bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of a High-Accuracy Numerical Method for Time-Fractional Integro-Differential Equations
Authors: Luo Ziyang , Zhang Xindong , Wei Leilei
Published: June 2023

A high-order finite difference numerical scheme based on the compact difference operator is proposed in this paper for time-fractional partial integro-differential equations with a weakly singular kernel, where the time-fractional derivative term is defined in the Riemann-Liouville sense. Here, the stability and convergence of the constructed compact finite difference scheme are proved in L∞ norm, with the accuracy order O(τ2+h4), where τ and h are temporal and spatial step sizes, respectively. The advantage of this numerical scheme is that arbitrary parameters can be applied to achieve the desired accuracy. Some numerical examples are presented to support the theoretical analysis.
Interpolated Coefficient Mixed Finite Elements for Semilinear Time Fractional Diffusion Equations
Authors: Li Xiaowu , Tang Yuelong
Published: June 2023

In this paper, we consider a fully discrete interpolated coefficient mixed finite element method for semilinear time fractional reaction–diffusion equations. The classic L1 scheme based on graded meshes and new mixed finite element based on triangulation is used for the temporal and spatial discretization, respectively. The interpolation coefficient technique is used to deal with the semilinear term, and the discrete nonlinear system is solved by a Newton-like iterative method. Stability and convergence results for both the original variable and its flux are derived. Numerical experiments confirm our theoretical analysis.
Genetic Variants of Gonadotropins and Their Receptors Could Influence Controlled Ovarian Stimulation: IVF Data from a Prospective Multicenter Study
Authors: Alviggi Carlo , Longobardi Salvatore , Papaleo Enrico , Santi Daniele , Alfano Simona , Vanni Valeria Stella , Campitiello Maria Rosaria , De Rosa Pasquale , Strina Ida , Huhtaniemi Ilpo , Pursiheimo Juha-Pekka , D’Hooghe Thomas , Humaidan Peter , Conforti Alessandro
Published: June 2023

Background: Specific polymorphisms might influence controlled ovarian stimulation in women undergoing assisted reproductive technologies (ARTs). Data regarding possible interactions of these polymorphisms are still scanty. The aim of this analysis was to evaluate the effect of polymorphisms of gonadotropins and their receptors in women undergoing ART. Methods: A total of 94 normogonadotropic patients from three public ART units were enrolled. Patients underwent a gonadotropin releasing hormone (GnRH) long down-regulation protocol with a starting dose of 150 IU of recombinant follicular stimulating hormone (FSH) daily. Eight polymorphisms were genotyped. Results: A total of 94 women (mean age 30.71 ± 2.61) were recruited. Fewer fertilized and mature oocytes were retrieved in homozygous carriers of luteinizing hormone/choriogonadotropin receptor (LHCGR) 291 (T/T) than in heterozygous C/T carriers (p = 0.035 and p = 0.05, respectively). In FSH receptor (FSHR) rs6165 and FSHR rs6166 carriers, the ratio between total gonadotropin consumption and number of oocytes retrieved differed significantly among three genotypes (p = 0.050), and the ratio was lower in homozygous A/A carriers than in homozygous G/G and heterozygous carriers. Women who co-expressed allele G in FSHR-29 rs1394205 and FSHR rs6166 and allele C LHCGR 291 rs12470652 are characterized by an increased ratio between total FSH dosage and number of oocytes collected after ovarian stimulation (risk ratio: 5.44, CI 95%: 3.18–7.71, p < 0.001). Conclusions: Our study demonstrated that specific polymorphisms affect the response to ovarian stimulation. Despite this finding, more robust studies are required to establish the clinical utility of genotype analysis before ovarian stimulation.
Ectopic Expression of BcCUC2 Involved in Sculpting the Leaf Margin Serration in Arabidopsis thaliana
Authors: Li Wanqi , Wang Tongtong , Ma Yu , Wang Nan , Wang Wenjing , Tang Jun , Zhang Changwei , Hou Xilin , Hou Hualan
Published: June 2023

Leaf margin serration is a morphological characteristic in plants. The CUC2 (CUP-SHAPED COTYLEDON 2) gene plays an important role in the outgrowth of leaf teeth and enhances leaf serration via suppression of growth in the sinus. In this study, we isolated the BcCUC2 gene from Pak-choi (Brassica rapa ssp. chinensis), which contains a 1104 bp coding sequence, encoding 367 amino acid residues. Multiple sequence alignment exhibited that the BcCUC2 gene has a typical conserved NAC domain, and phylogenetic relationship analysis showed that the BcCUC2 protein has high identity with Cruciferae plants (Brassica oleracea, Arabidopsis thaliana, and Cardamine hirsuta). The tissue-specific expression analysis displayed that the BcCUC2 gene has relatively high transcript abundance in floral organs. Meanwhile, the expression profile of BcCUC2 was relatively higher in the ‘082’ lines with serrate leaf margins than the ‘001’ lines with smooth leaf margins in young leaves, roots, and hypocotyls. In addition, the transcript level of BcCUC2 was up-regulated by IAA and GA3 treatment, especially at 1–3 h. The subcellular localization assay demonstrated that BcCUC2 was a nuclear-target protein. Furthermore, leaf serration occurred, and the number of the inflorescence stem was increased in the transgenic Arabidopsis thaliana plants’ overexpressed BcCUC2 gene. These data illustrated that BcCUC2 is involved in the development of leaf margin serration, lateral branches, and floral organs, contributing to further uncovering and perfecting the regulation mechanism of leaf serration in Pak-choi.
High-Latitude Depositional Systems, Provenance, and Basinal Setting of the Late Cretaceous Cantwell Basin, Denali National Park and Preserve, Alaska: A Stratigraphic Framework for Paleontological and Paleoclimatic Studies
Authors: Keough Brandon , Ridgway Kenneth
Published: June 2023

