bluuebunny/crossref_metadata_2025 huggingface dataset:
Graph-Based Deep Learning Model for Forecasting Chloride Concentration in Urban Streams to Protect Salt-Vulnerable Areas
Authors: Oliveira Santos Victor , Costa Rocha Paulo Alexandre , Thé Jesse Van Griensven , Gharabaghi Bahram
Published: September 2023

In cold-climate regions, road salt is used as a deicer for winter road maintenance. The applied road salt melts ice and snow on roads and can be washed off through storm sewer systems into nearby urban streams, harming the freshwater ecosystem. Therefore, aiming to develop a precise and accurate model to determine future chloride concentration in the Credit River in Ontario, Canada, the present work makes use of a “Graph Neural Network”–“Sample and Aggregate” (GNN-SAGE). The proposed GNN-SAGE is compared to other models, including a Deep Neural Network-based transformer (DNN-Transformer) and a benchmarking persistence model for a 6 h forecasting horizon. The proposed GNN-SAGE surpassed both the benchmarking persistence model and the DNN-Transformer model, achieving RMSE and R2 values of 51.16 ppb and 0.88, respectively. Additionally, a SHAP analysis provides insight into the variables that influence the model’s forecasting, showing the impact of the spatiotemporal neighboring data from the network and the seasonality variables on the model’s result. The GNN-SAGE model shows potential for use in the real-time forecasting of water quality in urban streams, aiding in the development of regulatory policies to protect vulnerable freshwater ecosystems in urban areas.
Groundwater Recharge Assessment for Small Karstic Catchment Basins with Different Extents of Anthropogenic Development
Authors: Anker Yaakov , Gimburg Alexander , Zilberbrand Michael , Livshitz Yakov , Mirlas Vladimir
Published: September 2023

Climate change and anthropogenic development considerably influence groundwater resource distribution and conditions. Catchment basin groundwater recharge—discharge computation reliability is needed for effective groundwater management policy formulation and implementation and also for resolving environmental challenges in such a watershed. This paper compares groundwater recharge patterns between urbanized and nearly natural small catchment basins of Israel’s Western Mountain Aquifer (WMA). The correlation between precipitation volumes and surface runoff shows that surface runoff volume constitutes 3–4% of the precipitation volume in the Natuf catchment and 1–2% in the Te’enim catchment. These assessments reflect the differences in the land use, outcrop lithology, topography and hydrodynamic properties of the WMA within the model basins. A groundwater recharge assessment based on water balance and water table fluctuation methods was performed for the mountainous karstic Te’enim and Natuf catchment basins for all the available data from 2000 to 2020. The water balance method provided reliable estimates. The groundwater recharge assessment considered land use classification and climate changes during this period. The average multiannual groundwater recharge values for the 2000–2021 period varied from 17.6 × 106–24.8 × 106 m3 to 24.5–29.2 × 106 m3 for the Te’enim and Natuf catchment basins, respectively. For the relatively dry period of the 2013/2014–2017/2018 hydrological years when detailed measurements of the surface runoff were available, the corresponding groundwater recharge volumes were 17.6 × 106 m3 and 24.5 × 106 m3. The corresponding local groundwater recharge coefficients constitute 0.46–0.57 for the mostly agricultural Te’enim basin and 0.29–0.32 for the urbanized Natuf basin. A significant difference in the groundwater recharge coefficients between the studied catchments is caused mostly by the differences in land use. It is suggested that applying such a groundwater recharge estimation for small hydrological sub-basins can improve one’s understanding of the groundwater recharge distribution within a major basin, enabling the application of an accurate regional hydrogeological model that may be extrapolated to other similar regions.
Recovery of Energy and Carbon Dioxide from Craft Brewery Wastes for Onsite Use
Authors: Rawalgaonkar Dhanashree , Zhang Yan , Walker Selina , Kirchman Paul , Zhang Qiong , Ergas Sarina J.
Published: September 2023

