bluuebunny/crossref_metadata_2025 huggingface dataset:
Stochastic Optimization of the Management Schedule of Korean Pine Plantations
Authors: Tong Qianping , Jin Xingji , Pukkala Timo , Dong Lihu , Li Fengri
Published: May 2024

Korean pine is one of the most important tree species in northeastern China, where Korean pine plantations produce timber and edible seeds. Often, seeds create more income than timber. Predicting the timber and cone yields of alternative management schedules of the plantations involves uncertainty because the future climatic conditions for tree growth and cone production are unknown. This study developed a simulation model that generates stochastic variation around the predictions of tree growth and cone yield models, allowing the forest manager to seek cutting schedules that maximize the expected amounts of timber or cones, or the expected economic profit, under uncertain future states of nature. Stochastic analysis also facilitates management optimizations for different risk attitudes. The differential evolution algorithm and the developed stochastic simulation model were used to optimize the management of planted Korean pine. Timber and cone yields of a management schedule were calculated under 100 different scenarios for tree growth and cone production. When the growth and cone yield scenarios were stationary (no temporal trends), the optimal management schedules were similar to those of deterministic optimization. The benefits of stochastic optimization increased when it was assumed that the tree growth scenarios may contain climate-change-induced trends. Non-stationary growth variation led to shorter optimal rotation lengths than stationary growth variation. Increasing risk tolerance shortened optimal rotations.
A Review of Leaf-Level Flammability Traits in Eucalypt Trees
Authors: Younes Nicolas , Yebra Marta , Boer Matthias M. , Griebel Anne , Nolan Rachael H.
Published: May 2024

With more frequent and intense fires expected under future climate conditions, it is important to understand the mechanisms that control flammability in Australian forests. We followed a systematic review approach to determine which physical traits make eucalypts leaves more or less flammable. Specifically, we reviewed 20 studies that covered 35 eucalypt species across five countries and found that leaf water content, leaf area (LA), and specific leaf area (SLA) are the main drivers of leaf flammability. These traits are easy and straightforward to measure, while more laborious traits (e.g., volatile organic compounds and structural carbohydrates) are seldom measured and reported. Leaf flammability also varies with species, and, while the biochemistry plays a role in how leaves burn, it plays a minor role in fire behaviour at landscape scales. This review highlights the range of different protocols used to measure flammability and leaf water content, warranting caution when comparing traits and results between studies. As a result, we propose a standardised protocol to measure leaf water content and advocate for long-term measurements of leaf traits and flammability. This study not only contributes to the understanding of how and why eucalypt leaves burn but also encourages research into the relative importance of traits in influencing flammability and provides a guide for selecting traits that can be monitored using satellite images to inform fire management policies and strategies.
Analyzing a Dynamical System with Harmonic Mean Incidence Rate Using Volterra–Lyapunov Matrices and Fractal-Fractional Operators
Authors: Riaz Muhammad , Alqarni Faez A. , Aldwoah Khaled , Birkea Fathea M. Osman , Hleili Manel
Published: May 2024

This paper investigates the dynamics of the SIR infectious disease model, with a specific emphasis on utilizing a harmonic mean-type incidence rate. It thoroughly analyzes the model’s equilibrium points, computes the basic reproductive rate, and evaluates the stability of the model at disease-free and endemic equilibrium states, both locally and globally. Additionally, sensitivity analysis is carried out. A sophisticated stability theory, primarily focusing on the characteristics of the Volterra–Lyapunov (V-L) matrices, is developed to examine the overall trajectory of the model globally. In addition to that, we describe the transmission of infectious disease through a mathematical model using fractal-fractional differential operators. We prove the existence and uniqueness of solutions in the SIR model framework with a harmonic mean-type incidence rate by using the Banach contraction approach. Functional analysis is used together with the Ulam–Hyers (UH) stability approach to perform stability analysis. We simulate the numerical results by using a computational scheme with the help of MATLAB. This study advances our knowledge of the dynamics of epidemic dissemination and facilitates the development of disease prevention and mitigation tactics.
A Narrative Review of Pharmacotherapy of Glaucoma
Authors: Virani Shalini , Rewri Parveen
Published: May 2024

Progressive loss of retinal ganglionic cells (RGC) causes degeneration of optic nerve axons, which leads to blindness in glaucoma. Elevated intraocular pressure (IOP) is the most important, treatable risk factor. Currently, the management of glaucoma is centred on reducing the IOP, and drugs in the form of topical drops are the first line of management. Drugs reduce IOP either by suppressing aqueous humour secretion or improving the aqueous humour outflow. Newer drugs added during the past three decades to the armamentarium of glaucoma treatment have targeted the aqueous outflow. With an evolving understanding of the pathogenesis of glaucoma, the role of 24-h IOP control and other IOP-independent risk factors affecting ocular blood flow and RGC toxicity is also being actively studied in clinical and pre-clinical models of glaucoma. The role of available drugs in controlling IOP over 24 h is being evaluated. Improvement of ocular blood flow and neuroprotection are seen as potential drug targets for preventing the loss of RGC. In this article, we review the pharmacotherapy of glaucoma based on current therapeutic principles.
Progress of Research into Preformed Particle Gels for Profile Control and Water Shutoff Techniques
Authors: Ma Wei , Li Yikun , Liu Pingde , Liu Zhichang , Song Tao
Published: May 2024