The Cantwell Formation of the central Alaska Range provides a robust archive of high-latitude, Late Cretaceous depositional systems and paleo-floral/faunal assemblages. Our stratigraphic analysis defines two mappable members. The lower member (1500–2000 m thick) represents vegetated alluvial fan and braided fluvial systems that transition up-section to fluvial–estuarine systems that drained into an inland continental seaway. The upper member (~2000 m thick) represents estuarine–marginal marine and lacustrine systems. Previous paleontological studies demonstrate that the Cantwell basin was populated by various dinosaurs, fishes, bivalves, birds, and marginal marine micro-organisms. Integration of new and published geologic mapping allows for reconstruction of depositional systems at the basin scale and provides additional paleogeographic context. The northern basin margin was defined by a previously unrecognized south-verging thrust belt, whereas the southern margin of the basin was defined by a north-verging thrust belt inboard of an active magmatic arc. Sediment sources interpreted from U-Pb detrital zircon geochronology included the coeval magmatic arc and older Cretaceous plutons, and Proterozoic–Mesozoic strata exhumed along the basin margins. Results of our study provide a depositional, stratigraphic, and structural framework that may serve as a guide for future paleontological and paleoclimatic investigations of Late Cretaceous Arctic environments of the Cantwell basin.
Forage Biomass Estimated with a Pre-Calibrated Equation of a Rising Platemeter in Pastures Grown in Tropical Conditions
Authors: Villalobos-Villalobos Luis Alonso , WingChing-Jones Rodolfo
Published: June 2023

Accurate estimates of forage biomass allow for better adjustments of stocking rate, carrying capacity, and dry matter intake in livestock operations. Among the most common methods to estimate biomass are platemeters, for which specific calibration equations have been developed for temperate conditions. However, platemeters are not commonly used in tropical livestock operations where their goodness of fit to estimate forage biomass remains unknown. In this study, we aimed to compare three methods (the rising platemeter, Botanal®, and hand-clipping) to estimate forage biomass throughout one year on perennial ryegrass (Lolium perenne), Kikuyu (Cenchrus clandestinus), and African stargrass (Cynodon nlemfuensis Vanderyst) pastures in Costa Rica. Estimates of forage biomass were consistently greater with the platemeter than with the Botanal® and clippings across the three grass species evaluated. In Ryegrass pastures, the residual standard deviation (1845 kg DM ha−1) of forage biomass estimated with the platemeter was two- and four-fold with respect to Stargrass and Kikuyu pastures (935 and 447 kg DM ha−1), respectively. Although platemeters are straightforward methods for biomass estimation in pastures, our data suggest that their use and implementation in tropical pastures may lead to overestimating indicators such as stocking rate and carrying capacity. We suggest developing calibration equations specific for tropical conditions that consider our findings as an input to adjust the sampling procedure necessary to improve the accuracy of platemeters and foster greater adoption among livestock producers.
Mechanical Behavior of One-Piece and Two-Piece Tapered Prosthetic Abutments with 11.5 and 16 Degrees
Authors: Tolesano Loureiro Karine Regina , Boaventura de Moura Marcos , de Oliveira Guilherme José Pimentel Lopes , Resende Novais Veridiana , Zancopé Karla , Simamoto Júnior Paulo Cézar
Published: June 2023

The objective of this study is to examine the mechanical behavior of two-piece abutments (Morse taper with 16° internal angulation and Morse taper with 11.5° internal angulation) before and after cyclic fatigue testing, following ISO 14801:2016 guidelines. The specimens were divided into three groups: a modified Morse taper with a taper angle of 16° (GM group), a conventional Morse taper (taper angle of 11.5° deg) with a two-piece (CMt group), and one-piece abutments (CMo group). Each experimental group was formed by ten implants and ten abutments (n = 10) for a total of 30 specimens (n = 30). The abutments were tightened and loosened, and a fatigue test was applied with 15 Hz and 5 × 106 cycles. Subsequently, the abutments were loosened, and a pull-out test was performed on the CMt group. Finite element analysis (FEA) was conducted on stress concentration regions. The statistical analysis of the loosening test was performed using two-way ANOVA and Tukey’s tests (p < 0.05) to compare screw loosening within each group and between the groups with and without mechanical fatigue. Significant differences were found among the three groups in the loosening test when analyzing the values with and without fatigue (p < 0.001) within each group. When the groups were compared with each other, there was also a significant difference between them (p < 0.001), except between groups GM and CMt without fatigue (p = 0.840). In the pull-out test of the CMt group, the sample exhibited frictional locking only after fatigue (mean = 94.2 N). The FEA demonstrated a varied stress distribution in all groups. The stress was found to be more concentrated in the upper third and middle third regions of the implant, as well as in the opposite region of the load application for all three groups. Although the CMo group showed lower rates of loosening, it displayed a poorer stress distribution in comparison to the GM and CMt groups. On the other hand, the CMt group exhibited a satisfactory frictional lock after undergoing the fatigue tests.
Parental Experiences of Melatonin Administration to Manage Sleep Disturbances in Autistic Children and Adolescent in the UK
Authors: Horsnell Jade , Mangar Stephen , Dimitriou Dagmara , Halstead Elizabeth J.
Published: June 2023