Interest in craft beers is increasing worldwide due to their flavor and variety. However, craft breweries have high water, energy, and carbon dioxide (CO2) demands and generate large quantities of high-strength waste and greenhouse gases. While many large breweries recover energy using anaerobic digestion (AD) and recapture CO2 from beer fermentation, little is known about the economic feasibility of applying these technologies at the scale of small craft breweries. In addition, compounds in hops (Humulus lupulus), which are commonly added to craft beer to provide a bitter or “hoppy” flavor, have been shown to adversely affect anaerobic microbes in ruminant studies. In this study, biochemical methane potential (BMP) assays and anaerobic sequencing batch reactor (ASBR) studies were used to investigate biomethane production from high-strength craft brewery waste, with and without hop addition. A spreadsheet tool was developed to evaluate the economic feasibility of bioenergy and CO2 recovery depending on the brewery’s location, production volume, waste management, CO2 requirement, energy costs, and hop waste addition. The results showed that co-digestion of yeast waste with 20% hops (based on chemical oxygen demand (COD)) resulted in slightly lower methane yields compared with mono-digestion of yeast; however, it did not significantly impact the economic feasibility of AD in craft breweries. The use of AD and CO2 recovery was found to be economically feasible if the brewery’s annual beer production is >50,000 barrels/year.
Tissue Regeneration with Gelatine/Polysaccharide Derived Hydrogel Scaffolds: From Formulation to In Vivo Efficacy
Authors: Li Jing , He Keying , Xu Qian
Published: September 2023

Combinations of different biomaterials with certain formulations may lead to improved properties and have significant potential for use in tissue regeneration applications. However, previously reported studies comparing biomaterials often suffered from inconsistent processing methods or inadequate comprehensive application research, hindering a comprehension of their efficacy in tissue engineering. This report explores the significance of screening the combination of gelatine with polysaccharide materials, specifically hyaluronic acid (HA) and carboxymethyl cellulose (CMC), using the same crosslinking method used for tissue regeneration. Hydrogel scaffolds (Gel/HA and Gel/CMC) at various concentrations were developed and characterized to assess their physiochemical properties. The results demonstrated that the hydrogels exhibited desirable mechanical properties, appropriate swelling behaviour, suitable porosity, and excellent cytocompatibility. In particular, the Gel1HA1 and Gel1CMC1 hydrogels showed remarkable cellular proliferation and aggregation. Further, we performed animal studies and explored the tissue regeneration effects of the Gel1HA1 and Gel1CMC1 hydrogels. Both hydrogels exhibited an accelerated wound closure rate and promoted vessel formation in a rodent full-thickness skin excisional model. Additionally, the subcutaneous implantation model demonstrated the induction of angiogenesis and collagen deposition within the implanted hydrogel samples. Overall, the hydrogels developed in this study demonstrated promising potential for use in the regeneration of soft tissue defects and this study emphasizes the significance of screening biomaterial combinations and formulations for tissue regeneration applications.
Evaluation of GSTP1, GSTA4 and AChE Gene Methylation in Bovine Lymphocytes Cultured In Vitro with Miconazole Alone and in Combination with Mospilan 20SP
Authors: Halušková Jana , Holečková Beáta , Schwarzbacherová Viera , Galdíková Martina , Sedláková Silvia , Bučan Jaroslav
Published: September 2023

5-methylcytosine (5mC) is one of the most important epigenetic modifications. Its increased occurrence in regulatory sequences of genes, such as promoters and enhancers, is associated with the inhibition of their expression. Methylation patterns are not stable but are sensitive to factors such as the environment, diet, and age. In the present study, we investigated the effects of fungicide miconazole, both alone and in combination with the insecticide Mospilan 20SP, on the methylation status of bovine GSTP1, GSTA4, and AChE genes in bovine lymphocytes cultured in vitro. The methylation-specific PCR technique was used for the objectives of this study. We found that miconazole alone at concentrations of 1.25, 2.5, 5, 10, 25, and 50 µg/mL after 24 h exposure probably did not induce changes in methylation for all three genes analysed. The same results were found for the combination of pesticides at 24 h exposure and the following concentrations for each of them: 0.625, 1.25, 2.5, 5, and 12.5 µg/mL. Thus, we can conclude that the fungicide miconazole alone, as well as in combination with the insecticide Mospilan 20SP, was unlikely to cause changes to the methylation of bovine GSTP1, GSTA4, and AChE genes.
Thrombotic Complications in Immune Thrombocytopenia Patients Treated with Avatrombopag
Authors: Abdelsamia Mahmoud , Farid Saira , Dean Steven , Cataland Spero R.
Published: September 2023

