bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Analysis of Estimated Small Wind Energy Using Different Probability Distributions in a Desert City in Northwestern México
Authors: Burgos-Peñaloza Juan A. , Lambert-Arista Alejandro A. , García-Cueto O. Rafael , Santillán-Soto Néstor , Valenzuela Edgar , Flores-Jiménez David E.
Published: July 2024

In this paper, four probability functions are compared with the purpose of establishing a methodology to improve the accuracy of wind energy estimations in a desert city in Northwestern Mexico. Three time series of wind speed data corresponding to 2017, 2018, and 2019 were used for statistical modeling. These series were recorded with a sonic anemometer at a sampling frequency of 10 Hz. Analyses based on these data were performed at different stationarity periods (5, 30, 60, and 600 s). The estimation of the parameters characterizing the probability density functions (PDFs) was carried out using different methods; the statistical models were evaluated by the coefficient of determination and Nash–Sutcliffe efficiency coefficient, and their accuracy was estimated by the measured quadratic error, mean square error, mean absolute error, and mean absolute percentage error. Weibull, using the energy pattern factor method, and Gamma, using the Method of Moments, were the probability density functions that best described the statistical behavior of wind speed and were better at estimating the generated energy. We conclude that the proposed methodology will increase the confidence of both wind speed estimation and the energy supplied by small-scale wind installations.
A Comprehensive Review of Alarm Processing in Power Systems: Addressing Overreliance on Fault Analysis and Projecting Future Directions
Authors: Oh Jae-Young , Yoon Yong Tae , Sohn Jin-Man
Published: July 2024

This paper reviews alarm processing methods in electrical power systems, focusing on evolving strategies beyond traditional fault analysis to accommodate modern grid complexities. Historically, alarm processing has predominantly aimed at fault analysis, increasingly merging with technological advances in communication and computing. However, it still needs to fully meet the challenges posed by the dynamic characteristics of modern power systems. This review points out certain inadequacies in current practices, notably their limited adaptation to new grid conditions. The authors propose a novel generation of alarm processing methodologies designed for future grids, emphasizing managing rare events and enhancing operator decision-making through advanced anomaly detection and explainable artificial intelligence. This synthesis presents a prospective direction for future research and applications in alarm processing, advocating for methodologies better suited to supporting system operators amidst technological advancements.
Neural Network Energy Management-Based Nonlinear Control of a DC Micro-Grid with Integrating Renewable Energies
Authors: Jouili Khalil , Jouili Mabrouk , Mohammad Alsharef , Babqi Abdulrahman J. , Belhadj Walid
Published: July 2024

The broad acceptance of sustainable and renewable energy sources as a means of integrating them into electrical power networks is essential to promote sustainable development. Microgrids using direct currents (DCs) are becoming more and more popular because of their great energy efficiency and straightforward design. In this work, we discuss the control of a PV-based renewable energy system and a battery- and supercapacitor-based energy storage system in a DC microgrid. We describe a hierarchical control approach based on sliding-mode controllers and the Lyapunov stability theory. To balance the load and generation, a fuzzy logic-based energy management system has been created. Using a neural network, maximum power defects for the PV system were determined. The global asymptotic stability of the framework has been verified using Lyapunov stability analysis. In order to simulate the proposed DC microgrid and controllers, MATLAB/SimulinkR (2019a) was utilized. The outcomes show that the system operates effectively with changing production and consumption.
Stoichiometric Homeostasis of N and P in the Leaves of Different-Aged Phyllostachys edulis after Bamboo Forest Expansion in Subtropical China
Authors: Shen Jingxin , Fan Shaohui , Zhang Jiapeng , Liu Guanglu
Published: July 2024

Stoichiometric homeostasis is an important mechanism in maintaining ecosystem structure, function, and stability. Phyllostachys edulis (moso bamboo) is a typical clone plant, forming pure bamboo forests or bamboo–wood mixed forests by expanding rhizomes around. Studying the stoichiometric homeostasis characteristics of moso bamboo at different ages after expansion contributes to a deeper understanding of the stability of bamboo forest ecosystems, and is of great significance for expanding the research scope of ecological stoichiometry. Based on the stoichiometric internal stability theory, the nitrogen (N) and phosphorus (P) elements in the soil and plants of typical moso bamboo forests in Tianbaoyan National Nature Reserve of Fujian Province were determined, and the internal stability index (H) of bamboo leaves of different ages (I-du, II-du, III-du, and IV-du bamboos) was calculated. The results showed that the dependence of moso bamboo on soil nutrients and the ability of moso bamboo to regulate nutrient elements were both significantly affected by the plant’s age. Under the condition of the same soil nutrients (N, P), the content of N and P in bamboo leaves decreased significantly with the increase in bamboo age. The limiting effect of phosphorus on the growth and development of moso bamboo was greater than that of nitrogen, and the limiting effect of phosphorus on aged bamboo was greater than that of young bamboo. The stoichiometric internal stability index of N and P in bamboo leaves is HN:P > HN > HP, which means that the internal stability of moso bamboo is closely related to the limiting elements. Therefore, the regulation ability of the internal stability of moso bamboo of different ages makes it grow well in the changeable environment, has stronger adaptability and competitiveness, and the leaf internal stability of I-du bamboo was higher than that of other ages, which may be one of the reasons for its successful expansion to form a stable bamboo stand structure.
Evaluating Convolutional Neural Networks and Vision Transformers for Baby Cry Sound Analysis
Authors: Younis Samir A. , Sobhy Dalia , Tawfik Noha S.
Published: July 2024