Background: Autistic children and adolescents are 40–80% more likely to experience sleep disturbances than their neurotypical peers. In the United Kingdom, melatonin is licensed for short-term usage in adults at age 55 years and above; however, it is often prescribed to autistic children and adolescents to help manage their sleep. The current study sought to understand parental experiences and their motivation of using melatonin to manage sleep disturbances of their autistic children. Methods: The sample included 26 parents who took part in online focus groups answering questions regarding their experiences of using melatonin as a sleep treatment for their children diagnosed with autism between 4 and 18 years old. Results: Four main themes were identified: (i) parental perception of melatonin used as ‘a naturally produced hormone’; (ii) perceived benefits of using melatonin to improve their child’s sleep; (iii) administration of melatonin: dosage amount, timing and pulverising; and (iv) expectation and apprehension over melatonin use. Conclusion: Some parents reported success with the use of melatonin, and others reported the effects being limited or diminishing in time. Suggestions for healthcare professionals and families regarding melatonin usage in the UK are made with respect to setting clear guidelines for usage, whilst ensuring expectations are set and managed appropriately.
Leaf Area Estimation by Photographing Leaves Sandwiched between Transparent Clear File Folder Sheets
Authors: Koyama Kohei
Published: June 2023

Image analysis is a promising method for in situ leaf area measurement. However, as leaves are three-dimensional, the use of two-dimensional images captured using a digital camera can result in underestimation. To overcome this problem, we tested a clear folder method. Before photographing leaves with a digital camera, we flattened the leaves by sandwiching them between a pair of transparent plastic clear file folder sheets, which are stationery implements for carrying documents. Although similar methods have been previously proposed, their applicability to species with different leaf shapes has never been investigated. We tested the efficacy of this method using 12 species from various taxa (monocots, magnoliids, and basal and core eudicots) and leaf morphology (entire vs. lobed, simple vs. compound leaves, small and large leaves). Individual leaf areas and the Montgomery parameters obtained using this method were then compared with those obtained using the standard method, which employs a flatbed digital scanner. We observed strong correlations (R2 > 0.98) between the camera and scanner data. The regression slopes were close to unity (0.96–1.01) and the intercepts were close to zero. These findings suggest that the clear folder method can be used as an inexpensive alternative method to estimate the area of leaves in situ with acceptable accuracy. An introductory manual for readers unfamiliar with image analysis using ImageJ is presented in the end of the paper.
Fungicidal Effect of Guava Wood Vinegar against Colletotrichum coccodes Causing Black Dot Disease of Potatoes
Authors: El-Fawy Mansour M. , Abo-Elyousr Kamal A. M. , Sallam Nashwa M. A. , El-Sharkawy Rafeek M. I. , Ibrahim Yasser Eid
Published: June 2023

Wood vinegar (WV) by-product of charcoal production is considered one of the most promising alternatives to synthetic pesticide and fertilizer applications, especially for organic production. Our goal in this study is to evaluate the efficacy of guava (Psidium guajava) WV to control Colletotrichum coccodes, which causes black dot disease, and how it influences potato plant development and yield. This study tested the efficacy of guava WV against the pathogen both in vitro and under greenhouse conditions. Different guava WV concentrations were tested on pathogen growth development, including 0, 0.25%, 0.50%, 1%, 2%, and 3% (v/v). Data revealed that the pathogen’s mycelial growth was significantly inhibited at all the concentrations, and the highest inhibition (100%) was obtained at 3% guava WV. In greenhouse trials conducted for two seasons (2021 and 2022), guava WV applied as a foliar spray at the concentration of 2% and 3% considerably reduced the potato black dot severity evaluated as stem colonization (average of 22.9% for 2021, average of 22.5% for 2022), root covering with sclerotia (average of 21.7% for 2021, average of 18.3% for 2022) and wilted plants percentage (average of 27.8% for 2021, average of 33.3% for 2022). Overall, guava WV also showed a positive effect on plant growth by increasing plant height, stem diameter, and tuber yield per plant of treated potato in both seasons. Gas chromatography-mass spectrometry (GC-MS) analyses revealed the presence in guava WV of phenols, esters, organic acids, antioxidants, and alcohols. In conclusion, guava WV could represent a viable alternative for potato black dot disease management and for plant growth promotion.
Gasification of Lower Monohydric Alcohols by Solution Plasma Treatment and Its Reaction Mechanism
Authors: Miyamoto Takaki , Minami Eiji , Kawamoto Haruo
Published: June 2023

Solution plasma is a gas-phase discharge in the vapor bubbles in a solution and has the potential to efficiently produce H2 by decomposing aqueous alcohols. However, the mechanism of alcohol decomposition in solution plasma remains unclear. In this study, lower monohydric alcohols (methanol and ethanol, as well as 1- and 2-propanol) were treated in solution plasma, and in this paper, the gasification mechanism is discussed. The gases produced from these alcohols were mainly H2 and CO, with small ratios of C1–C3 hydrocarbons. Thus, the O/C ratio in the product gas was close to 1 for all alcohols, and most of the C atoms in the alcohols were bonded to O atoms. This excess of O atoms could have only come from water, suggesting a strong contribution of OH radicals from water for gasification. However, the C1–C3 hydrocarbons were produced solely by the decomposition of the alcohol. For both decomposition routes, possible reaction pathways are proposed that are consistent with the experimental facts such as the composition of the product gas and the intermediates detected.
The Effects of Physical Activity, Exercise, and Sports Programs on Depressive Symptoms in Individuals with Disabilities: A Systematic Review with Meta-Analysis
Authors: Jacinto Miguel , Monteiro Diogo , Oliveira Joana , Diz Susana , Frontini Roberta , Matos Rui , Antunes Raul
Published: June 2023

