overall load analysis (electric load, air-conditioner load, and domestic hot water load during the operating period). Based on this load analysis, this research combined the energy consumption and the actual operating situation and then compared and analyzed different types and capacities of equipment in this case. Moreover, a comprehensive analysis of the economic benefits was estimated by comparing the natural-gas-fired DER system with conventional CESs. Overall, the total annual cost of the DER system was reduced by 18.73%, and its additional investment can be paid back within about 2.2 years. A better economic benefit was achieved by applying the natural-gas-fired DER system in an actual case, which will help encourage the widespread application of DER systems.
An Empirical Evaluation of a Novel Ensemble Deep Neural Network Model and Explainable AI for Accurate Segmentation and Classification of Ovarian Tumors Using CT Images
Authors: Kodipalli Ashwini , Fernandes Steven L. , Dasar Santosh
Published: March 2024

Ovarian cancer is one of the leading causes of death worldwide among the female population. Early diagnosis is crucial for patient treatment. In this work, our main objective is to accurately detect and classify ovarian cancer. To achieve this, two datasets are considered: CT scan images of patients with cancer and those without, and biomarker (clinical parameters) data from all patients. We propose an ensemble deep neural network model and an ensemble machine learning model for the automatic binary classification of ovarian CT scan images and biomarker data. The proposed model incorporates four convolutional neural network models: VGG16, ResNet 152, Inception V3, and DenseNet 101, with transformers applied for feature extraction. These extracted features are fed into our proposed ensemble multi-layer perceptron model for classification. Preprocessing and CNN tuning techniques such as hyperparameter optimization, data augmentation, and fine-tuning are utilized during model training. Our ensemble model outperforms single classifiers and machine learning algorithms, achieving a mean accuracy of 98.96%, a precision of 97.44%, and an F1-score of 98.7%. We compared these results with those obtained using features extracted by the UNet model, followed by classification with our ensemble model. The transformer demonstrated superior performance in feature extraction over the UNet, with a mean Dice score and mean Jaccard score of 0.98 and 0.97, respectively, and standard deviations of 0.04 and 0.06 for benign tumors and 0.99 and 0.98 with standard deviations of 0.01 for malignant tumors. For the biomarker data, the combination of five machine learning models—KNN, logistic regression, SVM, decision tree, and random forest—resulted in an improved accuracy of 92.8% compared to single classifiers.
The Role of Lysophosphatidic Acid in Neuropsychiatric and Neurodegenerative Disorders
Authors: Dedoni Simona , Camoglio Chiara , Siddi Carlotta , Scherma Maria , Fratta Walter , Fadda Paola
Published: March 2024

Individuals suffering from diverse neuropsychiatric and neurodegenerative disorders often have comparable symptoms, which may underline the implication of shared hereditary influences and the same biological processes. Lysophosphatidic acid (LPA) is a bioactive phospholipid and a crucial regulator of the development of adult neuronal systems; hence, it may play an important role in the onset of certain diseases such as Alzheimer’s, Parkinson’s disease, and schizophrenia. During development, LPA signaling regulates many cellular processes such as proliferation, survival, migration, differentiation, cytoskeleton reorganization, and DNA synthesis. So far, six lysophosphatidic acid receptors that respond to LPA have been discovered and categorized based on their homology. Despite the abundance of evidence relating LPA cellular activities to different pathological conditions, little is known about the involvement of LPA in the field of neuropsychiatric and neurodegenerative diseases. The purpose of this review is to define LPA activities related to the illnesses stated above in order to better understand these pathologies and provide future novel treatment strategies based on the latest data.
2-DOF Woven Tube Plane Surface Soft Actuator Using Extensional Pneumatic Artificial Muscle
Authors: Kuriyama Moe , Takayama Toshio
Published: March 2024