Gel treatment is an economical and efficient method of controlling excessive water production. The gelation of in situ gels is prone to being affected by the dilution of formation water, chromatographic during the transportation process, and thus controlling the gelation time and penetration depth is a challenging task. Therefore, a novel gel system termed preformed particle gels (PPGs) has been developed to overcome the drawbacks of in situ gels. PPGs are superabsorbent polymer gels which can swell but not dissolve in brines. Typically, PPGs are a granular gels formed based on the crosslinking of polyacrylamide, characterized by controllable particle size and strength. This work summarizes the application scenarios of PPGs and elucidates their plugging mechanisms. Additionally, several newly developed PPG systems such as high-temperature-resistant PPGs, re-crosslinkable PPGs, and delayed-swelling PPGs are also covered. This research indicates that PPGs can selectively block the formation of fractures or high-permeability channels. The performance of the novel modified PPGs was superior to in situ gels in harsh environments. Lastly, we outlined recommended improvements for the novel PPGs and suggested future research directions.
Transcriptomic Analysis of Newborn Hanwoo Calves: Effects of Maternal Overnutrition during Mid- to Late Pregnancy on Subcutaneous Adipose Tissue and Liver
Authors: Shokrollahi Borhan , Lee Hyun-Jeong , Baek Youl Chang , Jin Shil , Jang Gi-Suk , Moon Sung Jin , Um Kyung-Hwan , Jang Sun Sik , Park Myung Sun
Published: May 2024

This study investigated the transcriptomic responses of subcutaneous adipose tissue (SAT) and liver in newborn Hanwoo calves subjected to maternal overnutrition during mid- to late gestation. Eight Hanwoo cows were randomly assigned to control and treatment groups. The treatment group received a diet of 4.5 kg of concentrate and 6.5 kg of rice straw daily, resulting in intake levels of 8.42 kg DMI, 5.69 kg TDN, and 0.93 kg CP—higher than the control group (6.07 kg DMI, 4.07 kg TDN, and 0.65 kg CP), with respective NEm values of 9.56 Mcal and 6.68 Mcal. Following birth, newly born calves were euthanized humanely as per ethical guidelines, and SAT and liver samples from newborn calves were collected for RNA extraction and analysis. RNA sequencing identified 192 genes that were differentially expressed in the SAT (17 downregulated and 175 upregulated); notably, HSPA6 emerged as the most significantly upregulated gene in the SAT and as the singular upregulated gene in the liver (adj-p value < 0.05). Additionally, differential gene expression analysis highlighted extensive changes across genes associated with adipogenesis, fibrogenesis, and stress response. The functional enrichment pathway and protein–protein interaction (PPI) unraveled the intricate networks and biological processes impacted by overnutrition, including extracellular matrix organization, cell surface receptor signaling, and the PI3K-Akt signaling pathway. These findings underscore maternal overnutrition’s substantial influence on developmental pathways, suggesting profound cellular modifications with potential lasting effects on health and productivity. Despite the robust insights that are provided, the study’s limitations (sample size) underscore the necessity for further research.
Inherited Retinal Diseases and Retinal Organoids as Preclinical Cell Models for Inherited Retinal Disease Research
Authors: Ashworth Kristen E. , Weisbrod Jessica , Ballios Brian G.
Published: May 2024

Inherited retinal diseases (IRDs) are a large group of genetically and clinically diverse blinding eye conditions that result in progressive and irreversible photoreceptor degeneration and vision loss. To date, no cures have been found, although strides toward treatments for specific IRDs have been made in recent years. To accelerate treatment discovery, retinal organoids provide an ideal human IRD model. This review aims to give background on the development and importance of retinal organoids for the human-based in vitro study of the retina and human retinogenesis and retinal pathologies. From there, we explore retinal pathologies in the context of IRDs and the current landscape of IRD treatment discovery. We discuss the usefulness of retinal organoids in this context (as a patient-derived cell model for IRDs) to precisely understand the pathogenesis and potential mechanisms behind a specific IRD-causing variant of interest. Finally, we discuss the importance and promise of retinal organoids in treatment discovery for IRDs, now and in the future.
Investigating Students’ Perception with an Online Dynamic Earth Course during COVID-19: A Quantitative Inquiry
Authors: Alam Md Iftekhar , Su Jian , Yang Hongwei , Benner Jacob
Published: May 2024

This study investigated Earth science students’ experiences with online education during the COVID-19 pandemic at the University of Tennessee, Knoxville, in the US. We used an existing survey from the online education literature, the Online Learning Environment Survey (OLES), which consists of three instruments: (a) community of inquiry (CoI), (b) Institutional Support (IS), and (c) Self-Directed Online Learning Scale (SDOLS). The survey rating subscales ordered from highest to lowest are autonomous learning, asynchronous online learning, institutional support, teaching presence, social presence, and cognitive presence, respectively, indicating interest for the online learning environment. Among all of the subscales, the asynchronous online category was rated the highest by the students. The data were then analyzed using Rasch modeling. According to the Rasch analyses, asynchronous online teaching represents the most favorable course delivery technique for geoscience education. Overall, the survey data show a general interest in online delivery and the effectiveness of the modality, thus indicating potential for evolving into an online Earth science program. Finally, also discussed are possible future extensions of the research (e.g., extending the research to other introductory online geoscience courses).
Out-Patient versus In-Patient Arteriovenous Fistula Creation for Dialysis: Assessing Cost-Effectiveness Alongside Clinical Implications
Authors: Russu Eliza , Munteanu Andreea-Cătălina , Arbănași Emil-Marian , Szanto Ludovic-Alexandru , Bartus Reka , Florea Elena , Bandici Bogdan Corneliu , Arbănași Eliza-Mihaela , Ion Alexandru Petru , Cordoș Bogdan Andrei , Serac Gabriel , Ujlaki-Nagi Alexandru-Andrei , Ciucanu Claudiu Constantin , Mureșan Adrian Vasile
Published: May 2024