Crying is a newborn’s main way of communicating. Despite their apparent similarity, newborn cries are physically generated and have distinct characteristics. Experienced medical professionals, nurses, and parents are able to recognize these variations based on their prior interactions. Nonetheless, interpreting a baby’s cries can be challenging for carers, first-time parents, and inexperienced paediatricians. This paper uses advanced deep learning techniques to propose a novel approach for baby cry classification. This study aims to accurately classify different cry types associated with everyday infant needs, including hunger, discomfort, pain, tiredness, and the need for burping. The proposed model achieves an accuracy of 98.33%, surpassing the performance of existing studies in the field. IoT-enabled sensors are utilized to capture cry signals in real time, ensuring continuous and reliable monitoring of the infant’s acoustic environment. This integration of IoT technology with deep learning enhances the system’s responsiveness and accuracy. Our study highlights the significance of accurate cry classification in understanding and meeting the needs of infants and its potential impact on improving infant care practices. The methodology, including the dataset, preprocessing techniques, and architecture of the deep learning model, is described. The results demonstrate the performance of the proposed model, and the discussion analyzes the factors contributing to its high accuracy.
Design Considerations and Flow Characteristics for Couette-Type Blood-Shear Devices
Authors: Chen Xingbang , Avital Eldad J. , Imran Shahid , Abbas Muhammad Mujtaba , Hinkle Patrick , Alexander Theodosios
Published: July 2024

Cardiovascular prosthetic devices, stents, prosthetic valves, heart-assist pumps, etc., operate in a wide regime of flows characterized by fluid dynamic flow structures, laminar and turbulent flows, unsteady flow patterns, vortices, and other flow disturbances. These flow disturbances cause shear stress, hemolysis, platelet activation, thrombosis, and other types of blood trauma, leading to neointimal hyperplasia, neoatherosclerosis, pannus overgrowth, etc. Couette-type blood-shearing devices are used to simulate and then clinically measure blood trauma, after which the results can be used to assist in the design of the cardiovascular prosthetic devices. However, previous designs for such blood-shearing devices do not cover the whole range of flow shear, Reynolds numbers, and Taylor numbers characteristic of all types of implanted cardiovascular prosthetic devices, limiting the general applicability of clinical data obtained by tests using different blood-shearing devices. This paper presents the key fluid dynamic parameters that must be met. Based on this, Couette device geometric parameters such as diameter, gap, flow rate, shear stress, and temperature are carefully selected to ensure that the device’s Reynolds numbers, Taylor number, operating temperature, and shear stress in the gap fully represent the flow characteristics across the operating range of all types of cardiovascular prosthetic devices. The outcome is that the numerical data obtained from the presented device can be related to all such prosthetic devices and all flow conditions, making the results obtained with such shearing devices widely applicable across the field. Numerical simulations illustrate that the types of flow patterns generated in the blood-shearing device meet the above criteria.
Fermented Gastrodia elata Bl. Alleviates Cognitive Deficits by Regulating Neurotransmitters and Gut Microbiota in D-Gal/AlCl3-Induced Alzheimer’s Disease-like Mice
Authors: Wang Yu , Zhao Min , Xie Chunzhi , Li Lilang , Lin Ling , Li Qiji , Li Liangqun , Chen Faju , Yang Xiaosheng , Yang Juan , Gao Ming
Published: July 2024

Alzheimer’s disease (AD) is a common neurological disease with recognition ability loss symptoms and a major contributor to dementia cases worldwide. Gastrodia elata Bl. (GE), a food of medicine–food homology, has been reported to have a mitigating effect on memory and learning ability decline. However, the effect of GE fermented by Lactobacillus plantarum, Acetobacter pasteurianus, and Saccharomyces (FGE) on alleviating cognitive deficits in AD was not studied. Mice were randomly divided into six groups, control, model, donepezil, low, medium, and high doses of FGE, and D-Galactose/Aluminum chloride (D-Gal/AlCl3) was used to establish an AD-like mouse model. The results indicated that FGE could improve the production of neurotransmitters and relieve oxidative stress damage in AD-like mice, which was evidenced by the declined levels of amyloid-β (Aβ), Tau, P-Tau, acetylcholinesterase (AchE), and malondialdehyde (MDA), and increased acetylcholine (Ach), choline acetyltransferase (ChAT), and superoxide dismutase (SOD) levels in brain tissue. Notably, FGE could enhance the richness of the gut microbiota, especially for beneficial bacteria such as Lachnospira and Lactobacillus. Non-target metabolomics results indicated that FGE could affect neurotransmitter levels by regulating amino acid metabolic pathways to improve AD symptoms. The FGE possessed an ameliorative effect on AD by regulating neurotransmitters, oxidative stress levels, and gut microbiota and could be considered a good candidate for ameliorating AD.
Applications of Fractional-Order Calculus in Robotics
Authors: Singh Abhaya Pal , Bingi Kishore
Published: July 2024

Fractional calculus, a branch of mathematical analysis, extends traditional calculus that encompasses integrals and derivatives of non-integer orders [...]
Correlations between IR Luminosity, Star Formation Rate, and CO Luminosity in the Local Universe
Authors: Bonato Matteo , Baronchelli Ivano , Casasola Viviana , De Zotti Gianfranco , Trobbiani Leonardo , Ruli Erlis , Tailor Vidhi , Bianchi Simone
Published: July 2024