Soft actuators, designed for fragile item conveyance and navigation in complex environments, have garnered recent attention. This study proposes a cost-effective soft actuator, created by weaving tubes into twill patterns, capable of transportation and movement. The actuator achieves this by inducing traveling waves on its upper and lower surfaces through sequential pressurization of tubes. Notably, its fabrication does not require specialized molds, contributing to cost efficiency. The single actuator generates traveling waves with two degrees of freedom. Conventional silicone tube-based actuators demonstrate slow transport speeds (3.5 mm/s). To address this, this study replaced silicone tubes with pneumatic artificial muscles, enhancing overall body deformation and actuator speed. Experiments involving both extensional and contractional artificial muscles demonstrated that soft actuators with extensional artificial muscles significantly improved transportation and movement speed to 8.0 mm/s.
Low-Noise Airfoils for Turbomachinery Applications: Two Examples of Optimization
Authors: Casari Nicola , Fadiga Ettore , Oliani Stefano , Piovan Mattia , Pinelli Michele , Suman Alessio
Published: March 2024

Automotive fans, small wind turbines, and manned and unmanned aerial vehicles (MAVs/UAVs) are just a few examples in which noise generated by the flow’s interaction with aerodynamic surfaces is a major concern. The current work shows the potential of a new airfoil shape to minimize noise generation, maintaining a high lift-to-drag ratio in a prescribed Reynolds regime. This investigation uses a multifidelity approach: a low-fidelity semiempirical model is exploited to evaluate the sound pressure level (SPL). Fast evaluation of a low-cost function enables the computation of a large range of possible profiles, and accuracy is added to the low-fidelity response surface with high-fidelity CFD data. The constraint of maintaining a predefined range of the lift coefficient and lift-to-drag ratio ensures the possibility of using this profile in usual design procedures.
The Role of IRF8 Polymorphisms in Systemic Sclerosis Development and Pathogenesis
Authors: Mennella Anna , Ocone Giuseppe , Stefanantoni Katia , Frasca Loredana
Published: March 2024

Systemic sclerosis (SSc) is a rare autoimmune disease whose molecular mechanisms are not yet fully understood. There is no definitive cure, and the main causes of death are pulmonary fibrosis and pulmonary arterial hypertension. Here, we focus on the interferon regulators factor 8 (IRF8), a factor involved in the type I interferon (IFN-I) signature, which is present in about half of SSc patients. Variants of this factor may play a role in autoimmunity, but little is known regarding the role of IRF8 in SSc pathogenesis. We carried out a literature search to address the association between the IRF8 factor and SSc susceptibility and clinical manifestations. The current studies appear to confirm a possible association between the alteration of the gene for IRF8 and SSc susceptibility. A link between IRF8 mutations and expression of a pro-fibrotic phenotype at the cellular level also emerges. Additional investigations are needed to confirm the role of IRF8 in SSc. However, IRF8 is worth consideration as a possible new disease marker of fibrosis in SSc patients.
Influence of Radio Messages on the Awareness and Adoption of Malaria Preventive Measures among Rural Dwellers in South-West Nigeria
Authors: Talabi Felix Olajide , Oko-Epelle Lydia
Published: March 2024

This paper examined the influence of radio messages on the awareness and adoption of malaria preventive measures among rural dwellers in South-west Nigeria. The study investigated the participants’ frequency of exposure to radio messages on malaria preventive measures, message adoption, and attitudes towards adopting measures. We used a multiple-stage sampling technique to select 48 participants from Aye North, Orile-Oshodi, Ofada, Owobaale/kasumu, Isale Oba II, and Ilepa II. The findings showed that the participants were exposed to messages on malaria preventive measures through radio broadcasts; however, exposure did not necessarily influence message adoption. Instead, a positive attitude towards the message influenced adoption. The study concluded that there is a need for radio stations to engage people’s participation daily in health-related issues to achieve the desired change in health behaviour. The authors recommend that radio stations provide time to create daily health messages that influence people’s engagement to achieve the desired change in health behaviour.
Improvement in Microstructure and Properties of 304 Steel Wire Arc Additive Manufacturing by the Micro-Control Deposition Trajectory
Authors: Zhang Huijing , Liu Weihang , Zhao Xiaohui , Zhang Xinlong , Chen Chao
Published: March 2024