Studies show that physical activity, exercise, or sport reduces depressive symptoms in the general population. However, little is known about its effects on individuals with disabilities. Thus, this systematic review with meta-analysis aims to verify the effects of this practice on depressive symptoms in individuals with disabilities. The Pubmed, Web of Science, Scopus, and SportDiscus databases were used, with several descriptors and Boolean operators. A total of 1509 studies were identified through searching the databases. Studies that met the eligibility criteria were subsequently assessed for their methodological quality (Downs and Black scale), and a meta-analysis was performed. The Z-values that were obtained to test the null hypothesis, which states that there is no difference in means, showed Z = −2.294 and a corresponding p-value = 0.022. We can, therefore, reject the null hypothesis in the sense that exercise seems to reduce depressive symptoms in individuals with disabilities. In sum, participants from the intervention group presented more probability of reducing depressive symptoms when compared to the control group (approximately −1.4 standard differences in means; 95% CI −2.602 to −0.204).
Analysis of the 2007–2018 National Health Interview Survey (NHIS): Examining Neurological Complications among Children with Sickle Cell Disease in the United States
Authors: Peprah Emmanuel , Gyamfi Joyce , Lee Justin Tyler , Islam Farha , Opeyemi Jumoke , Tampubolon Siphra , Ojo Temitope , Qiao Wanqiu , Mai Andi , Wang Cong , Vieira Dorice , Meda Shreya , Adenikinju Deborah , Osei-Tutu Nana , Ryan Nessa , Ogedegbe Gbenga
Published: June 2023

This study compared neurological complications among a national sample of United States children with or without sickle cell disease (SCD) and evaluated health status, healthcare and special education utilization patterns, barriers to care, and association of SCD status and demographics/socioeconomic status (SES) on comorbidities and healthcare utilization. Data was acquired from the National Health Interview Survey (NHIS) Sample Child Core questionnaire 2007–2018 dataset that included 133,542 children. An affirmation from the guardian of the child determined the presence of SCD. Regression analysis was used to compare the associations between SCD and demographics/SES on neurological conditions at p < 0.05. Furthermore, adjusted odds ratios (AORs) were estimated for having various neurological conditions. Of the 133,481 children included in the NHIS, the mean age was 8.5 years (SD: 0.02) and 215 had SCD. Of the children with SCD, the sample composition included male (n = 110), and Black (n = 82%). The SCD sample had higher odds of having neuro-developmental conditions (p < 0.1). Families of Black children (55% weighted) reported household incomes < 100% of federal poverty level. Black children were more likely to experience longer wait times to see the doctor (AOR, 0.3; CI 0.1–1.1). Compared to children without SCD, those with SCD had a greater chance of seeing a medical specialist within 12 months (AOR 2.3; CI 1.5–3.7). This representative sample of US children with SCD shows higher odds of developing neurological complications, increased healthcare and special education services utilization, with Black children experiencing a disproportionate burden. This creates the urgency to address the health burden for children with SCD by implementing interventions in healthcare and increasing education assistance programs to combat neurocognitive impairments, especially among Black children.
Prevalence of Hypertensive Disorders, Antihypertensive Therapy and Pregnancy Outcomes among Pregnant Women: A Retrospective Review of Cases at Tamale Teaching Hospital, Ghana
Authors: Bugri Amos Adapalala , Gumanga Solomon Kwabena , Yamoah Peter , Frimpong Ebenezer Kwabena , Nlooto Manimbulu
Published: June 2023

Hypertensive disorders associated with pregnancy are a major health concern and a leading cause of maternal indisposition and transience. The main objective of this study was to assess the prevalence of hypertension in pregnancy as well as antihypertensive therapy and pregnancy outcomes among pregnant women at Tamale Teaching Hospital (TTH) in Ghana. This was a retrospective study conducted using data from the folders of pregnant hypertensive patients. The study was conducted at the maternity ward of TTH from 1 June 2018 to 31 May 2019. Participants were all pregnant women with a diagnosis of hypertensive disorders. The prevalence of hypertensive disorders in pregnancy was 12.5%. The most common antihypertensive medication prescribed was sustained-release oral nifedipine, which was prescribed for 548 (81.4%) participants either alone or with methyldopa, followed by oral methyldopa: 506 (75.2%), intravenous hydralazine: 94 (14.0%), intravenous labetalol: 28 (4.2%) and diuretics: 10 (1.5%). Thirty-eight (5.7%) babies died before delivery, whereas 635 (94.3%) babies were born alive. Twenty-six out of the 38 dead babies (68.4%) were babies of pregnant women with elevated BP, whereas 12 (31.6%) were babies of those with normal BP. There was a statistically significant association between BP control and delivery outcomes. The study observed adherence to antihypertensive medicines recommended by the standard treatment guidelines of Ghana for the management of hypertensive disorders in pregnancy. The BPs of about two-thirds of the study participants were well controlled with the antihypertensive therapy. The majority of the study participants with well-controlled BP had positive delivery outcomes.
Maternal Attachment Networks and Mother–Infant Bonding Disturbances among Mothers with Postpartum Major Depression
Authors: Vanwalleghem Stéphanie , Miljkovitch Raphaële , Sirparanta Aino , Toléon Camille , Leclercq Stéphanie , Deborde Anne-Sophie
Published: June 2023