We exploit the DustPedia sample of galaxies within approximately 40 Mpc, selecting 388 sources, to investigate the correlations between IR luminosity (LIR), the star formation rate (SFR), and the CO(1-0) luminosity (LCO) down to much lower luminosities than reached by previous analyses. We find a sub-linear dependence of the SFR on LIR. Below log(LIR/L⊙)≃10 or SFR≃1M⊙yr−1, the SFR/LIR ratio substantially exceeds the standard ratio for dust-enshrouded star formation, and the difference increases with decreasing LIR values. This implies that the effect of unobscured star formation overcomes that of dust heating by old stars, at variance with results based on the Planck ERCSC galaxy sample. We also find that the relations between the LCO and LIR or the SFR are consistent with those obtained at much higher luminosities.
Comparing Cancer Risk Management between Females with Truncating CHEK2 1100delC versus Missense CHEK2 I157T Variants
Authors: Garmendia Diego , Weidner Anne , Venton Lindsay , Pal Tuya
Published: July 2024

Breast cancer (BC) risks imparted by CHEK2 c.1100delC (“1100delC”) germline pathogenic/likely pathogenic variant (GPV) are 20–30%, compared to CHEK2 c.470T>C (“I157T”) GPV with <20%, leading to different breast screening recommendations through MRI. We compared cancer risk management (CRM) across these two GPVs. Study participants were adult females with an 1100delC or I157T GPV drawn from the Inherited Cancer Registry (ICARE) across the United States. Cancer history, clinical characteristics, and CRM were compared using chi-squared tests, t-tests, and logistic regression. Of 150 CHEK2 carriers, 40.7% had BC, with a mean age of 50. Comparing 1100delC and I157T GPVs, there were no differences in rates of (1) breast MRI among those with (65.2% versus 55.6% of 23 and 9; p = 0.612) and without (44.0% versus 44.8% of 50 and 29; p = 0.943) BC; (2) risk-reducing mastectomy among those with (50% versus 38.9% of 46 and 15; p = 0.501) and without (13.8% versus 6.5% of 58 and 31; p = 0.296) BC; and (3) risk-reducing salpingo-oophorectomy among those with (24.2% versus 22.2% of 45 and 18; p = 0.852) and without (17.5% versus 16.7% of 57 and 30; p = 0.918) BC. The results suggest over-screening with breast MRI among CHEK2 I157T GPV carriers and possible overuse of risk-reducing surgeries among CHEK2 carriers.
Somatic Variants Acquired Later in Life Associated with Thoracic Aortic Aneurysms: JAK2 V617F
Authors: Waldron Christina , Zafar Mohammad A. , Ma Deqiong , Zhang Hui , Dykas Daniel , Ziganshin Bulat A. , Popa Andreea , Jha Alokkumar , Kwan Jennifer M. , Elefteriades John A.
Published: July 2024

The JAK2 V617F somatic variant is a well-known driver of myeloproliferative neoplasms (MPN) associated with an increased risk for athero-thrombotic cardiovascular disease. Recent studies have demonstrated its role in the development of thoracic aortic aneurysm (TAA). However, limited clinical information and level of JAK2 V617F burden have been provided for a comprehensive evaluation of potential confounders. A retrospective genotype-first study was conducted to identify carriers of the JAK2 V617F variant from an internal exome sequencing database in Yale DNA Diagnostics Lab. Additionally, the overall incidence of somatic variants in the JAK2 gene across various tissue types in the healthy population was carried out based on reanalysis of SomaMutDB and data from the UK Biobank (UKBB) cohort to compare our dataset to the population prevalence of the variant. In our database of 12,439 exomes, 594 (4.8%) were found to have a thoracic aortic aneurysm (TAA), and 12 (0.049%) were found to have a JAK2 V617F variant. Among the 12 JAK2 V617F variant carriers, five had a TAA (42%), among whom four had an ascending TAA and one had a descending TAA, with a variant allele fraction ranging from 11.2% to 20%. Among these five patients, 60% were female, and average age at diagnosis was 70 (49–79). The mean ascending aneurysm size was 5.05 cm (range 4.6–5.5 cm), and four patients had undergone surgical aortic replacement or repair. UKBB data revealed a positive correlation between the JAK2 V617F somatic variant and aortic valve disease (effect size 0.0086, p = 0.85) and TAA (effect size = 0.004, p = 0.92), although not statistically significant. An unexpectedly high prevalence of TAA in our dataset (5/594, 0.84%) is greater than the prevalence reported before for the general population, supporting its association with TAA. JAK2 V617F may contribute a meaningful proportion of otherwise unexplained aneurysm patients. Additionally, it may imply a potential JAK2-specific disease mechanism in the developmental of TAA, which suggests a possible target of therapy that warrants further investigation.
Screening of CIMMYT and South Asian Bread Wheat Germplasm Reveals Marker–Trait Associations for Seedling Resistance to Septoria Nodorum Blotch
Authors: Mandal Rupsanatan , He Xinyao , Singh Gyanendra , Kabir Muhammad Rezaul , Joshi Arun Kumar , Singh Pawan Kumar
Published: July 2024

Wheat (Triticum aestivum L.) production is adversely impacted by Septoria nodorum blotch (SNB), a fungal disease caused by Parastagonospora nodorum. Wheat breeders are constantly up against this biotic challenge as they try to create resistant cultivars. The genome-wide association study (GWAS) has become an efficient tool for identifying molecular markers linked with SNB resistance. This technique is used to acquire an understanding of the genetic basis of resistance and to facilitate marker-assisted selection. In the current study, a total of 174 bread wheat accessions from South Asia and CIMMYT were assessed for SNB reactions at the seedling stage in three greenhouse experiments at CIMMYT, Mexico. The results indicated that 129 genotypes were resistant to SNB, 39 were moderately resistant, and only 6 were moderately susceptible. The Genotyping Illumina Infinium 15K Bead Chip was used, and 11,184 SNP markers were utilized to identify marker–trait associations (MTAs) after filtering. Multiple tests confirmed the existence of significant MTAs on chromosomes 5B, 5A, and 3D, and the ones at Tsn1 on 5B were the most stable and conferred the highest phenotypic variation. The resistant genotypes identified in this study could be cultivated in South Asian countries as a preventative measure against the spread of SNB. This work also identified molecular markers of SNB resistance that could be used in future wheat breeding projects.
Influence of ACTN3 R577X Polymorphism on Blood Creatine Kinase Levels Relative to Number of Sprints in Brazilian Professional Soccer Players
Authors: de Almeida Kathleen Y. , Zempo Hirofumi , Saito Mika , Cetolin Tiago , dos Santos Guimarães Rodrigo , Marrero Andrea Rita , Aguiar Aderbal S. , Kikuchi Naoki
Published: July 2024