(1) Background: The surgical procedure to create an arteriovenous fistula (AVF) can be performed in either an ambulatory or in-patient hospital setting, depending on the case’s complexity, the anesthesia type used, and the patient’s comorbidities. The main scope of this study is to assess the cost-effectiveness and clinical implications of surgically creating an AVF in both ambulatory and in-hospital settings. (2) Methods: We conducted a retrospective observational study, in which we initially enrolled all patients with end-stage kidney disease (ESKD) admitted to the Vascular Surgery Department, Emergency County Hospital of Targu Mures, Romania, to surgically create an AVF for dialysis, between January 2020 and December 2022. The primary endpoint of this study is to assess the cost-effectiveness of surgically creating an AVF in an ambulatory vs. in-hospital setting by comparing the costs required for the two types of admissions. Further, the 116 patients enrolled in this study were divided into two groups based on their preference for hospitalization: out-patients and in-patients. (3) Results: Regarding in-patient comorbidities, there was a higher prevalence of peripheral artery disease (PAD) (p = 0.006), malignancy (p = 0.020), and previous myocardial infarction (p = 0.012). In addition, active smoking (p = 0.006) and obesity (p = 0.018) were more frequent among these patients. Regarding the laboratory data, the in-patients had lower levels of white blood cells (WBC) (p = 0.004), neutrophils count (p = 0.025), lymphocytes (p = 0.034), and monocytes (p = 0.032), but there were no differences between the two groups regarding the systemic inflammatory biomarkers or the AVF type. Additionally, we did not register any difference regarding the outcomes: local complications (p = 0.588), maturation failure (p = 0.267), and primary patency (p = 0.834). In our subsequent analysis, we discovered no significant difference between the hospitalization type chosen by patients regarding AVF primary patency failure (p = 0.195). We found no significant association between the hospitalization type and the recorded outcomes (all ps > 0.05) in both multivariate linear regression and Cox proportional hazard analysis. (4) Conclusions: In conclusion, there are no significant differences in the clinical implications, short-term and long-term complications of AVF for out-patient and in-patient admissions. Additionally, we found no variation in the costs associated with laboratory tests and surgical supplies for an AVF creation. Therefore, it is safe to perform ambulatory AVFs, which can reduce the risk of hospital-acquired infections and provide greater comfort to the patient.
Enhancing the Nutritional Profile of Crataegus monogyna Fruits by Optimizing the Extraction Conditions
Authors: Kotsou Konstantina , Magopoulou Dimitra , Chatzimitakos Theodoros , Athanasiadis Vassilis , Bozinou Eleni , Sfougaris Athanassios , Lalas Stavros
Published: May 2024

Crataegus monogyna (CM) fruits are highly regarded for their rich nutritional content, boasting elevated levels of various beneficial secondary metabolites like total polyphenols, including anthocyanins, and ample amounts of ascorbic acid and antioxidant activity. Despite the acknowledged benefits of CM fruits, researchers have directed more attention toward its leaves and flowers. Consequently, the current research attempts to optimize extraction techniques for CM fruit using a multifaceted approach involving varied durations, temperatures, and concentrations of ethanol solvent to isolate the diverse range of bioactive components present effectively. High-performance liquid chromatography coupled with a diode array detector (HPLC-DAD) is employed for the identification and quantification of polyphenolic compounds. According to the results, by following the optimum extraction parameters (50% ethanolic solvent, 50 °C extraction temperature, and 60 min extraction time), the total polyphenol content can be increased up to 410%, reaching 55.59 mg gallic acid equivalents/g. Using 50% ethanolic solvent, 80 °C extraction temperature, and extraction time of 90 min, the total anthocyanin content can be enhanced by more than 560%, reaching a quantity of 51.83 μg cyanidin equivalents/g. Moreover, the antioxidant activity of CM fruit extracts can reach 415.95 μmol ascorbic acid equivalents (AAE)/g dw (by FRAP method), using 50% ethanolic solvent, 50 °C extraction temperature, and 60 min extraction time, and 270.26 μmol AAE/g dw (by DPPH method) and 1053.28 mg/100 g dw ascorbic acid content, using 50% ethanolic solvent, 80 °C extraction temperature, and 90 min extraction time. This comprehensive study seeks to augment the already substantial content of bioactive compounds found in CM, resulting in an extract with promising applications across the pharmaceutical, food, and cosmetics industries.
Chemical Variability, Antioxidant and Larvicidal Efficacy of EOs from Citrus sinensis (L.) Osbeck Peel, Leaf, and Flower
Authors: Bhandari Devi Prasad , Chaudhary Pratiksha , Upadhyaya Siddha Raj , Ranjitkar Rajeshwor , Satyal Rakesh , Adhikari Achyut , Satyal Prabodh , Parajuli Niranjan
Published: May 2024