In this study, the GMAW welding torch was controlled by a stepping motor to achieve a periodic swing. By controlling the swing speed, a micro-variable deposition path was obtained, which was called the micro-control deposition trajectory. The influence of the micro-control deposition trajectory on the arc characteristics, microstructure, and mechanical properties of 304 steel wire arc additive manufacturing was studied. The results showed that the micro-control deposition process was affected by the swing arc and the deposition trajectory and that the arc force was dispersed over the whole deposition layer, which effectively reduced the welding heat input. However, the arc centrifugal force increased with the increase in the swing speed, which easily caused instability of the arc and large spatter. Compared with common thin-walled deposition, the deposition width of micro-control thin-walled deposition components was increased. In addition, the swinging arc had a certain stirring effect on the molten pool, which was conducive to the escape of the molten pool gas and refinement of the microstructure. Below, the interface of the deposition layer, the microstructure of the common thin-walled deposition components, and the micro-control thin-walled deposition components were composed of lathy ferrite and austenite. Compared with the common deposition, when the swing speed increased to 800 °/s, the microstructure consisted of vermicular ferrite and austenite. The tensile strength and elongation of the micro-control thin-walled deposition components are higher than those of the common thin-walled deposition components. The tensile fracture mechanism of the common thin-walled deposition components and the micro-control thin-walled deposition components was the ductile fracture mechanism.
Study on the Compatibility of SBR and Asphalt Base Based on Molecular Simulation
Authors: Jiao Xiaolei , Huang Dandan , Zhao Song , Ouyang Jian
Published: March 2024

In the field of highway construction, the application of styrene–butadiene rubber (SBR)-modified asphalt has gained popularity across different levels of road surfaces. A crucial aspect in ensuring the efficacy of this modification lies in the compatibility between SBR and the matrix asphalt. To address this, the current study utilizes molecular dynamics simulation as a technique. By establishing a model for the SBR-modified asphalt mixture, the research quantifies the compatibility level between the SBR modifier and the asphalt. The aim is to uncover the underlying mechanisms of compatibility between the SBR modifier and the base asphalt, ultimately contributing to the improvement of the storage stability of SBR-modified asphalt, which holds significant importance. The investigation began with the creation of models for both the base asphalt and the SBR modifier. A model for the SBR-modified asphalt blending system was then formulated based on these initial models. After undergoing geometry optimization and annealing procedures, the model attained its lowest energy state, providing a reliable basis for examining the performance of SBR-modified asphalt. The study proceeded to calculate solubility parameters and interaction energies of the system to evaluate the compatibility between the SBR modifier and the base asphalt at various temperatures. The analysis of these parameters shed light on the compatibility mechanism between the two components. Notably, it was found that at a temperature of 160 ℃, the compatibility was significantly enhanced. The findings were further corroborated through scanning electron microscope and rheological tests. The outcomes of this research offer theoretical guidance for the application of SBR-modified asphalt.
Development of a New Bioequivalent Omeprazole Product
Authors: Kumisbek Gulzina , Vetchý David , Kadyrbay Arshyn
Published: March 2024

Background and Objectives: The enteric form of omeprazole is one of the most commonly prescribed medications. Similarly to Europe, Kazakhstan relies on the localization of pharmaceutical drug production as one of its primary strategies to ensure that its population has access to affordable and good-quality medicines. This study comprehensively describes the technologically available development of bioequivalent delayed-release omeprazole. Materials and Methods: Various regimes and technological parameters were tested on laboratory- and production-scale equipment to establish a technical process where a functional and gastro-protective layer is essential. According to the ICH guidance on stability testing and Kazakhstan local rules, stability studies were conducted under conditions appropriate for climate zone II. The comparison of the rate and extent of absorption with subsequent assessment of the bioequivalence of the generic and reference drugs after a single dose of each drug at a dose of 40 mg was performed. Results: The quantitative and qualitative composition and technology of producing a new generic enteric form of omeprazole in capsules were developed and implemented at the manufacturing site of solid forms. Dissolution profiles in media with pH 1.2 and 6.8 were proven. During the accelerated six-month and long-term twelve-month studies, the developed formulation in both packaging materials at each control point passed the average weight and mass uniformity test, dissolution test, acid-resistance stage test, buffer stage test, impurity assay, and microbiological purity test and met all the specification criteria. A bioequivalence study in 24 healthy volunteers compared against the innovative drug showed the bioequivalency of the new generic system. The obtained values from the test and reference products were 1321 ± 249.0 ng/mL and 1274 ± 233 ng/mL for Cmax, 4521 ± 841 ng·h /mL and 4371 ± 695 ng·h /mL for AUC0-t, and 4636 ± 814 ng·h /mL and 4502 ± 640 ng·h /mL for AUC0-∞. Conclusions: Using affordable technologies, a bioequivalent generic delayed-release formulation of 20 and 40 mg omeprazole has been developed.
Reduced Corticosteroid Exposure Is Safe and Does Not Reduce Disease Control among Hodgkin Lymphoma Patients Treated with Escalated BEACOPP (eBEACOPP)
Authors: Hude Dragičević Ida , Bašić-Kinda Sandra , Markotić Helena , Morić-Perić Martina , Dujmović Dino , Radman Ivo , Dreta Barbara , Dotlić Snježana , Ilić Ivana , Galunić Bilić Lea , Dobrenić Margareta , Kralik Marko , Aurer Igor
Published: March 2024