This study sought to assess how post-game creatine kinase (CK) levels correlate with the number of sprints and the impact of the ACTN3 polymorphism on this response. This research constituted a descriptive/observational, retrospective cross-sectional study. DNA was extracted from blood samples for ACTN3 polymorphism genotyping. CK was measured 48 h after official matches, and the number of sprints (>19 km/h) was tracked using Global Positioning System (GPS) technology. The main cohort included 23 professional soccer players from the top tier of the Brazilian Championship. We analyzed 115 GPS + CK data sets. The replication cohort comprised 18 professional soccer players from the First Division of the Championship, had the same methodology applied, and featured a total of 90 GPS (sprints > 25.2 km/h) + CK data sets. For the main cohort, a significant positive correlation was seen between the number of sprints and the CK levels (p = 0.009). Athletes with the ACTN3 RR genotype had higher CK levels as more sprints were performed during the match (p = 0.017). However, the relationship was not found for X allele carriers (p > 0.05). For the replication cohort, there was a near-significant correlation between CK levels and the number of sprints (p = 0.05), and RR individuals showed a significant association (p = 0.01), whereas X allele carriers did not (p = 0.06). A greater number of sprints during matches is linked to higher CK levels, primarily among players with the ACTN3 RR genotype, which is potentially due to an increased presence of type II muscle fibers. These findings were replicated for both cohorts of elite Brazilian soccer players, emphasizing the importance of genetic factors in injury prevention.
Effectiveness of Online Programmes for Family Carers of People with Intellectual Disabilities: Systematic Review of the International Evidence Base
Authors: Leonard Rachel , Hughes Nathan , Forbes Trisha , Brown Michael , Marsh Lynne , Truesdale Maria , Todd Stuart , Linden Mark
Published: July 2024

This systematic literature review examines the evidence base on the effectiveness of online programmes on the mental health and well-being of family carers of people with intellectual disabilities. Databases (ERIC, Medline, PsycINFO and CINAHL) were searched for intervention studies that considered online interventions for family carers of people with intellectual disabilities. Data were extracted using standardised data extraction tools. Bias was assessed using the Cochrane risk of bias tool for randomised trials (RoB 2). Screening, extraction and assessment of bias were completed independently by two members of the research team. Given the low number of included studies and different outcomes assessed within them, it was not possible to conduct a meta-analysis; therefore, data are presented narratively. Two studies met the criteria to be included in the review. Both studies utilised a feasibility randomised controlled trial methodology. One study found a significant decrease in parental stress, while the other found a significant increase in psychological well-being. Caution must be taken in drawing firm conclusions, given the small sample sizes and low retention rates in both studies. Online programmes seem to offer potential benefits to family carers of people with intellectual disabilities. However, further investigation is needed to examine these programmes, adopting a collaborative approach with family carers.
The Prevalence of Candida albicans and Malassezia globosa in Preschool Children with Severe Early Childhood Caries: A Case-Control Study
Authors: Man Vanessa C. W. , Neelakantan Prasanna , Yiu Cynthia K. Y.
Published: July 2024

Background: This cross-sectional study aimed to identify the prevalence of Candida albicans and Malassezia globosa in children with severe early childhood caries and caries-free children in Hong Kong. Methods: This study first recruited a total of 80 children aged between 48 and 72 months old, 40 children with severe early childhood caries, and 40 caries-free children. The children were then further divided into four groups, with 20 children in each group: Group 1: Severe early childhood caries—C. albicans, Group 2: Severe early childhood caries—M. globosa, Group 3: Caries-free—C. albicans and Group 4: Caries-free—M. globosa. Saliva, plaque, and caries lesion samples were collected from participants with severe early childhood caries, while only saliva and plaque samples were collected from caries-free participants. Caries status of the primary molars was assessed using WHO’s decayed, missing, and filled tooth index, and the severity of cavitated lesions was determined based on International Caries Diagnosis and Assessment System criteria as caries code 5 or 6. The samples were analyzed using an Internal Transcribed Space and Quantitative Real-Time Polymerase Chain Reaction. Results:C. albicans was more prevalent in saliva and plaque samples of severe early childhood caries than in the caries-free group. Proportion of C. albicans in both saliva and plaque samples differed significantly between severe early childhood caries and caries-free groups (p < 0.05). Within the severe early childhood caries group, the proportion of children with C. albicans varied between 6 and 46%. No significant difference in M. globosa load was found between plaque samples of the severe early childhood caries and caries-free groups (p = 0.159). Conversely, no significant difference in M. globosa load was observed between saliva samples of severe early childhood caries and caries-free groups (p = 0.051). Conclusions: This study demonstrated a strong association between C. albicans and severe early childhood caries. M. globosa was detected in both the caries-free and severe early childhood caries groups, albeit at low levels.
Moral Distress of Nurses Working in Paediatric Healthcare Settings
Authors: Miranda Ana Cristina Ribeiro , Fernandes Sara Duarte , Ramos Sílvia , Nunes Elisabete , Fabri Janaína , Caldeira Sílvia
Published: July 2024