Avatrombopag is a novel oral non-peptide thrombopoietin receptor agonist (TPO-RA) that was approved by the FDA as a second-line therapy for chronic immune thrombocytopenia (cITP). Avatrombopag has shown promising results in regards to efficacy and tolerability, but to our knowledge, there are no reports of thrombotic complications associated with avatrombopag. We present two patients with chronic ITP who suffered thromboembolic events shortly after starting treatment with avatrombopag. The first case is that of a 30-year-old female with refractory cITP who failed multiple lines of ITP therapy and was hospitalized with an intracranial bleed. The patient eventually recovered after an emergent splenectomy but subsequently developed a right lower lobe pulmonary embolism three weeks after starting treatment with avatrombopag. The second case is that of a 58-year-old female with a prolonged history of ITP, and no prior history of peripheral vascular disease, who suffered from both arterial and venous thrombotic events four weeks after starting avatrombopag. Given the new arterial and venous thrombotic complications, avatrombopag was stopped. She was challenged with avatrombopag again and developed yet another thrombotic complication.
Real-World Clinical Characterisation of Polycythaemia Vera Patients from a Prospective Registry in Portugal: Is Resistance to Hydroxyurea a Reality?
Authors: Sarmento Maria , Duarte Marta , Ponte Sandra , Sanchez Juan , Roriz Diana , Fernandes Laura , Silva Maria José Monteiro , Pacheco Judite , Ferreira Gisela , Freitas Jorge , Costa Inês , Brás Daniel
Published: September 2023

Patients with polycythaemia vera (PV) are at increased risk of thrombosis and haemorrhages. Although hydroxyurea (HU) has been the frontline therapy for patients at high risk of vascular complications, about 25% of patients develop resistance/intolerance to this therapy. The aim of this non-interventional, multicentre cohort study was to understand the clinical characteristics and HU treatment response of Portuguese PV patients. HU resistance/intolerance was defined according to adjusted European LeukemiaNet (ELN) criteria. In total, 134 PV patients with a mean (SD) disease duration of 4.8 (5.0) years were included and followed up for 2 years. At baseline, most patients were ≥60 years old (83.2%), at high risk for thrombotic events (87.2%), and receiving HU therapy (79.1%). A total of 10 thrombotic events and 8 haemorrhagic events were reported, resulting in a 5-year probability of thrombo-haemorrhagic events of 17.2%. Haematocrit (p = 0.007), haemoglobin (p = 0.012) and MPN10 symptom score (12.0 (11.6) vs. 10.3 (9.1); p = 0.041) decreased significantly at the 24-month visit compared to baseline. Overall, 75.9% of patients met at least one of the adjusted ELN criteria for HU resistance, and 14.4% of patients remained on HU throughout the study. The results from this real-world study may help identify the subset of patients at higher risk for disease sequelae who may benefit from earlier second-line treatment.
Understanding Key Predictors of Life Satisfaction in a Nationally Representative Sample of Koreans
Authors: Choi Yun-Kyeung , Joshanloo Mohsen , Lee Jae-Ho , Lee Hong-Seock , Lee Heung-Pyo , Song Jonghwan
Published: September 2023