Background and Objectives: eBEACOPP is the most effective chemotherapy regimen for younger patients with early unfavorable (EU) and advanced-stage (AS) Hodgkin lymphoma (HL), albeit with significant toxicities. The 14-day/cycle prednisone course contributes to side effects, including osteoarticular events like avascular bone necrosis (AVN). Our center has been using eBEACOPP since 2009 for AS and 2014 for EU patients. In 2016, we reduced prednisone treatment to 7–10 days to lessen AVN risk. We analyzed the effects of this approach. Materials and Methods: We retrospectively collected data on patients who received at least two cycles of eBEACOPP for first-line HL treatment. Results: A total of 162 patients (33 EU, 129 AS) were included. Their median age was 31 (range 19–59 years), and 88 were males. A total of 94 patients received full corticosteroid courses, and 68 received reduced corticosteroid courses. The overall response rate (ORR) was 98%. Different corticosteroid dosings had no significant effect on ORR, febrile neutropenia episodes, or hospital admissions. After a median follow-up (mFU) of 58 months, the 5yPFS for the entire cohort was 98% vs. 95% for the standard course vs. the short corticosteroids course, respectively (p = 0.37), while the 5yOS was 98% vs. 99% for the standard course vs. short corticosteroids course, respectively (p = 0.87). In AS patients intended to be treated with six eBEACOPP cycles, 5yPFS and 5yOS were 100% vs. 97% and 100% vs. 99% for standard vs. short corticosteroid courses, respectively (p = 0.56 and p = 0.17). In EU patients, 5yPFS was 97% (standard) vs. 95% (short) (p = 0.98) and 5yOS 100% vs. 93.3% (p = 0.87). Osteoarticular events were numerically lower in patients receiving the shorter prednisone course, both in the whole cohort and in the subgroup of patients treated with six cycles of eBEACOPP, but this difference failed to reach statistical significance. Conclusions: eBEACOPP provides excellent and durable first-line disease control. Shortening the corticosteroid course does not compromise efficacy, potentially reducing toxicity. However, longer follow-ups and larger studies are needed for confirmation.
Effect of Particle Size on the Biomethanation Kinetics of Mechanically Pretreated Sargassum spp. Biomass
Authors: Paletta Rosy , Girimonte Rossella , Castro Yessica A. , De Frias Jose Atilio , Calabrò Vincenza
Published: March 2024