The literature suggests that maternal insecure attachment is a risk factor for postpartum depression which, in turn, affects motherinfant bonding. However, recent research in attachment suggests that the investigation of attachment networks provides further insight in the understanding of psychological outcomes. This study aims to test a model according to which mothers’ attachment towards each of their parents contributes to explain attachment towards their romantic partners, which itself is associated with maternal postpartum depression and, in turn, with motherinfant bonding. The Attachment Multiple Model Interview, the Edinburgh Postnatal Depression Scale, and the Postpartum Bonding Questionnaire were administered to 90 mothers of infants under 6 months of age (32 with postpartum major depression). Results showed that attachment towards the partner (1) is best explained by attachment to the father and (2) mediates the link between attachment to the father and depression severity. Also, depression severity mediates the link between attachment to the partner and motherinfant bonding. These results highlight the role of attachment models towards the romantic partner and the father in the perinatal period and the relevance of attachment-focused therapeutic programs in treating postpartum maternal depression.
Exosomes as Novel Diagnostic Biomarkers and Therapeutic Tools in Gliomas
Authors: Skouras Panagiotis , Gargalionis Antonios N. , Piperi Christina
Published: June 2023

Exosomes constitute small extracellular vesicles that contain lipids, proteins, nucleic acids, and glycoconjugates from the secreted cells and are capable of transmitting signals between cells and coordinating cellular communication. By this means, they are ultimately involved in physiology and disease, including development, homeostasis, and immune system regulation, as well as contributing to tumor progression and neurodegenerative diseases pathology. Recent studies have shown that gliomas secrete a panel of exosomes which have been associated with cell invasion and migration, tumor immune tolerance, potential for malignant transformation, neovascularization, and resistance to treatment. Exosomes have therefore emerged as intercellular communicators, which mediate the tumor–microenvironment interactions and exosome-regulated glioma cell stemness and angiogenesis. They may induce tumor proliferation and malignancy in normal cells by carrying pro-migratory modulators from cancer cells as well as many different molecular cancer modifiers, such as oncogenic transcripts, miRNAs, mutant oncoproteins, etc., which promote the communication of cancer cells with the surrounding stromal cells and provide valuable information on the molecular profile of the existing tumor. Moreover, engineered exosomes can provide an alternative system for drug delivery and enable efficient treatment. In the present review, we discuss the latest findings regarding the role of exosomes in glioma pathogenesis, their utility in non-invasive diagnosis, and potential applications to treatment.
Endogenous Biological Drivers in Diabetic Lower Limb Wounds Recurrence: Hypothetical Reflections
Authors: Berlanga-Acosta Jorge , Garcia-Ojalvo Ariana , Guillen-Nieto Gerardo , Ayala-Avila Marta
Published: June 2023

An impaired healing response underlies diabetic foot wound chronicity, frequently translating to amputation, disability, and mortality. Diabetics suffer from underappreciated episodes of post-epithelization ulcer recurrence. Recurrence epidemiological data are alarmingly high, so the ulcer is considered in “remission” and not healed from the time it remains epithelialized. Recurrence may result from the combined effects of behavioral and endogenous biological factors. Although the damaging role of behavioral, clinical predisposing factors is undebatable, it still remains elusive in the identification of endogenous biological culprits that may prime the residual scar tissue for recurrence. Furthermore, the event of ulcer recurrence still waits for the identification of a molecular predictor. We propose that ulcer recurrence is deeply impinged by chronic hyperglycemia and its downstream biological effectors, which originate epigenetic drivers that enforce abnormal pathologic phenotypes to dermal fibroblasts and keratinocytes as memory cells. Hyperglycemia-derived cytotoxic reactants accumulate and modify dermal proteins, reduce scar tissue mechanical tolerance, and disrupt fibroblast-secretory activity. Accordingly, the combination of epigenetic and local and systemic cytotoxic signalers induce the onset of “at-risk phenotypes” such as premature skin cell aging, dysmetabolism, inflammatory, pro-degradative, and oxidative programs that may ultimately converge to scar cell demise. Post-epithelialization recurrence rate data are missing in clinical studies of reputed ulcer healing therapies during follow-up periods. Intra-ulcer infiltration of epidermal growth factor exhibits the most consistent remission data with the lowest recurrences during 12-month follow-up. Recurrence data should be regarded as a valuable clinical endpoint during the investigational period for each emergent healing candidate.
Complement Drives Chronic Inflammation and Progressive Hydrocephalus in Murine Neonatal Germinal Matrix Hemorrhage
Authors: Alshareef Mohammed , Hatchell Devin , Vasas Tyler , Mallah Khalil , Shingala Aakash , Cutrone Jonathan , Alawieh Ali , Guo Chunfang , Tomlinson Stephen , Eskandari Ramin
Published: June 2023