This scoping review aims to map the evidence on moral distress of nurses working in paediatric healthcare settings from homecare to hospital. It was conducted according to the Joanna Briggs Institute. International databases were searched according to the specific thesaurus and free search terms. Independent screening and analysis were conducted using Rayyan QCRI. This review considered a total of 54 studies, including quantitative and qualitative studies, systematic reviews, and grey literature; English and Portuguese languages were included. Moral distress is a phenomenon discussed in nursing literature and in the paediatric context but is considered absent from discussion in clinical practice. It is caused by disproportionate care associated with overtreatment. Nurses can present a variety of symptoms, characterising moral distress as a highly subjective experience. The paediatric contexts of practice should promote a healthy ethical climate and work towards a moral community built with peer support, education, communication, leadership, and management involvement. Moral distress is still a complex and challenging multidimensional concept, and the aim should be to promote a culture of prevention of the devastating consequences of moral distress and work towards moral resilience.
Alpha-Synuclein Interaction with UBL3 Is Upregulated by Microsomal Glutathione S-Transferase 3, Leading to Increased Extracellular Transport of the Alpha-Synuclein under Oxidative Stress
Authors: Yan Jing , Kahyo Tomoaki , Zhang Hengsen , Ping Yashuang , Zhang Chi , Jiang Shuyun , Ji Qianqing , Ferdous Rafia , Islam Md. Shoriful , Oyama Soho , Aramaki Shuhei , Sato Tomohito , Mimi Mst. Afsana , Hasan Md. Mahmudul , Setou Mitsutoshi
Published: July 2024

Aberrant aggregation of misfolded alpha-synuclein (α-syn), a major pathological hallmark of related neurodegenerative diseases such as Parkinson’s disease (PD), can translocate between cells. Ubiquitin-like 3 (UBL3) is a membrane-anchored ubiquitin-fold protein and post-translational modifier. UBL3 promotes protein sorting into small extracellular vesicles (sEVs) and thereby mediates intercellular communication. Our recent studies have shown that α-syn interacts with UBL3 and that this interaction is downregulated after silencing microsomal glutathione S-transferase 3 (MGST3). However, how MGST3 regulates the interaction of α-syn and UBL3 remains unclear. In the present study, we further explored this by overexpressing MGST3. In the split Gaussia luciferase complementation assay, we found that the interaction between α-syn and UBL3 was upregulated by MGST3. While Western blot and RT-qPCR analyses showed that silencing or overexpression of MGST3 did not significantly alter the expression of α-syn and UBL3, the immunocytochemical staining analysis indicated that MGST3 increased the co-localization of α-syn and UBL3. We suggested roles for the anti-oxidative stress function of MGST3 and found that the effect of MGST3 overexpression on the interaction between α-syn with UBL3 was significantly rescued under excess oxidative stress and promoted intracellular α-syn to extracellular transport. In conclusion, our results demonstrate that MGST3 upregulates the interaction between α-syn with UBL3 and promotes the interaction to translocate intracellular α-syn to the extracellular. Overall, our findings provide new insights and ideas for promoting the modulation of UBL3 as a therapeutic agent for the treatment of synucleinopathy-associated neurodegenerative diseases.
MMP-3 Knockout Induces Global Transcriptional Changes and Reduces Cerebral Infarction in Both Male and Female Models of Ischemic Stroke
Authors: Hamblin Milton H. , Boese Austin C. , Murad Rabi , Lee Jean-Pyo
Published: July 2024

Ischemic stroke followed by reperfusion (IR) leads to extensive cerebrovascular injury characterized by neuroinflammation and brain cell death. Inhibition of matrix metalloproteinase-3 (MMP-3) emerges as a promising therapeutic approach to mitigate IR-induced stroke injury. We employed middle cerebral artery occlusion with subsequent reperfusion (MCAO/R) to model ischemic stroke in adult mice. Specifically, we investigated the impact of MMP-3 knockout (KO) on stroke pathophysiology using RNA sequencing (RNA-seq) of stroke brains harvested 48 h post-MCAO. MMP-3 KO significantly reduced brain infarct size following stroke. Notably, RNA-seq analysis showed that MMP-3 KO altered expression of 333 genes (252 downregulated) in male stroke brains and 3768 genes (889 downregulated) in female stroke brains. Functional pathway analysis revealed that inflammation, integrin cell surface signaling, endothelial- and epithelial-mesenchymal transition (EndMT/EMT), and apoptosis gene signatures were decreased in MMP-3 KO stroke brains. Intriguingly, MMP-3 KO downregulated gene signatures more profoundly in females than in males, as indicated by greater negative enrichment scores. Our study underscores MMP-3 inhibition as a promising therapeutic strategy, impacting multiple cellular pathways following stroke.
Hair Growth Promoting Effects of 15-Hydroxyprostaglandin Dehydrogenase Inhibitor in Human Follicle Dermal Papilla Cells
Authors: Lim Hye Won , Kim Hak Joong , Jeon Chae Young , Lee Yurim , Kim Mujun , Kim Jinsick , Kim Soon Re , Lee Sanghwa , Lim Dong Chul , Park Hee Dong , Park Byung Cheol , Shin Dong Wook
Published: July 2024