The collection and use of Sargassum spp. as feedstock for the production of valuable products such as biomethane by anaerobic digestion (AD) would mitigate the negative impact of the blooms and the costs related to waste management in the Dominican Republic. In this work, the effect of the particle size of pelagic Sargassum spp. biomass, as a result of mechanical pretreatments, on the biomethanation was determined. The granulometric analysis of the mechanically pre-treated biomass was carried out using a Mastersize2000. The Biochemical Methane Potential (BMP) of the samples was determined using an Automatic Potential System Test II (AMPTS® II). The kinetic parameters of the reaction were scientifically evaluated by using First order kinetic Model and modified Gompertz Model. The granulometric analysis showed a monomodal distribution on crushed biomass (505 µm) and a bimodal distribution on the milling sample (107 µm). The bimodal biomass means the biomass is characterized by the presence of fine and large particles. We observed that BMP increased by 78.85% when particles were reduced from 50,000 µm to 505 µm and by 73.61% when particles were reduced from 50,000 µm to 107 µm. A low methane yield from the milling biomass (107 µm) compared to the crushed biomass (505 µm) could be related to the excessive reduction of particle size. The fine particles are subject to the formation of aggregates and consequently, the contact area between the algae cells and the microorganisms that operate the anaerobic digestion process decreases.
Two-Phase Fermentation Systems for Microbial Production of Plant-Derived Terpenes
Authors: Li Tuo , Liu Ximeng , Xiang Haoyu , Zhu Hehua , Lu Xuan , Feng Baomin
Published: March 2024

Microbial cell factories, renowned for their economic and environmental benefits, have emerged as a key trend in academic and industrial areas, particularly in the fermentation of natural compounds. Among these, plant-derived terpenes stand out as a significant class of bioactive natural products. The large-scale production of such terpenes, exemplified by artemisinic acid—a crucial precursor to artemisinin—is now feasible through microbial cell factories. In the fermentation of terpenes, two-phase fermentation technology has been widely applied due to its unique advantages. It facilitates in situ product extraction or adsorption, effectively mitigating the detrimental impact of product accumulation on microbial cells, thereby significantly bolstering the efficiency of microbial production of plant-derived terpenes. This paper reviews the latest developments in two-phase fermentation system applications, focusing on microbial fermentation of plant-derived terpenes. It also discusses the mechanisms influencing microbial biosynthesis of terpenes. Moreover, we introduce some new two-phase fermentation techniques, currently unexplored in terpene fermentation, with the aim of providing more thoughts and explorations on the future applications of two-phase fermentation technology. Lastly, we discuss several challenges in the industrial application of two-phase fermentation systems, especially in downstream processing.
Research Progress on the Degradation of Organic Pollutants in Water by Activated Persulfate Using Biochar-Loaded Nano Zero-Valent Iron
Authors: Lu Hai , Wang Xiaoyan , Cong Qiao , Chen Xinglin , Li Qingpo , Li Xueqi , Zhong Shuang , Deng Huan , Yan Bojiao
Published: March 2024

Biochar (BC) is a new type of carbon material with a high specific surface area, porous structure, and good adsorption capacity, which can effectively adsorb and enrich organic pollutants. Meanwhile, nano zero-valent iron (nZVI) has excellent catalytic activity and can rapidly degrade organic pollutants through reduction and oxidation reactions. The combined utilization of BC and nZVI can not only give full play to their advantages in the adsorption and catalytic degradation of organic pollutants, but also help to reduce the agglomeration of nZVI, thus improving its efficiency in water treatment and providing strong technical support for water resources protection and environmental quality improvement. This article provides a detailed introduction to the preparation method and characterization technology, reaction mechanism, influencing factors, and specific applications of BC and nZVI, and elaborates on the research progress of BC-nZVI in activating persulfate (PS) to degrade organic pollutants in water. It has been proven experimentally that BC-nZVI can effectively remove phenols, dyes, pesticides, and other organic pollutants. Meanwhile, in response to the existing problems in current research, this article proposes future research directions and challenges, and summarizes the application prospects and development trends of BC-nZVI in water treatment. In summary, BC-nZVI-activated PS is an efficient technology for degrading organic pollutants in water, providing an effective solution for protecting water resources and improving environmental quality, and has significant application value.
Potential Anti-Inflammatory Constituents from Aesculus wilsonii Seeds
Authors: Zhang Ping , Yu Lequan , Cao Huina , Ruan Jingya , Li Fei , Wu Lijie , Zhang Yi , Wang Tao
Published: March 2024