Germinal matrix hemorrhage (GMH) is a pathology that occurs in infancy, with often devastating long-term consequences. Posthemorrhagic hydrocephalus (PHH) can develop acutely, while periventricular leukomalacia (PVL) is a chronic sequala. There are no pharmacological therapies to treat PHH and PVL. We investigated different aspects of the complement pathway in acute and chronic outcomes after murine neonatal GMH induced at postnatal day 4 (P4). Following GMH-induction, the cytolytic complement membrane attack complex (MAC) colocalized with infiltrating red blood cells (RBCs) acutely but not in animals treated with the complement inhibitor CR2-Crry. Acute MAC deposition on RBCs was associated with heme oxygenase-1 expression and heme and iron deposition, which was reduced with CR2-Crry treatment. Complement inhibition also reduced hydrocephalus and improved survival. Following GMH, there were structural alterations in specific brain regions linked to motor and cognitive functions, and these changes were ameliorated by CR2-Crry, as measured at various timepoints through P90. Astrocytosis was reduced in CR2-Crry-treated animals at chronic, but not acute, timepoints. At P90, myelin basic protein and LAMP-1 colocalized, indicating chronic ongoing phagocytosis of white matter, which was reduced by CR2-Crry treatment. Data indicate acute MAC-mediated iron-related toxicity and inflammation exacerbated the chronic effects of GMH.
Less Severe Polymicrobial Sepsis in Conditional mgmt-Deleted Mice Using LysM-Cre System, Impacts of DNA Methylation and MGMT Inhibitor in Sepsis
Authors: Sae-khow Kritsanawan , Phuengmaung Pornpimol , Issara-Amphorn Jiraphorn , Makjaroen Jiradej , Visitchanakun Peerapat , Boonmee Atsadang , Benjaskulluecha Salisa , Palaga Tanapat , Leelahavanichkul Asada
Published: June 2023

The O6-methylguanine-DNA methyltransferase (MGMT) is a DNA suicide repair enzyme that might be important during sepsis but has never been explored. Then, the proteomic analysis of lipopolysaccharide (LPS)-stimulated wild-type (WT) macrophages increased proteasome proteins and reduced oxidative phosphorylation proteins compared with control, possibly related to cell injury. With LPS stimulation, mgmt null (mgmtflox/flox; LysM-Crecre/-) macrophages demonstrated less profound inflammation; supernatant cytokines (TNF-α, IL-6, and IL-10) and pro-inflammatory genes (iNOS and IL-1β), with higher DNA break (phosphohistone H2AX) and cell-free DNA, but not malondialdehyde (the oxidative stress), compared with the littermate control (mgmtflox/flox; LysM-Cre-/-). In parallel, mgmt null mice (MGMT loss only in the myeloid cells) demonstrated less severe sepsis in the cecal ligation and puncture (CLP) model (with antibiotics), as indicated by survival and other parameters compared with sepsis in the littermate control. The mgmt null protective effect was lost in CLP mice without antibiotics, highlighting the importance of microbial control during sepsis immune modulation. However, an MGMT inhibitor in CLP with antibiotics in WT mice attenuated serum cytokines but not mortality, requiring further studies. In conclusion, an absence of mgmt in macrophages resulted in less severe CLP sepsis, implying a possible influence of guanine DNA methylation and repair in macrophages during sepsis.
A Systematic Review of the Effects of Capsaicin on Alzheimer’s Disease
Authors: Inyang Deborah , Saumtally Tasneem , Nnadi Chinelo Nonyerem , Devi Sharmila , So Po-Wah
Published: June 2023

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterised by cognitive impairment, and amyloid-β plaques and neurofibrillary tau tangles at neuropathology. Capsaicin is a spicy-tasting compound found in chili peppers, with anti-inflammatory, antioxidant, and possible neuroprotective properties. Capsaicin intake has been associated with greater cognitive function in humans, and attenuating aberrant tau hyperphosphorylation in a rat model of AD. This systematic review discusses the potential of capsaicin in improving AD pathology and symptoms. A systematic analysis was conducted on the effect of capsaicin on AD-associated molecular changes, cognitive and behaviour resulting in 11 studies employing rodents and/or cell cultures, which were appraised with the Cochrane Risk of Bias tool. Ten studies showed capsaicin attenuated tau deposition, apoptosis, and synaptic dysfunction; was only weakly effective on oxidative stress; and had conflicting effects on amyloid processing. Eight studies demonstrated improved spatial and working memory, learning, and emotional behaviours in rodents following capsaicin treatment. Overall, capsaicin showed promise in improving AD-associated molecular, cognitive, and behavioural changes in cellular and animal models, and further investigations are recommended to test the readily available bioactive, capsaicin, to treat AD.
The Role of Cyclic Adenosine Monophosphate (cAMP) in Modulating Glucocorticoid Receptor Signaling and Its Implications on Glucocorticoid-Related Collagen Loss
Authors: Kang Wesuk , Choi Dabin , Roh Jiyun , Jung Yearim , Ha Yoojeong , Yang Suhjin , Park Taesun
Published: June 2023

Glucocorticoid receptors (GRs) play a pivotal role in the stress response of the body, but overactivation can disrupt normal physiological functions. This study explores the role of cyclic adenosine monophosphate (cAMP) in GR activation and the associated mechanisms. We initially used the human embryonic kidney 293 cell line (HEK293) and found that cAMP enhancement, using forskolin and 3-isobutyl-1-methylxanthine (IBMX), did not alter glucocorticoid signaling under normal conditions, as evidenced by glucocorticoid response element (GRE) activity and the translocation of GR. However, in stressful conditions induced by dexamethasone, a synthetic glucocorticoid, cAMP was found to lessen glucocorticoid signaling within a short time frame but amplify it over an extended period in HEK293 cells. Bioinformatic analysis revealed that cAMP upregulation triggers the extracellular signal-regulated kinase (ERK) pathway, which influences GR translocation and ultimately regulates its activity. This stress-modulating function of cAMP was also investigated in the Hs68 dermal fibroblast line, known for its susceptibility to glucocorticoids. We found that cAMP enhancement via forskolin reduces GRE activity and reverses collagen loss in Hs68 cells exposed to dexamethasone. These findings underline the context-specific role of cAMP signaling in managing glucocorticoid signaling and its potential therapeutic application in treating stress-related pathological conditions like skin aging characterized by collagen reduction.
Tenascin-C in Tissue Repair after Myocardial Infarction in Humans
Authors: Matsui Kenta , Torii Sota , Hara Shigeru , Maruyama Kazuaki , Arai Tomio , Imanaka-Yoshida Kyoko
Published: June 2023