The purpose of this study was to examine the factors that predict life satisfaction in a large representative sample of Koreans by analyzing data from the Gallup World Poll. The primary objective was to identify important predictors and suggest strategies to improve quality of life in Korea. The study used available Korean data from 2006 to 2017, which included 14,101 participants (mean age = 46.42). Predictors included demographic and psychological variables, with the Cantril Ladder of Life Scale serving as the outcome variable. The results show a decline in life satisfaction with advancing age, and that the relationship between life satisfaction and age varied by gender. Among the predictors examined, satisfaction with the standard of living and household income emerged as the most influential factors in determining life evaluation; other strong predictors included positive affect and negative affect, social support, gender, and education level. These results imply that, to increase life satisfaction, it is imperative to provide job opportunities and social services specifically targeted to individuals in low-income groups. In addition, it is crucial to implement tailored psychosocial interventions that address the unique developmental tasks and psychological challenges experienced by individuals according to their gender and life cycle stage.
Local Food Environment and Consumption of Ultra-Processed Foods: Cross-Sectional Data from the Nutritionists’ Health Study—NutriHS
Authors: Barbosa Brena Barreto , Nielsen Lucca , de Aguiar Breno Souza , Failla Marcelo Antunes , Araújo Larissa Fortunato , Mendes Larissa Loures , Machado Soraia Pinheiro , Carioca Antonio Augusto Ferreira
Published: September 2023

This study aimed to analyze whether community food environments are associated with individual food consumption among nutrition students and newly graduated nutritionists. This cross-sectional study used data from the Nutritionists’ Health Study cohort, which included 357 undergraduate nutrition students from the city of Fortaleza, Ceará, Brazil. Exposure to the food environment was defined as the proximity and availability of food outlets within a 500 m buffer from the participants’ homes. Food consumption was assessed using a Food Frequency Questionnaire and analyzed according to the NOVA classification. Multi-level linear regression models with fixed effects were used to estimate the presence of food outlets within the buffer and their association with food consumption. The presence of mini-markets in the buffer in the fourth quartile was associated with lower consumption of ultra-processed foods (UPF) when observing socioeconomic and lifestyle conditions (β = −3.29; 95% CI = −6.39 to −0.19). The presence of bakeries and coffee shops was related to lower consumption of ultra-processed foods among participants when observing socioeconomic conditions (β = −3.10; 95% CI = −6.18 to −0.02). There was no clear evidence of an association between the type of food outlet and UPF consumption. The community food environment seemed to influence food consumption among study participants, although clearer and more consistent evidence on this subject is needed.
Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice
Authors: Ashby Frederick James , Castillo Evelyn J. , Ludwig Yan , Andraka Natalia K. , Chen Cong , Jamieson Julia C. , Kabbej Nadia , Sommerville John D. , Aguirre Jose I. , Heldermon Coy D.
Published: September 2023

Sanfilippo syndrome Type-B, also known as mucopolysaccharidosis IIIB (MPS IIIB), accounts for approximately one-third of all Sanfilippo syndrome patients and is characterized by a similar natural history as Type-A. Patients suffer from developmental regression, bone malformation, organomegaly, GI distress, and profound neurological deficits. Despite human trials of enzyme replacement therapy (ERT) (SBC-103, AX250) in MPS IIIB, there is currently no FDA approved treatment and a few palliative options. The major concerns of ERT and gene therapy for the treatment of bone malformation are the inadequate biodistribution of the missing enzyme, N-acetyl-α-glucosaminidase (NAGLU), and that the skeleton is a poorly hit target tissue in ERT and gene therapy. Each of the four known human types of MPS III (A, B, C, and D) is usually regarded as having mild bone manifestations, yet it remains poorly characterized. This study aimed to determine bone mineral content (BMC), volumetric bone mineral density (vBMD), and biomechanical properties in femurs MPS IIIB C57BL/6 mice compared to phenotypic control C57BL/6 mice. Significant differences were observed in MPS IIIB mice within various cortical and cancellous bone parameters for both males and females (p < 0.05). Here, we establish some osteogenic manifestations of MPS IIIB within the mouse model by radiographic and biomechanical tests, which are also differentially affected by age and sex. This suggests that some skeletal features of the MPS IIIB mouse model may be used as biomarkers of peripheral disease correction for preclinical treatment of MPS IIIB.
Latest Review Papers in Molecular Microbiology
Authors: Burkovski Andreas
Published: September 2023