A chemical study of Aesculus wilsonii Rehd. (also called Suo Luo Zi) and the in vitro anti-inflammatory effects of the obtained compounds was conducted. Retrieving results through SciFinder showed that there were four unreported compounds, aeswilosides I–IV (1–4), along with fourteen known isolates (5–18). Their structures were elucidated by extensive spectroscopic methods such as UV, IR, NMR, [α]D, and MS spectra, as well as acid hydrolysis. Among the known ones, compounds 5, 6, 8–10, and 12–16 were obtained from the Aesculus genus for the first time; compounds 7, 11, 17, and 18 were first identified from this plant. The NMR data of 5 and 18 were reported first. The effects of 1–18 on the release of nitric oxide (NO) from lipopolysaccharide (LPS)-induced RAW264.7 cells were determined. The results showed that at concentrations of 10, 25, and 50 μM, the novel compounds, aeswilosides I (1) and IV (4), along with the known ones, 1-(2-methylbutyryl)phloroglucinyl-glucopyranoside (10) and pisuminic acid (15), displayed significant inhibitory effects on NO production in a concentration-dependent manner. It is worth mentioning that compound 10 showed the best NO inhibitory effect with a relative NO production of 88.1%, which was close to that of the positive drug dexamethasone. The Elisa experiment suggested that compounds 1, 4, 10, and 15 suppressed the release of TNF-α and IL-1β as well. In conclusion, this study enriches the spectra of compounds with potential anti-inflammatory effects in A. wilsonii and provides new references for the discovery of anti-inflammatory lead compounds, but further mechanistic research is still needed.
Antibacterial and Anticandidal Activity of the Nanostructural Composite of a Spirothiazolidine-Derivative Assembled on Silver Nanoparticles
Authors: Alshammari Odeh A. O. , Azzam Eid. M. S. , Alhar Munirah S. , Alanazi Kaseb D. , Aljuhani Sara A. A. , Elsofany Walaa I.
Published: March 2024

Our aims in this work are the preparation of an ionic liquid based on heterocyclic compounds with Ag nanoparticles and the investigation of its application as an antibacterial and anticandidal agent. These goals were achieved through the fabrication of an ionic liquid based on Ag nanoparticles with 5-Amino-3-(4-fluorophenyl)-N-hexadecyl-7-(4-methylphenyl)-2-H spiro[cyclohexane1,2’-[1,3]thiazolo [4,5-b]pyridine]-6-carbonitrile (P16). The nanostructure of the prepared ionic liquid was characterized using techniques such as FTIR, 1HNMR, 13CNMR, UV, SEM, and TEM. The biological activity of the prepared compound (P16) and its nanocomposites with Ag nanoparticles was tested using five clinical bacteria (Pseudomonas aeruginosa 249; Escherichia coli 141; Enterobacter cloacae 235; Staphylococcus epidermidis BC 161, and methicillin-resistant S. aureus 217), and three Candida species (Candida utilis ATCC 9255; C. tropicalis ATCC 1362, and C. albicans ATCC 20402). The FTIR, 1HNMR, and 13CNMR results confirmed the chemical structure of the synthesized P16 compound. The nanostructure of the prepared ionic liquid was determined based on data obtained from the UV, SEM, and TEM tests. The antibacterial and anticandidal results showed that the biological activity of the compound (P16) was enhanced after the formation of nanocomposite structures with Ag nanoparticles. Moreover, the biological activity of the compound itself (P16) and that of its nanocomposite structure with Ag nanoparticles was higher than that of ampicillin and amphotericin B, which were used as control drugs in this work.
SAR, Molecular Docking and Molecular Dynamic Simulation of Natural Inhibitors against SARS-CoV-2 Mpro Spike Protein
Authors: Salamat Aqsa , Kosar Naveen , Mohyuddin Ayesha , Imran Muhammad , Zahid Muhammad Nauman , Mahmood Tariq
Published: March 2024