Prostaglandin E2 (PGE2) is known to be effective in regenerating tissues, and bimatoprost, an analog of PGF2α, has been approved by the FDA as an eyelash growth promoter and has been proven effective in human hair follicles. Thus, to enhance PGE2 levels while improving hair loss, we found dihydroisoquinolinone piperidinylcarboxy pyrazolopyridine (DPP), an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using DeepZema®, an AI-based drug development program. Here, we investigated whether DPP improved hair loss in human follicle dermal papilla cells (HFDPCs) damaged by dihydrotestosterone (DHT), which causes hair loss. We found that DPP enhanced wound healing and the expression level of alkaline phosphatase in DHT-damaged HFDPCs. We observed that DPP significantly down-regulated the generation of reactive oxygen species caused by DHT. DPP recovered the mitochondrial membrane potential in DHT-damaged HFDPCs. We demonstrated that DPP significantly increased the phosphorylation levels of the AKT/ERK and activated Wnt signaling pathways in DHT-damaged HFDPCs. We also revealed that DPP significantly enhanced the size of the three-dimensional spheroid in DHT-damaged HFDPCs and increased hair growth in ex vivo human hair follicle organ culture. These data suggest that DPP exhibits beneficial effects on DHT-damaged HFDPCs and can be utilized as a promising agent for improving hair loss.
Inhibition of Indoleamine 2,3-Dioxygenase Exerts Antidepressant-like Effects through Distinct Pathways in Prelimbic and Infralimbic Cortices in Rats under Intracerebroventricular Injection with Streptozotocin
Authors: Qin Yu , Hu Xiao , Zhao Hui-Ling , Kurban Nurhumar , Chen Xi , Yi Jing-Kun , Zhang Yuan , Cui Su-Ying , Zhang Yong-He
Published: July 2024

The application of intracerebroventricular injection of streptozotocin (ICV-STZ) is considered a useful animal model to mimic the onset and progression of sporadic Alzheimer’s disease (sAD). In rodents, on day 7 of the experiment, the animals exhibit depression-like behaviors. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn), is closely related to depression and AD. The present study aimed to investigate the pathophysiological mechanisms of preliminary depression-like behaviors in ICV-STZ rats in two distinct cerebral regions of the medial prefrontal cortex, the prelimbic cortex (PrL) and infralimbic cortex (IL), both presumably involved in AD progression in this model, with a focus on IDO-related Kyn pathways. The results showed an increased Kyn/Trp ratio in both the PrL and IL of ICV-STZ rats, but, intriguingly, abnormalities in downstream metabolic pathways were different, being associated with distinct biological effects. In the PrL, the neuroprotective branch of the Kyn pathway was attenuated, as evidenced by a decrease in the kynurenic acid (KA) level and Kyn aminotransferase II (KAT II) expression, accompanied by astrocyte alterations, such as the decrease in glial fibrillary acidic protein (GFAP)-positive cells and increase in morphological damage. In the IL, the neurotoxicogenic branch of the Kyn pathway was enhanced, as evidenced by an increase in the 3-hydroxy-kynurenine (3-HK) level and kynurenine 3-monooxygenase (KMO) expression paralleled by the overactivation of microglia, reflected by an increase in ionized calcium-binding adaptor molecule 1 (Iba1)-positive cells and cytokines with morphological alterations. Synaptic plasticity was attenuated in both subregions. Additionally, microinjection of the selective IDO inhibitor 1-Methyl-DL-tryptophan (1-MT) in the PrL or IL alleviated depression-like behaviors by reversing these different abnormalities in the PrL and IL. These results suggest that the antidepressant-like effects linked to Trp metabolism changes induced by 1-MT in the PrL and IL occur through different pathways, specifically by enhancing the neuroprotective branch in the PrL and attenuating the neurotoxicogenic branch in the IL, involving distinct glial cells.
Final Results from the First European Real-World Experience on Lusutrombopag Treatment in Cirrhotic Patients with Severe Thrombocytopenia: Insights from the REAl-World Lusutrombopag Treatment in ITalY Study
Authors: Gallo Paolo , De Vincentis Antonio , Terracciani Francesca , Falcomatà Andrea , Pace Palitti Valeria , Russello Maurizio , Vignone Anthony , Alvaro Domenico , Tortora Raffaella , Biolato Marco , Pompili Maurizio , Calvaruso Vincenza , Marzia Veneziano , Tizzani Marco , Caneglias Alessandro , Frigo Francesco , Gesualdo Marcantonio , Marzano Alfredo , Rosato Valerio , Claar Ernesto , Villani Rosanna , Izzi Antonio , Cozzolongo Raffaele , Cozzolino Antonio , Airoldi Aldo , Mazzarelli Chiara , Distefano Marco , Iegri Claudia , Fagiuoli Stefano , Messina Vincenzo , Ragone Enrico , Sacco Rodolfo , Cacciatore Pierluigi , Masutti Flora , Crocé Saveria Lory , Moretti Alessandra , Flagiello Valentina , Di Pasquale Giulia , Picardi Antonio , Vespasiani-Gentilucci Umberto
Published: July 2024