Essential oils (EOs) from Citrus sinensis (Rutaceae) possess diverse biological activities. However, a comprehensive comparison of their chemical composition and bioactivity across different plant parts has not been studied yet. The current research comparatively assesses the yield, chemical composition, chiral distribution, antioxidant properties, and larvicidal activity of EOs extracted from the peels, leaves, and flowers of C. sinensis. EOs extracted via hydro-distillation (HD) and steam distillation (SD) were analyzed by gas chromatography–mass spectrometry (GC-MS) and chiral GC-MS to explore their chemical composition and enantiomeric distribution. In addition, their larvicidal and antioxidant potentials were evaluated following standard protocols. Peels of C. sinensis exhibited significantly higher oil content (1.75–2.25%) compared to its leaves (0.75–0.78%) and flowers (0.20–0.25%). The GC-MS analysis identified around 60 compounds, including terpenoids, sesquiterpenoids, and oxygenated terpenoids in the HD and SD extractions. Higher concentrations of sabinene were found in flower extract (38.05–39.89%) and leaf extract (32.30–36.91%), while peel extract contained more than 90% limonene. The larvicidal activity of peel oil was primarily attributed to limonene, with an LC50 value of 0.0031 µL/mL. The current study reports the first chiral (GC-MS) analysis in the essential oil of the leaves and flowers of C. sinensis, paving the way for authenticity and purity. Furthermore, the chemical profiling of citrus EOs, particularly from the peel, demonstrates a safe and promising candidate for diverse biological applications.
Characterization of Mixtures of Rugulopteryx okamurae Compost and Plant Residues to Determine the Most Effective Composition as a Substrate and Source of Nutrients
Authors: Correa-Bustos Amelia , Berti Francesca , Salas-Sanjuán María del Carmen , Segura-Pérez María Luz
Published: May 2024

The increasing invasion of Rugulopteryx okamurae algae along the coast of southeastern Spain has prompted efforts to explore its potential as a resource. Consequently, composting this alga is considered a viable solution for agricultural applications. This study investigates the composting process of mixtures of R. okamurae seaweed with plant residues and characterizes the final compost for its use as a substrate and/or source of nutrients to determine the most effective composition of the mixture. The composting process was conducted using varying proportions of seaweed (100%, 30–35%, and 15%) combined with plant residues (from vegetable plants, fruits, and gardens) and included both washed and unwashed seaweed. The first trials revealed challenges associated with Rugulopteryx okamurae, such as a low C/N ratio and algae washing. Consequently, a second trial was conducted to optimize the mixtures, aiming for a C/N ratio close to 30. Additionally, it was decided not to wash the algae to reduce the electrical conductivity (EC) in the mixtures. The findings indicate that the composting process remains unaffected by high electrical conductivity when algae are unwashed. However, washing the algae before composting did affect the compost quality, as the composts with washed algae with garden waste (SwP 34.0 dS m−1) had a lower electrical conductivity (EC) than did the unwashed composts with garden waste (SP 51.6 dS m−1 and SFP 64.9 dS m−1). On the other hand, the compost-only horticultural and garden waste (FHP 43.7 dS m−1) had a high EC; therefore, the EC was not increased with low proportions of unwashed algae, as was seen with the compost with 15% unwashed algae (SFHP 47.6 dS m−1). The other quality parameters were not affected by the absence of algae washing at the beginning of the composting process.
Models of Governance of Disability Therapy Support Workers in Rural and Remote Settings: A Systematic Scoping Review
Authors: Moran Anna , Bulkeley Kim , Johnsson Genevieve , Tam Elaine , Maloney Catherine
Published: May 2024

The National Disability Insurance Scheme (NDIS) ushered in a transformative era in disability services in Australia, requiring new workforce models to meet evolving participant needs. Therapy Assistants are utilised to increase the capacity of therapy services in areas of workforce shortage. The governance arrangements required to support this emergent workforce have received limited attention in the literature. This review examined the key components and contextual factors of governance in rural settings, specifically focusing on therapy support workers under the guidance of allied health professionals in rural and remote areas. Guided by the social model of disability and the International Classification of Functioning, Disability and Health, a realist perspective was used to analyse 26 papers (after deduplication), mostly Australian and qualitative, with an emphasis on staff capabilities, training, and credentialling. Success measures were often vaguely defined, with most papers focusing on staff improvement and few focusing on client or organisational improvement. Consistent staffing, role clarity, community collaboration, and supportive leadership were identified as enabling contexts for successful governance of disability therapy support workers in rural areas. Investment in capability (soft skills) development, tailored training, competency assessment, credentialling, and supervision were identified as key activities that, when coupled with the identified enabling contexts, were likely to influence staff, client and organisational outcomes. Further research is warranted to explore long-term impacts of governance arrangements, educational program accountability, and activities targeted at enhancing staff capabilities.
High Overexpression of SiAAP9 Leads to Growth Inhibition and Protein Ectopic Localization in Transgenic Arabidopsis
Authors: Meng Ru , Li Zhipeng , Kang Xueting , Zhang Yujia , Wang Yiru , Ma Yuchao , Wu Yanfeng , Dong Shuqi , Li Xiaorui , Gao Lulu , Chu Xiaoqian , Yang Guanghui , Yuan Xiangyang , Wang Jiagang
Published: May 2024