The SARS-CoV-2 virus and its mutations have affected human health globally and created significant danger for the health of people all around the world. To cure this virus, the human Angiotensin Converting Enzyme-2 (ACE2) receptor, the SARS-CoV-2 main protease (Mpro), and spike proteins were found to be likely candidates for the synthesis of novel therapeutic drug. In the past, proteins were capable of engaging in interaction with a wide variety of ligands, including both manmade and plant-derived small molecules. Pyrus communis L., Ginko bibola, Carica papaya, Syrian rue, and Pimenta dioica were some of the plant species that were studied for their tendency to interact with SARS-CoV-2 main protease (Mpro) in this research project (6LU7). This scenario investigates the geometry, electronic, and thermodynamic properties computationally. Assessing the intermolecular forces of phytochemicals with the targets of the SARS-CoV-2 Mpro spike protein (SP) resulted in the recognition of a compound, kaempferol, as the most potent binding ligand, −7.7 kcal mol−1. Kaempferol interacted with ASP-187, CYS-145, SER-144, LEU 141, MET-165, and GLU-166 residues. Through additional molecular dynamic simulations, the stability of ligand–protein interactions was assessed for 100 ns. GLU-166 remained intact with 33% contact strength with phenolic OH group. We noted a change in torsional conformation, and the molecular dynamics simulation showed a potential variation in the range from 3.36 to 7.44 against a 45–50-degree angle rotation. SAR, pharmacokinetics, and drug-likeness characteristic investigations showed that kaempferol may be the suitable candidate to serve as a model for designing and developing new anti-COVID-19 medicines.
Expansion of Electron Transport Chain Mutants That Cause Anesthetic-Induced Toxicity in Drosophila melanogaster
Authors: Borchardt Luke A. , Olufs Zachariah P. G. , Morgan Philip G. , Wassarman David A. , Perouansky Misha
Published: March 2024

The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places individuals with mETC mutations at risk for anesthetic complications, as exemplified by patients with Leigh syndrome (LS). The Drosophila melanogaster homozygous mutant for ND-23, which encodes a subunit of mETC Complex I, replicates numerous characteristics of LS, including neurodegeneration, shortened lifespan, behavioral anesthetic hypersensitivity, and toxicity. The anesthetic phenotype of toxicity (lethality) is also observed in flies homozygous for mutations in other Complex I subunits. By contrast, mutations conferring sensitivity have not yet been identified for subunits of Complexes II–V. Furthermore, anesthetic phenotypes are thought to be recessive; that is, risk is not conferred by heterozygous mutations. However, at older ages, exposure of heterozygous mutant ND-23 flies to the VGA isoflurane in 75% oxygen (hyperoxia) results in toxicity. It is also unknown whether combinations of heterozygous mutations in different subunits of the mETC can result in anesthetic toxicity. Here, we show that, following exposure to isoflurane in hyperoxia, flies carrying heterozygous mutations in two Complex I subunits, ND-23 and ND-SGDH (NADH dehydrogenase (ubiquinone) SGDH subunit), had a level of anesthetic toxicity that exceeded the added toxicities of the individual heterozygous mutations. In addition, we show that flies heterozygous for two different alleles of the Complex II gene SdhB were susceptible to isoflurane/hyperoxia-induced anesthetic toxicity. Finally, a mutation in the SdhC subunit of Complex II of Caenorhabditis elegans resulted in isoflurane-induced mortality, supporting the role of Complex II in anesthetic toxicity. These data expand the landscape of mutations in the mETC that increase sensitivity to anesthetic toxicity.
Exploring the Distribution and Impact of Bosonic Dark Matter in Neutron Stars
Authors: Rafiei Karkevandi Davood , Shahrbaf Mahboubeh , Shakeri Soroush , Typel Stefan
Published: March 2024

The presence of dark matter (DM) within neutron stars (NSs) can be introduced by different accumulation scenarios in which DM and baryonic matter (BM) may interact only through the gravitational force. In this work, we consider asymmetric self-interacting bosonic DM, which can reside as a dense core inside the NS or form an extended halo around it. It is seen that depending on the boson mass (mχ), self-coupling constant (λ) and DM fraction (Fχ), the maximum mass, radius and tidal deformability of NSs with DM admixture will be altered significantly. The impact of DM causes some modifications in the observable features induced solely by the BM component. Here, we focus on the widely used nuclear matter equation of state (EoS) called DD2 for describing NS matter. We show that by involving DM in NSs, the corresponding observational parameters will be changed to be consistent with the latest multi-messenger observations of NSs. It is seen that for mχ≳200 MeV and λ≲2π, DM-admixed NSs with 4%≲Fχ≲20% are consistent with the maximum mass and tidal deformability constraints.