Adverse ventricular remodeling after myocardial infarction (MI) is progressive ventricular dilatation associated with heart failure for weeks or months and is currently regarded as the most critical sequela of MI. It is explained by inadequate tissue repair due to dysregulated inflammation during the acute stage; however, its pathophysiology remains unclear. Tenascin-C (TNC), an original member of the matricellular protein family, is highly up-regulated in the acute stage after MI, and a high peak in its serum level predicts an increased risk of adverse ventricular remodeling in the chronic stage. Experimental TNC-deficient or -overexpressing mouse models have suggested the diverse functions of TNC, particularly its pro-inflammatory effects on macrophages. The present study investigated the roles of TNC during human myocardial repair. We initially categorized the healing process into four phases: inflammatory, granulation, fibrogenic, and scar phases. We then immunohistochemically examined human autopsy samples at the different stages after MI and performed detailed mapping of TNC in human myocardial repair with a focus on lymphangiogenesis, the role of which has recently been attracting increasing attention as a mechanism to resolve inflammation. The direct effects of TNC on human lymphatic endothelial cells were also assessed by RNA sequencing. The results obtained support the potential roles of TNC in the regulation of macrophages, sprouting angiogenesis, the recruitment of myofibroblasts, and the early formation of collagen fibrils during the inflammatory phase to the early granulation phase of human MI. Lymphangiogenesis was observed after the expression of TNC was down-regulated. In vitro results revealed that TNC modestly down-regulated genes related to nuclear division, cell division, and cell migration in lymphatic endothelial cells, suggesting its inhibitory effects on lymphatic endothelial cells. The present results indicate that TNC induces prolonged over-inflammation by suppressing lymphangiogenesis, which may be one of the mechanisms underlying adverse post-infarct remodeling.
Standardized Extract from Wastes of Edible Flowers and Snail Mucus Ameliorate Ultraviolet B-Induced Damage in Keratinocytes
Authors: Vanella Luca , Consoli Valeria , Burò Ilaria , Gulisano Maria , Giglio Manuela Stefania , Maugeri Ludovica , Petralia Salvatore , Castellano Angela , Sorrenti Valeria
Published: June 2023

Several studies have highlighted the ability of snail mucus in maintaining healthy skin conditions due to its emollient, regenerative, and protective properties. In particular, mucus derived from Helix aspersa muller has already been reported to have beneficial properties such as antimicrobial activity and wound repair capacity. In order to enhance the beneficial effects of snail mucus, a formulation enriched with antioxidant compounds derived from edible flower waste (Acmella oleracea L., Centaurea cyanus L., Tagetes erecta L., Calendula officinalis L., and Moringa oleifera Lam.) was obtained. UVB damage was used as a model to investigate in vitro the cytoprotective effects of snail mucus and edible flower extract. Results demonstrated that polyphenols from the flower waste extract boosted the antioxidant activity of snail mucus, providing cytoprotective effects in keratinocytes exposed to UVB radiation. Additionally, glutathione content, reactive oxygen species (ROS), and lipid peroxidation levels were reduced following the combined treatment with snail mucus and edible flower waste extract. We demonstrated that flower waste can be considered a valid candidate for cosmeceutical applications due to its potent antioxidant activity. Thus, a new formulation of snail mucus enriched in extracts of edible flower waste could be useful to design innovative and sustainable broadband natural UV-screen cosmeceutical products.
Isoespintanol Antifungal Activity Involves Mitochondrial Dysfunction, Inhibition of Biofilm Formation, and Damage to Cell Wall Integrity in Candida tropicalis
Authors: Contreras Martínez Orfa Inés , Angulo Ortíz Alberto , Santafé Patiño Gilmar , Peñata-Taborda Ana , Berrio Soto Ricardo
Published: June 2023

The growing increase in infections caused by C. tropicalis, associated with its drug resistance and consequent high mortality, especially in immunosuppressed people, today generates a serious global public health problem. In the search for new potential drug candidates that can be used as treatments or adjuvants in the control of infections by these pathogenic yeasts, the objective of this research was to evaluate the action of isoespintanol (ISO) against the formation of fungal biofilms, the mitochondrial membrane potential (ΔΨm), and its effect on the integrity of the cell wall. We report the ability of ISO to inhibit the formation of biofilms by up to 89.35%, in all cases higher than the values expressed by amphotericin B (AFB). Flow cytometric experiments using rhodamine 123 (Rh123) showed the ability of ISO to cause mitochondrial dysfunction in these cells. Likewise, experiments using calcofluor white (CFW) and analyzed by flow cytometry showed the ability of ISO to affect the integrity of the cell wall by stimulating chitin synthesis; these changes in the integrity of the wall were also observed through transmission electron microscopy (TEM). These mechanisms are involved in the antifungal action of this monoterpene.
Surface Stiffness Has No Impact on MCF-7 Sensitivity to Doxorubicin
Authors: Šimoliūnas Egidijus , Jasmontaitė Daiva , Skinderskis Algimantas , Rinkūnaitė Ieva , Alksnė Milda , Liudvinaitis Mantas , Baltriukienė Daiva
Published: June 2023