Amino acid permeases (AAPs) transporters are crucial for the long-distance transport of amino acids in plants, from source to sink. While Arabidopsis and rice have been extensively studied, research on foxtail millet is limited. This study identified two transcripts of SiAAP9, both of which were induced by NO3− and showed similar expression patterns. The overexpression of SiAAP9L and SiAAP9S in Arabidopsis inhibited plant growth and seed size, although SiAAP9 was found to transport more amino acids into seeds. Furthermore, SiAAP9-OX transgenic Arabidopsis showed increased tolerance to high concentrations of glutamate (Glu) and histidine (His). The high overexpression level of SiAAP9 suggested its protein was not only located on the plasma membrane but potentially on other organelles, as well. Interestingly, sequence deletion reduced SiAAP9’s sensitivity to Brefeldin A (BFA), and SiAAP9 had ectopic localization on the endoplasmic reticulum (ER). Protoplast amino acid uptake experiments indicated that SiAAP9 enhanced Glu transport into foxtail millet cells. Overall, the two transcripts of SiAAP9 have similar functions, but SiAAP9L shows a higher colocalization with BFA compartments compared to SiAAP9S. Our research identifies a potential candidate gene for enhancing the nutritional quality of foxtail millet through breeding.
Molecular Aspects of Cardiometabolic Diseases: From Etiopathogenesis to Potential Therapeutic Targets
Authors: Bernatova Iveta , Bartekova Monika
Published: May 2024

Cardiometabolic diseases (CMDs) encompass a range of prevalent, often preventable, non-communicable illnesses, including myocardial infarction, stroke, cardiac insufficiency, arterial hypertension, obesity, type 2 diabetes mellitus, insulin resistance, chronic renal dysfunction, non-alcoholic fatty liver disease, and rare metabolic disorders [...]
Therapies for Cirrhotic Cardiomyopathy: Current Perspectives and Future Possibilities
Authors: Liu Hongqun , Ryu Daegon , Hwang Sangyoun , Lee Samuel S.
Published: May 2024

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction associated with cirrhosis in the absence of pre-existing heart disease. CCM manifests as the enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM significantly contributes to mortality and morbidity in patients who undergo liver transplantation and contributes to the pathogenesis of hepatorenal syndrome/acute kidney injury. There is currently no specific treatment. The traditional management for non-cirrhotic cardiomyopathies, such as vasodilators or diuretics, is not applicable because an important feature of cirrhosis is decreased systemic vascular resistance; therefore, vasodilators further worsen the peripheral vasodilatation and hypotension. Long-term diuretic use may cause electrolyte imbalances and potentially renal injury. The heart of the cirrhotic patient is insensitive to cardiac glycosides. Therefore, these types of medications are not useful in patients with CCM. Exploring the therapeutic strategies of CCM is of the utmost importance. The present review summarizes the possible treatment of CCM. We detail the current status of non-selective beta-blockers (NSBBs) in the management of cirrhotic patients and discuss the controversies surrounding NSBBs in clinical practice. Other possible therapeutic agents include drugs with antioxidant, anti-inflammatory, and anti-apoptotic functions; such effects may have potential clinical application. These drugs currently are mainly based on animal studies and include statins, taurine, spermidine, galectin inhibitors, albumin, and direct antioxidants. We conclude with speculations on the future research directions in CCM treatment.
Alpha Carbonic Anhydrase from Nitratiruptor tergarcus Engineered for Increased Activity and Thermostability
Authors: Manyumwa Colleen Varaidzo , Zhang Chenxi , Jers Carsten , Mijakovic Ivan
Published: May 2024

The development of carbon capture and storage technologies has resulted in a rising interest in the use of carbonic anhydrases (CAs) for CO2 fixation at elevated temperatures. In this study, we chose to rationally engineer the α-CA (NtCA) from the thermophilic bacterium Nitratiruptor tergarcus, which has been previously suggested to be thermostable by in silico studies. Using a combination of analyses with the DEEPDDG software and available structural knowledge, we selected residues in three regions, namely, the catalytic pocket, the dimeric interface and the surface, in order to increase thermostability and CO2 hydration activity. A total of 13 specific mutations, affecting seven amino acids, were assessed. Single, double and quadruple mutants were produced in Escherichia coli and analyzed. The best-performing mutations that led to improvements in both activity and stability were D168K, a surface mutation, and R210L, a mutation in the dimeric interface. Apart from these, most mutants showed improved thermostability, with mutants R210K and N88K_R210L showing substantial improvements in activity, up to 11-fold. Molecular dynamics simulations, focusing particularly on residue fluctuations, conformational changes and hydrogen bond analysis, elucidated the structural changes imposed by the mutations. Successful engineering of NtCA provided valuable lessons for further engineering of α-CAs.
Transdermal Delivery of Cannabidiol for the Management of Acute Inflammatory Pain: A Comprehensive Review of the Literature
Authors: Lefebvre Ève , Tawil Nancy , Yahia L’Hocine
Published: May 2024