Background and aims: Management of severe thrombocytopenia poses significant challenges in patients with chronic liver disease. Here, we aimed to evaluate the first real-world European post-marketing cohort of cirrhotic patients treated with lusutrombopag, a thrombopoietin receptor agonist, verifying the efficacy and safety of the drug. Methods: In the REAl-world Lusutrombopag treatment in ITalY (REALITY) study, we collected data from consecutive cirrhotic patients treated with lusutrombopag in 19 Italian hepatology centers, mostly joined to the “Club Epatologi Ospedalieri” (CLEO). Primary and secondary efficacy endpoints were the ability of lusutrombopag to avoid platelet transfusions and to raise the platelet count to ≥50,000/μL, respectively. Treatment-associated adverse events were also collected. Results: A total of 66 patients and 73 cycles of treatment were included in the study, since 5 patients received multiple doses of lusutrombopag over time for different invasive procedures. Fourteen patients (19%) had a history of portal vein thrombosis (PVT). Lusutrombopag determined a significant increase in platelet count [from 37,000 (33,000–44,000/μL) to 58,000 (49,000–82,000), p < 0.001]. The primary endpoint was met in 84% of patients and the secondary endpoint in 74% of patients. Baseline platelet count was the only independent factor associated with response in multivariate logistic regression analysis (OR for any 1000 uL of 1.13, CI95% 1.04–1.26, p 0.01), with a good discrimination power (AUROC: 0.78). Notably, a baseline platelet count ≤ 29,000/μL was identified as the threshold for identifying patients unlikely to respond to the drug (sensitivity of 91%). Finally, de novo PVT was observed in four patients (5%), none of whom had undergone repeated treatment, and no other safety or hemorrhagic events were recorded in the entire population analyzed. Conclusions: In this first European real-world series, lusutrombopag demonstrated efficacy and safety consistent with the results of registrational studies. According to our results, patients with baseline platelet counts ≤29,000/μL are unlikely to respond to the drug.
Young Women with Early-Stage Breast Cancer Treated with Upfront Surgery: Overview of Oncological Outcomes
Authors: Scardina Lorenzo , Carnassale Beatrice , Di Leone Alba , Sanchez Alejandro Martin , Biondi Ersilia , Moschella Francesca , D’Archi Sabatino , Franco Antonio , De Lauretis Flavia , Di Guglielmo Enrico , Petrazzuolo Eleonora , Magno Stefano , Masetti Riccardo , Franceschini Gianluca
Published: July 2024

Background: Breast cancer in young women aged < 40 years is rare and often aggressive with less favorable survival rates. The lack of systematic screening, later stage at diagnosis, and a more aggressive disease biology may all contribute to their poor prognosis. Data on the best management remain conflicting, especially those regarding surgical management, either breast-conserving or mastectomy. To our knowledge, there are limited studies surrounding the treatment of young women with early breast cancer, and this analysis evaluated the oncological outcomes for those patients who underwent surgery upfront. Methods: We conducted a retrospective study including 130 young women with early breast cancer from a total of 373 consecutive patients treated with upfront surgery between January 2016 and December 2021 at our institution. Local recurrence-free survival (LR-FS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were evaluated. Results: The median follow-up was 61.1 months (range, 25–95). A total of 92 (70.8%) patients underwent breast-conserving surgery, while 38 (29.2%) patients underwent conservative mastectomy with immediate implant breast reconstruction. In total, 8 of 130 patients (6.2%) developed a local recurrence in the treated breast, an7 (5.4%) patients presented distant metastasis. Overall, two (1.6%) patients died due to breast cancer recurrence. Conclusions: The results of our study interestingly support breast-conserving surgery in young patients with early-stage breast cancer. While appropriate breast-conserving surgery can achieve favorable oncological outcomes and can always be considered a valid alternative to conservative mastectomy in upfront surgery, a younger age at diagnosis should never be used alone to choose the type of surgery.
Associations of Intact and C-Terminal FGF23 with Inflammatory Markers in Older Patients Affected by Advanced Chronic Kidney Disease
Authors: Abinti Matteo , Vettoretti Simone , Caldiroli Lara , Mattinzoli Deborah , Ikehata Masami , Armelloni Silvia , Molinari Paolo , Alfieri Carlo Maria , Castellano Giuseppe , Messa Piergiorgio
Published: July 2024

Background: In patients with chronic kidney disease (CKD), Fibroblast Growth Factor 23 (FGF23) is markedly increased and has been proposed to interact with systemic inflammation. Methods: In this cross-sectional study, we evaluated the correlations of intact FGF23, c-terminal FGF23, and the FGF23 ratio (c-terminal to intact) with some inflammatory cytokines in 111 elderly patients with advanced CKD not yet in dialysis. Results: Estimated glomerular filtration rate (eGFR) was inversely correlated with intact FGF23 and c-terminal FGF23, as well as with interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP-1). Intact FGF23 levels were directly correlated with IL-6 (r = 0.403; p < 0.001) and TNFα (r = 0.401; p < 0.001) while c-terminal FGF23 was directly correlated with MCP-1 (r = 0.264; p = 0.005). The FGF23 ratio was, instead, inversely correlated with IL-6 (r = −0.326; p < 0.001). Multivariate analysis revealed that intact FGF23 was directly associated with TNFα [B = 0.012 (95% CI 0.006, 0.019); p = 0.003] and c-terminal FGF23 was directly associated with MCP-1 [B = 0.001 (95% CI 0.000, 0.002); p = 0.038], while the FGF23 ratio was inversely correlated with IL-6 [B = −0.028 (95% CI −0.047, −0.010); p = 0.002]. Conclusions: Our data demonstrate that, in CKD patients, intact FGF23 and the metabolites deriving from its proteolytic cleavage are differently associated with some inflammatory pathways. In particular, intact FGF23 is mainly associated with IL-6 and TNFα, c-terminal FGF23 with MCP-1, and the FGF23 ratio with IL6.
3D Printing for Customized Bone Reconstruction in Spheno-Orbital Meningiomas: A Systematic Literature Review and Institutional Experience
Authors: Serioli Simona , Pietrantoni Alberto , Benato Alberto , Galeazzi Marco , Piazza Amedeo , Lauretti Liverana , Mattogno Pier Paolo , Olivi Alessandro , Fontanella Marco Maria , Doglietto Francesco
Published: July 2024