Resistance to the chemotherapeutic agents in the clinical management of cancer remains a significant challenge, and the mechanical environment of cancer cells is one of the major determinants of this. Stiffening of the environment is usually associated with increased chemoresistance of cancer cells, although this process depends on the type of cancer. Breast cancer is the most frequently diagnosed cancer, and more than half a million people die from it each year worldwide. In this study, we used the most frequent (70% of diagnosed cases) breast cancer phenotype, representing the MCF-7 cell line, to investigate the influence of surface stiffness on its sensitivity to one of the most commonly used anticancer drugs—doxorubicin. We showed that the mechanical environment affected MCF-7 proliferation, adhesion, and the expression and activation of mitogen-activated protein kinases (MAPKs). Furthermore, the role of MAPKs in response to doxorubicin was dependent on surface stiffness; nevertheless, surface stiffness did not affect MCF-7 resistance to doxorubicin.
Assessments of Alpha-Amylase Inhibitory Potential of Tagetes Flavonoids through In Vitro, Molecular Docking, and Molecular Dynamics Simulation Studies
Authors: Mohamed Gamal A. , Omar Abdelsattar M. , El-Araby Moustafa E. , Mass Shaza , Ibrahim Sabrin R. M.
Published: June 2023

Diabetes is a chronic fast-growing metabolic disorder that is characterized by high blood glucose levels. Tagetes minuta L. has been used as a traditional remedy for various illnesses for many years, and, furthermore, its oil is used in the perfume and flavor industries. T. minuta contains various metabolites, such as flavonoids, thiophenes, terpenes, sterols, and phenolics, with varied bioactivities. Flavonoids can inhibit carbohydrate-digesting enzymes, such as alpha-amylase, which is a convenient dietary strategy for controlling hyperglycemia. In the current investigation, the isolated flavonoids quercetagetin-6-O-(6-O-caffeoyl-β-D-glucopyranoside), quercetagetin-7-O-β-D-glucopyranoside, quercetagetin-6-O-β-D-glucopyranoside, minutaside A, patuletin-7-O-β-D-glucopyranoside, quercetagetin-7-methoxy-6-O-β-D-glucopyranoside, tagenols A and B, quercetagetin-3,7-dimethoxy-6-O-β-D-glucopyranoside, patuletin, quercetin-3,6-dimethyl ether, and quercetin-3-methyl ether from T. minuta were assessed for their alpha-amylase inhibition (AAI) efficacy using an in vitro assay, as well as molecular docking, dynamics simulation, and ADMET analyses. Our findings show that quercetagetin-6-O-(6-O-caffeoyl-β-D-glucopyranoside) (1), quercetagetin-7-O-β-D-glucopyranoside (2), quercetagetin-6-O-β-D-glucopyranoside (3), minutaside A (4), patuletin-7-O-β-D-glucopyranoside (5), and quercetagetin-7-methoxy-6-O-β-D-glucopyranoside (6) had a notable AAI capacity (IC50s ranged from 7.8 to 10.1 μM) compared to acarbose (IC50 7.1 μM). Furthermore, these compounds with the highest binding affinity among the tested flavonoids revealed high docking scores for AA (ranging from −12.171 to 13.882 kcal/mol) compared to that of acarbose (−14.668 kcal/mol). In MDS, these compounds were observed to show maximum stability and the greatest binding free energy, suggesting that they may contend with native ligands. In addition, the ADMET analysis showed that these active compounds had a broad span of drug-like, pharmacokinetic, and physicochemical features and did not possess any considerable undesired effects. The current results suggest the potential of these metabolites as AAI candidates. However, further in vivo and mechanistic studies are warranted to specify the efficacy of these metabolites.
Insights into Endothelin Receptors in Pulmonary Hypertension
Authors: Liu Ruiqi , Yuan Tianyi , Wang Ranran , Gong Difei , Wang Shoubao , Du Guanhua , Fang Lianhua
Published: June 2023

Pulmonary hypertension (PH) is a disease which affects the cardiopulmonary system; it is defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg as measured by right heart catheterization at rest, and is caused by complex and diverse mechanisms. In response to stimuli such as hypoxia and ischemia, the expression and synthesis of endothelin (ET) increase, leading to the activation of various signaling pathways downstream of it and producing effects such as the induction of abnormal vascular proliferation during the development of the disease. This paper reviews the regulation of endothelin receptors and their pathways in normal physiological processes and disease processes, and describes the mechanistic roles of ET receptor antagonists that are currently approved and used in clinical studies. Current clinical researches on ET are focused on the development of multi-target combinations and novel delivery methods to improve efficacy and patient compliance while reducing side effects. In this review, future research directions and trends of ET targets are described, including monotherapy and precision medicine.
A New, Convenient Way to Fully Substituted α,β-Unsaturated γ-Hydroxy Butyrolactams
Authors: Aksenov Alexander V. , Aksenov Dmitrii A. , Kurenkov Igor A. , Leontiev Alexander V. , Aksenov Nicolai A.
Published: June 2023

The synthesis of novel, highly functionalized 5-hydroxy 3-pyrrolin-2-ones via a two-step procedure involving an addition reaction between KCN and corresponding chalcones, followed by ring condensation of the obtained β-cyano ketones with het(aryl)aldehydes under basic conditions is described. This protocol enables the preparation of various 3,5-di-aryl/heteroaryl-4-benzyl substituted α,β-unsaturated γ-hydroxy butyrolactams, which are subjects of significant interest to synthetic organic and medicinal chemistry.