The emerging field of nanotechnology has paved the way for revolutionary advancements in drug delivery systems, with nanosystems emerging as a promising avenue for enhancing the therapeutic potential and the stability of various bioactive compounds. Among these, cannabidiol (CBD), the non-psychotropic compound of the Cannabis sativa plant, has gained attention for its therapeutic properties. Consequently, researchers have devoted significant efforts to unlock the full potential of CBD’s clinical benefits, where various nanosystems and excipients have emerged to overcome challenges associated with its bioavailability, stability, and controlled release for its transdermal application. Therefore, this comprehensive review aims to explain CBD’s role in managing acute inflammatory pain and offers an overview of the state of the art of existing delivery systems and excipients for CBD. To summarize this review, a summary of the cannabinoids and therapeutical targets of CBD will be discussed, followed by its conventional modes of administration. The transdermal route of administration and the current topical and transdermal delivery systems will also be reviewed. This review will conclude with an overview of in vivo techniques that allow the evaluation of the anti-inflammatory and analgesic potentials of these systems.
Bioinformatic Analysis of Roquin Family Reveals Their Potential Role in Immune System
Authors: Li Xianpeng , Yang Shuaiqi , Zhang Xiangmin , Zhang Yi , Zhang Yu , Li Hongyan
Published: May 2024

The Roquin family is a recognized RNA-binding protein family that plays vital roles in regulating the expression of pro-inflammatory target gene mRNA during the immune process in mammals. However, the evolutionary status of the Roquin family across metazoans remains elusive, and limited studies are found in fish species. In this study, we discovered that the RC3H genes underwent a single round of gene duplication from a primitive ancestor during evolution from invertebrates to vertebrates. Furthermore, there were instances of species-specific gene loss events or teleost lineage-specific gene duplications throughout evolution. Domain/motif organization and selective pressure analysis revealed that Roquins exhibit high homology both within members of the family within the same species and across species. The three rc3h genes in zebrafish displayed similar expression patterns in early embryos and adult tissues, with rc3h1b showing the most prominent expression among them. Additionally, the promoter regions of the zebrafish rc3h genes contained numerous transcription factor binding sites similar to those of mammalian homologs. Moreover, the interaction protein network of Roquin and the potential binding motif in the 3’-UTR of putative target genes analysis both indicated that Roquins have the potential to degrade target mRNA through mechanisms similar to those of mammalian homologs. These findings shed light on the evolutionary history of Roquin among metazoans and hypothesized their role in the immune systems of zebrafish.
The Impact of Antenatal Corticosteroids on the Metabolome of Preterm Newborns: An Untargeted Approach
Authors: Valerio Enrico , Meneghelli Marta , Stocchero Matteo , Galderisi Alfonso , Visentin Silvia , Bonadies Luca , Pirillo Paola , Poloniato Gabriele , Giordano Giuseppe , Baraldi Eugenio
Published: May 2024

We analyzed and compared variations in the urinary metabolome, as well as postnatal clinical outcomes among preterm infants, based on the timing of antenatal corticosteroid (ACS) administration in response to preterm labor onset in their mothers. This was a prospective observational study held in the Neonatal Intensive Care Unit, Department of Woman’s and Child’s Health, Padova University Hospital (Italy). A urine sample was obtained from each patient within 24 h of birth; Mass Spectrometry-based untargeted metabolomics analysis was then conducted. We searched for any significant disparities in the metabolomic profile of preterm newborns subjected to antenatal corticosteroid (ACS) treatment at varying timings; their correlation with clinical outcomes were also evaluated. The group receiving ACS within the optimal time window (1–7 days before delivery) exhibited elevated levels of cysteine, N-acetylglutamine, propionyl carnitine and 5-hydroxyindolacetic acid, coupled with a decrease in pipecolic acid. Clinically, this group demonstrated a reduced need for invasive ventilation (p = 0.04). In conclusion, metabolomics analysis identified several metabolites that discriminated preterm infants whose mothers received ACS within the recommended time window. Elevated levels of cysteine and 5-Hydroxyindoleacetic acid, metabolites characterized by antioxidant and anti-inflammatory properties, were observed in these infants. This metabolic profile correlated with improved respiratory outcomes, as evidenced by a reduced necessity for invasive ventilation at birth.
Melanin for Photoprotection and Hair Coloration in the Emerging Era of Nanocosmetics
Authors: Menichetti Arianna , Mordini Dario , Vicenzi Silvia , Montalti Marco
Published: May 2024

Nanotechnology is revolutionizing fields of high social and economic impact. such as human health preservation, energy conversion and storage, environmental decontamination, and art restoration. However, the possible global-scale application of nanomaterials is raising increasing concerns, mostly related to the possible toxicity of materials at the nanoscale. The possibility of using nanomaterials in cosmetics, and hence in products aimed to be applied directly to the human body, even just externally, is strongly debated. Preoccupation arises especially from the consideration that nanomaterials are mostly of synthetic origin, and hence are often seen as “artificial” and their effects as unpredictable. Melanin, in this framework, is a unique material since in nature it plays important roles that specific cosmetics are aimed to cover, such as photoprotection and hair and skin coloration. Moreover, melanin is mostly present in nature in the form of nanoparticles, as is clearly observable in the ink of some animals, like cuttlefish. Moreover, artificial melanin nanoparticles share the same high biocompatibility of the natural ones and the same unique chemical and photochemical properties. Melanin is hence a natural nanocosmetic agent, but its actual application in cosmetics is still under development, also because of regulatory issues. Here, we critically discuss the most recent examples of the application of natural and biomimetic melanin to cosmetics and highlight the requirements and future steps that would improve melanin-based cosmetics in the view of future applications in the everyday market.
Free Fatty Acid 4 Receptor Activation Attenuates Collagen-Induced Arthritis by Rebalancing Th1/Th17 and Treg Cells
Authors: Lee Jung-Eun , Lee Ju-Hyun , Koh Jung-Min , Im Dong-Soon
Published: May 2024

Dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) has been found to be beneficial in rodent rheumatoid arthritis models and human trials. However, the molecular targets of n-3 PUFAs and their beneficial effects on rheumatoid arthritis are under-researched. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor for n-3 PUFA. We aim to investigate whether FFA4 activation reduces collagen-induced rheumatoid arthritis (CIA) by using an FFA4 agonist, compound A (CpdA), in combination with DBA-1J Ffa4 gene wild-type (WT) and Ffa4 gene knock-out (KO) mice. CIA induced an increase in the arthritis score, foot edema, synovial hyperplasia, pannus formation, proteoglycan loss, cartilage damage, and bone erosion, whereas the administration of CpdA significantly suppressed those increases in Ffa4 WT mice but not Ffa4 gene KO mice. CIA increased mRNA expression levels of pro-inflammatory Th1/Th17 cytokines, whereas CpdA significantly suppressed those increases in Ffa4 WT mice but not Ffa4 gene KO mice. CIA induced an imbalance between Th1/Th17 and Treg cells, whereas CpdA rebalanced them in spleens from Ffa4 WT mice but not Ffa4 gene KO mice. In SW982 synovial cells, CpdA reduced the LPS-induced increase in pro-inflammatory cytokine levels. In summary, the present results suggest that the activation of FFA4 in immune and synovial cells could suppress the characteristics of rheumatoid arthritis and be an adjuvant therapy.
Resolution of RHCE Haplotype Ambiguities in Transfusion Settings
Authors: Izard Caroline , Laget Laurine , Beley Sophie , Bichel Nelly , De Boisgrollier Lugdivine , Picard Christophe , Chiaroni Jacques , Di Cristofaro Julie
Published: May 2024

Red blood cell (RBC) transfusion, limited by patient alloimmunization, demands accurate blood group typing. The Rh system requires specific attention due to the limitations of serological phenotyping methods. Although these have been compensated for by molecular biology solutions, some RhCE ambiguities remain unresolved. The RHCE mRNA length is compatible with full-length analysis and haplotype discrimination, but the RHCE mRNA analyses reported so far are based on reticulocyte isolation and molecular biology protocols that are fastidious to implement in a routine context. We aim to present the most efficient reticulocyte isolation method, combined with an RT-PCR sequencing protocol that embraces the phasing of all haplotype configurations and identification of any allele. Two protocols were tested for reticulocyte isolation based either on their size/density properties or on their specific antigenicity. We show that the reticulocyte sorting method by antigen specificity from EDTA blood samples collected up to 48 h before processing is the most efficient and that the combination of an RHCE-specific RT-PCR followed by RHCE allele-specific sequencing enables analysis of cDNA RHCE haplotypes. All samples analyzed show full concordance between RHCE phenotype and haplotype sequencing. Two samples from the immunohematology laboratory with ambiguous results were successfully analyzed and resolved, one of them displaying a novel RHCE allele (RHCE*03 c.340C>T).
The Effect of Mediterranean Diet on Thyroid Gland Activity
Authors: Jureško Iva , Pleić Nikolina , Gunjača Ivana , Torlak Vesela , Brdar Dubravka , Punda Ante , Polašek Ozren , Hayward Caroline , Zemunik Tatijana , Babić Leko Mirjana
Published: May 2024

The main goal of this research was to determine whether there is a correlation between adherence to the Mediterranean diet (assessed by the Mediterranean Diet Serving Score (MDSS)) and parameters indicating thyroid gland activity, such as concentration of thyroid-stimulating hormone (TSH), thyroid hormones (free triiodothyronine (fT3), free thyroxine (fT4)), thyroglobulin (Tg), antibodies to thyroid proteins (thyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb)), and calcitonin (CT) in plasma and serum samples. An additional objective was to investigate whether there are differences in the values of the MDSS among clinical groups (euthyroid individuals, euthyroid individuals with positive TgAb and/or TPOAb, and hypothyroid and hyperthyroid participants). This cross-sectional study included 4620 participants over 18 years of age from the islands of Korčula and Vis, and the mainland city of Split. The MDSS was assessed from a food frequency questionnaire (FFQ). MDSS values were significantly higher in females compared to males and showed a positive association with the age of the participants. There was no significant difference in the MDSS values among the examined clinical groups. In the group of subjects with euthyroidism, a significant positive association was found between fT3 and the MDSS, while in the group of subjects with subclinical hypothyroidism, a significant positive association was observed between the MDSS and both fT3 and fT4. CT levels were also positively associated with the MDSS. Considering the significant positive association of the MDSS and both fT3 and fT4 levels in patients with subclinical hypothyroidism, the results of this study could be used to create guidelines for selecting an appropriate, potentially protective diet for these patients.
Migratory Tumor Cells Cooperate with Cancer Associated Fibroblasts in Hormone Receptor-Positive and HER2-Negative Breast Cancer
Authors: Joo Eun Hye , Kim Sangmin , Park Donghyun , Lee Taeseob , Park Woong-Yang , Han Kyung Yeon , Lee Jeong Eon
Published: May 2024

Hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-BC) is the most common type with a favorable prognosis under endocrine therapy. However, it still demonstrates unpredictable progression and recurrences influenced by high tumoral diversity and microenvironmental status. To address these heterogeneous molecular characteristics of HR+/HER2-BC, we aimed to simultaneously characterize its transcriptomic landscape and genetic architecture at the same resolution. Using advanced single-cell RNA and DNA sequencing techniques together, we defined four distinct tumor subtypes. Notably, the migratory tumor subtype was closely linked to genomic alterations of EGFR, related to the tumor-promoting behavior of IL6-positive inflammatory tumor-associated fibroblast, and contributing to poor prognosis. Our study comprehensively utilizes integrated analysis to uncover the complex dynamics of this breast cancer subtype, highlighting the pivotal role of the migratory tumor subtype in influencing surrounding cells. This sheds light on potential therapeutic targets by offering enhanced insights for HR+/HER2-BC treatment.
A Pilot Study on Circulating, Cellular, and Tissue Biomarkers in Osteosarcopenic Patients
Authors: Salamanna Francesca , Faldini Cesare , Veronesi Francesca , Borsari Veronica , Ruffilli Alberto , Manzetti Marco , Viroli Giovanni , Traversari Matteo , Marchese Laura , Fini Milena , Giavaresi Gianluca
Published: May 2024

Aging comes with the loss of muscle and bone mass, leading to a condition known as osteosarcopenia. Circulating, cellular, and tissue biomarkers research for osteosarcopenia is relatively scarce and, currently, no established biomarkers exist. Here we find that osteosarcopenic patients exhibited elevated basophils and TNFα levels, along with decreased aPPT, PT/INR, IL15, alpha-Klotho, DHEA-S, and FGF-2 expression and distinctive bone and muscle tissue micro-architecture and biomarker expressions. They also displayed an increase in osteoclast precursors with a concomitant imbalance towards spontaneous osteoclastogenesis. Similarities were noted with osteopenic and sarcopenic patients, including a lower neutrophil percentage and altered cytokine expression. A linear discriminant analysis (LDA) on models based on selected biomarkers showed a classification accuracy in the range of 61–78%. Collectively, our data provide compelling evidence for novel biomarkers for osteosarcopenia that may hold potential as diagnostic tools to promote healthy aging.
1,3,5-Triazine as Branching Connector for the Construction of Novel Antimicrobial Peptide Dendrimers: Synthesis and Biological Characterization
Authors: Sheyi Rotimi , Mhlongo Jessica T. , Jorba Marta , Fusté Ester , Sharma Anamika , Viñas Miguel , Albericio Fernando , Espinal Paula , de la Torre Beatriz G.
Published: May 2024

Peptides displaying antimicrobial properties are being regarded as useful tools to evade and combat antimicrobial resistance, a major public health challenge. Here we have addressed dendrimers, attractive molecules in pharmaceutical innovation and development displaying broad biological activity. Triazine-based dendrimers were fully synthesized in the solid phase, and their antimicrobial activity and some insights into their mechanisms of action were explored. Triazine is present in a large number of compounds with highly diverse biological targets with broad biological activities and could be an excellent branching unit to accommodate peptides. Our results show that the novel peptide dendrimers synthesized have remarkable antimicrobial activity against Gram-negative bacteria (E. coli and P. aeruginosa) and suggest that they may be useful in neutralizing the effect of efflux machinery on resistance.
Anti-HMGB1 mAb Therapy Reduces Epidural Hematoma Injury
Authors: Gao Shangze , Wang Dengli , Liu Keyue , Tomono Yasuko , Fu Li , Gao Yuan , Takahashi Yohei , Yata Mariko , Nishibori Masahiro
Published: May 2024

Epidural and subdural hematomas are commonly associated with traumatic brain injury. While surgical removal is the primary intervention for these hematomas, it is also critical to prevent and reduce complications such as post-traumatic epilepsy, which may result from inflammatory responses in the injured brain areas. In the present study, we observed that high mobility group box-1 (HMGB1) decreased in the injured brain area beneath the epidural hematoma (EDH) in rats, concurrent with elevated plasma levels of HMGB1. Anti-HMGB1 monoclonal antibody therapy strongly inhibited both HMGB1 release and the subsequent increase in plasma levels. Moreover, this treatment suppressed the up-regulation of inflammatory cytokines and related molecules such as interleukin-1-beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and inducible nitric oxide synthase (iNOS) in the injured areas. Our in vitro experiments using SH-SY5Y demonstrated that hematoma components—thrombin, heme, and ferrous ion— prompted HMGB1 translocation from the nuclei to the cytoplasm, a process inhibited by the addition of the anti-HMGB1 mAb. These findings suggest that anti-HMGB1 mAb treatment not only inhibits HMGB1 translocation but also curtails inflammation in injured areas, thereby protecting the neural tissue. Thus, anti-HMGB1 mAb therapy could serve as a complementary therapy for an EDH before/after surgery.