This Special Issue—dedicated to high-quality review papers in molecular microbiology—is highlighting two important developments in the field: (i) the analysis of microbiome data in health and disease and (ii) the search for strategies against bacteria showing antimicrobial resistance [...]
Enamel Matrix Derivative Suppresses Chemokine Expression in Oral Epithelial Cells
Authors: Panahipour Layla , Botta Sara , Abbasabadi Azarakhsh Oladzad , Afradi Zohreh , Gruber Reinhard
Published: September 2023

Epithelial cells in periodontitis patients increasingly express chemokines, suggesting their active involvement in the inflammatory process. Enamel matrix derivative (EMD) is an extract of porcine fetal tooth germs clinically applied to support the regrowth of periodontal tissues. Periodontal regeneration might benefit from the potential anti-inflammatory activity of EMD for epithelial cells. Our aim was, therefore, to set up a bioassay where chemokine expression is initiated in the HSC2 oral squamous carcinoma cell line and then test EMD for its capacity to lower the inflammatory response. To establish the bioassay, HSC2 cells being exposed to TNFα and LPS from E. coli (Escherichia coli) or P. gingivalis (Porphyromonas gingivalis) were subjected to RNAseq. Here, TNFα but not LPS caused a robust increase of chemokines, including CXCL1, CXCL2, CXCL8, CCL5, and CCL20 in HSC2 cells. Polymerase chain reaction confirmed the increased expression of the respective chemokines in cells exposed to TNFα and IL-1β. Under these conditions, EMD reduced the expression of all chemokines at the transcriptional level and CXCL8 by immunoassay. The TGF-β receptor type I kinase-inhibitor SB431542 reversed the anti-inflammatory activity. Moreover, EMD-activated TGF-β-canonical signaling was visualized by phosphorylation of smad3 and nuclear translocation of smad2/3 in HSC2 cells and blocked by SB431542. This observation was confirmed with primary oral epithelial cells where EMD significantly lowered the SB431542-dependent expression of CXCL8. In summary, our findings suggest that TGF-β signaling mediates the effects of EMD to lower the forced expression of chemokines in oral epithelial cells.
Ezetimibe Induces Vasodilation in Rat Mesenteric Resistance Arteries through Inhibition of Extracellular Ca2+ Influx
Authors: Oh Eun Yi , Haam Chae Eun , Choi Sooyeon , Byeon Seonhee , Choi Soo-Kyoung , Lee Young-Ho
Published: September 2023

Ezetimibe is a lipid-lowering agent that selectively inhibits cholesterol absorption by binding to the Niemann–Pick C1-like 1 (NPC1L1) protein. Although it is well known that administration of ezetimibe in hypercholesterolemia patients reduces the risk of cardiovascular events through attenuation of atherosclerosis, studies on the direct effect of ezetimibe on vascular function are not sufficient. The aim of the present study was to investigate the vascular effects of ezetimibe in rat mesenteric arteries. In the present study, 12-week-old male Sprague Dawley rats were used. After the rats were sacrificed, the second branches of the mesenteric arteries were isolated and cut into 2–3 mm segments and mounted in a multi-wire myography system to measure isometric tension. Ezetimibe reduced vasoconstriction induced by U46619 (500 nM) in endothelium-intact and endothelium-denuded arteries. Ezetimibe-induced vasodilation was not affected by the endothelial nitric oxide synthase (eNOS) inhibitor Nω-Nitro-L-arginine (L-NNA, 300 μM) or the non-selective potassium channel blocker, tetraethylammonium (TEA, 10 mM). Moreover, ezetimibe also completely blocked the contraction induced by an increase in external calcium concentration. Ezetimibe significantly reduced vascular contraction induced by L-type Ca2+ channel activator (Bay K 8644, 30 nM). Treatment with ezetimibe decreased the phosphorylation level of 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that ezetimibe has a significant vasodilatory effect in rat mesenteric resistance arteries. These results suggest that ezetimibe may have beneficial cardiovascular effects beyond its cholesterol-lowering properties.
Integrated Analysis of the Transcriptome and Metabolome of Brassica rapa Revealed Regulatory Mechanism under Heat Stress
Authors: Yu Jing , Li Pengli , Tu Song , Feng Ningxiao , Chang Liying , Niu Qingliang
Published: September 2023