Background: The treatment of spheno-orbital meningiomas (SOMs) requires extensive bone resections, creating significant defects in a complex geometrical space. Bone reconstruction represents a fundamental step that optimizes long-term aesthetic and functional outcomes. In recent years, 3D printing technology has also been exploited for complex skull base reconstructions, but reports remain scarce. Methods: We retrospectively analyzed four consecutive patients who underwent SOM resection and one-step 3D PEEK customized reconstruction from 2019 to 2023. A systematic review of 3D printing customized implants for SOM was then performed. Results: All patients underwent a frontotemporal craniotomy, removal of SOM, and reconstruction of the superolateral orbital wall and pterional region. The aesthetic outcome was extremely satisfactory in all cases. No orbital implant malposition or infectious complications were documented. Eleven papers were included in the literature review, describing 27 patients. Most (23) patients underwent a single-stage reconstruction; in three cases, the implant was positioned to correct postoperative delayed enophthalmos. Porous titanium was the most used material (16 patients), while PEEK was used in three cases. Prosthesis malposition was described in two (7.4%) patients. Conclusions: Single-step reconstruction with a personalized 3D PEEK prosthesis represents a valid reconstruction technique for the treatment of SOMs with good aesthetic outcomes.
Epithelial Remodeling and Epithelial Wavefront Aberrometry after Spherical vs. Cylindrical Myopic Small Incision Lenticule Extraction (SMILE)
Authors: Brunner Barbara S. , Feldhaus Lukas , Mayer Wolfgang J. , Siedlecki Jakob , Dirisamer Martin , Priglinger Siegfried G. , Kassumeh Stefan , Luft Nikolaus
Published: July 2024

Background/Objectives: To compare the epithelial thickness changes and the changes in epithelial wavefront aberrometry following spherical versus astigmatic myopic small incision lenticule extraction (SMILE). Methods: Eighty-six eyes of 86 patients who underwent SMILE were included in this retrospective study. A total of 43 eyes underwent myopic spherical correction (spherical group) and 43 eyes underwent myopic cylindrical correction (cylindrical group). The groups were matched according to the spherical equivalent of surgically corrected refraction. Subjective manifest refraction as well as high-resolution anterior segment optical coherence tomography (MS-39; CSO; Florence, Italy) were obtained preoperatively as well as 3 months postoperatively. The latter was utilized for computing epithelial wavefront aberrometry in addition to epithelial thickness mapping. Results: Epithelial thickness increased significantly in both groups after SMILE (p < 0.01). In the cylindrical group, epithelial thickening was more pronounced on the flat meridian compared to the steep meridian (p = 0.04). In both groups, epithelial wavefront aberrometry showed a significant postoperative increase in the epithelium’s spherical refractive power, causing a myopization of −0.24 ± 0.42 diopters (D) in the spherical group (p < 0.01) and −0.41 ± 0.52 D in the cylindrical group (p < 0.0001). While no significant changes in epithelial cylindrical refractive power were observed in the spherical group, a significant increase was noted in the cylindrical group from −0.21 ± 0.24 D to −0.37 ± 0.31 D (p = 0.01). In both groups, epithelial higher-order aberrations increased significantly (p < 0.001). Conclusions: Postoperative epithelial remodeling after SMILE alters lower-order (sphere and cylinder) and higher-order aberrations of the corneal epithelial wavefront and might contribute to refractive undercorrection, especially in astigmatic corrections. Epithelial wavefront aberrometry can be used to quantify the refractive effect of epithelial remodeling processes after keratorefractive surgery.
Multimorbidity in Incident Heart Failure: Characterisation and Impact on 1-Year Outcomes
Authors: Gracia Gutiérrez Anyuli , Moreno-Juste Aida , Laguna-Berna Clara , Santos-Mejías Alejandro , Poblador-Plou Beatriz , Gimeno-Miguel Antonio , Ruiz Laiglesia Fernando J.
Published: July 2024

Background/Objectives: Heart failure (HF) is usually accompanied by other comorbidities, which, altogether, have a major impact on patients and healthcare systems. Our aim was to analyse the demographic and clinical characteristics of incident HF patients and the effect of comorbidities on one-year health outcomes. Methods: This was an observational, retrospective, population-based study of incident HF patients between 2014 and 2018 in the EpiChron Cohort, Spain. The included population contained all primary and hospital care patients with a diagnosis of HF. All chronic diseases in their electronic health records were pooled into three comorbidity clusters (cardiovascular, mental, other physical). These comorbidity groups and the health outcomes were analysed until 31 December 2018. A descriptive analysis was performed. Cox regression models and survival curves were calculated to determine the hazard risk (HR) of all-cause mortality, all-cause and HF-related hospital admissions, hospital readmissions, and emergency room visits for each comorbidity group. Results: In total, 13,062 incident HF patients were identified (mean age = 82.0 years; 54.8% women; 93.7% multimorbid; mean of 4.52 ± 2.06 chronic diseases). After one-year follow-up, there were 3316 deaths (25.3%) and 4630 all-cause hospitalisations (35.4%). After adjusting by gender, age, and inpatient/outpatient status, the mental cluster was associated (HR; 95% confidence interval) with a higher HR of death (1.08; 1.01–1.16) and all-cause hospitalisation (1.09; 1.02–1.16). Conclusions: Cardiovascular comorbidities are the most common and studied ones in HF patients; however, they are not the most strongly associated with negative impacts on health outcomes in these patients. Our findings suggest the importance of a holistic and integral approach in the care of HF patients and the need to take into account the entire spectrum of comorbidities for improving HF management in clinical practice.