Affected by global warming; heat stress is the main limiting factor for crop growth and development. Brassica rapa prefers cool weather, and heat stress has a significant negative impact on its growth, development, and metabolism. Understanding the regulatory patterns of heat–resistant and heat–sensitive varieties under heat stress can help deepen understanding of plant heat tolerance mechanisms. In this study, an integrative analysis of transcriptome and metabolome was performed on the heat–tolerant (‘WYM’) and heat–sensitive (‘AJH’) lines of Brassica rapa to reveal the regulatory networks correlated to heat tolerance and to identify key regulatory genes. Heat stress was applied to two Brassica rapa cultivars, and the leaves were analyzed at the transcriptional and metabolic levels. The results suggest that the heat shock protein (HSP) family, plant hormone transduction, chlorophyll degradation, photosynthetic pathway, and reactive oxygen species (ROS) metabolism play an outstanding role in the adaptation mechanism of plant heat tolerance. Our discovery lays the foundation for future breeding of horticultural crops for heat resistance.
Modulation of LPS-Induced Neurodegeneration by Intestinal Helminth Infection in Ageing Mice
Authors: Jermakow Natalia , Skarżyńska Weronika , Lewandowska Katarzyna , Kiernozek Ewelina , Goździk Katarzyna , Mietelska-Porowska Anna , Drela Nadzieja , Wojda Urszula , Doligalska Maria
Published: September 2023

Parasitic helminths induce a transient, short-term inflammation at the beginning of infection, but in persistent infection may suppress the systemic immune response by enhancing the activity of regulatory M2 macrophages. The aim of the study was to determine how nematode infection affects age-related neuroinflammation, especially macrophages in the nervous tissue. Here, intraperitoneal LPS-induced systemic inflammation resulting in brain neurodegeneration was enhanced by prolonged Heligmosomoides polygyrus infection in C57BL/6 mice. The changes in the brain coincided with the increase in M1 macrophages, reduced survivin level, enhanced APP and GFAP expression, chitin-like chains deposition in the brain and deterioration behaviour manifestations. These changes were also observed in transgenic C57BL/6 mice predisposed to develop neurodegeneration typical for Alzheimer’s disease in response to pathogenic stimuli. Interestingly, in mice infected with the nematode only, the greater M2 macrophage population resulted in better results in the forced swim test. Given the growing burden of neurodegenerative diseases, understanding such interactive associations can have significant implications for ageing health strategies and disease monitoring.
Dynamic Interplay in Tumor Ecosystems: Communication between Hepatoma Cells and Fibroblasts
Authors: Petővári Gábor , Tóth Gábor , Turiák Lilla , L. Kiss Anna , Pálóczi Krisztina , Sebestyén Anna , Pesti Adrián , Kiss András , Baghy Kornélia , Dezső Katalin , Füle Tibor , Tátrai Péter , Kovalszky Ilona , Reszegi Andrea
Published: September 2023

Tumors are intricate ecosystems where cancer cells and non-malignant stromal cells, including cancer-associated fibroblasts (CAFs), engage in complex communication. In this study, we investigated the interaction between poorly (HLE) and well-differentiated (HuH7) hepatoma cells and LX2 fibroblasts. We explored various communication channels, including soluble factors, metabolites, extracellular vesicles (EVs), and miRNAs. Co-culture with HLE cells induced LX2 to produce higher levels of laminin β1, type IV collagen, and CD44, with pronounced syndecan-1 shedding. Conversely, in HuH7/LX2 co-culture, fibronectin, thrombospondin-1, type IV collagen, and cell surface syndecan-1 were dominant matrix components. Integrins α6β4 and α6β1 were upregulated in HLE, while α5β1 and αVβ1 were increased in HuH7. HLE-stimulated LX2 produced excess MMP-2 and 9, whereas HuH7-stimulated LX2 produced excess MMP-1. LX2 activated MAPK and Wnt signaling in hepatoma cells, and conversely, hepatoma-derived EVs upregulated MAPK and Wnt in LX2 cells. LX2-derived EVs induced over tenfold upregulation of SPOCK1/testican-1 in hepatoma EV cargo. We also identified liver cancer-specific miRNAs in hepatoma EVs, with potential implications for early diagnosis. In summary, our study reveals tumor type-dependent communication between hepatoma cells and fibroblasts, shedding light on potential implications for tumor progression. However, the clinical relevance of liver cancer-specific miRNAs requires further investigation.
The Effect of Fenugreek in Type 2 Diabetes and Prediabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Kim Jiwon , Noh Woojeong , Kim Ahrim , Choi Yoomin , Kim Young-Sik
Published: September 2023

Fenugreek is a widely used herbal medicine as a complementary therapy for diabetes mellitus. Lots of clinical trials have proved its beneficial effect on glycemic control parameters and lipid profiles. Thus, we conducted a systematic review and meta-analysis to evaluate the effectiveness and safety of fenugreek as a treatment for type 2 diabetes mellitus. We searched PubMed, Embase, Cochrane, China Knowledge Resource Integrated Database (CNKI), Korean studies Information Service System (KISS), Research Information Sharing Service (RISS), and ScienceON to select RCTs which used fenugreek targeting hyperglycemia with a control group. We used either a random effect model or a fixed model in a meta-analysis of Fasting blood glucose (FBG), 2 h plasma glucose during a 75 g oral glucose tolerance test (OGTT) (2-hPG), homeostatic model assessment for insulin resistance (HOMA-IR), glycosylated hemoglobin (HbA1c)/total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), body mass index (BMI). After screening, a total of 10 studies (706 participants) remained. Fenugreek significantly reduced FBG, 2-hPG, and HbA1c, but it did not significantly decrease HOMA-IR. Moreover, it significantly improved TC, TG, and HDL-C, while there were no significant differences in LDL-C and BMI. Hepatic or renal toxicity was not observed, and there were no severe adverse events associated with fenugreek despite mild gastrointestinal side effects in some studies. In conclusion, fenugreek improves overall glycemic control parameters and lipid profile safely.
Prolactin and Growth Hormone Signaling and Interlink Focused on the Mammosomatotroph Paradigm: A Comprehensive Review of the Literature
Authors: Araujo-Castro Marta , Marazuela Mónica , Puig-Domingo Manel , Biagetti Betina
Published: September 2023

Prolactin (PRL) and growth hormone (GH) are peptide hormones that bind to the class 1 cytokine receptor superfamily, a highly conserved cell surface class of receptors. Both hormones control their own secretion via a negative autocrine loop in their own mammosomatotroph, lactotroph or somatotroph. In this regard, GH and PRL are regulated by similar signaling pathways involving cell growth and hormone secretion. Thus, GH and PRL dysregulation and pituitary neuroendocrine tumor (PitNET) development may have common pathogenic pathways. Based on cell linage, lactotroph and somatotroph PitNETs come from pituitary-specific POU-class homeodomain transcription factor (Pit-1). Mammosomatotroph and plurihormonal PitNETs are a unique subtype of PitNETs that arise from a single-cell population of Pit-1 lineage. In contrast, mixed somatotroph–lactotroph PitNETs are composed of two distinct cell populations: somatotrophs and lactotrophs. Morphologic features that distinguish indolent PitNETs from locally aggressive ones are still unidentified, and no single prognostic parameter can predict tumor aggressiveness or treatment response. In this review, we aim to explore the latest research on lactotroph and somatotroph PitNETs, the molecular mechanisms involved in PRL and GH axis regulation and the signaling pathways involved in their aggressiveness, particularly focused on mammosomatotroph and mixed subtypes. Finally, we summarize epidemiological, clinical, and radiological features of these exceptional tumors. We aim to shed light, from basic to clinical settings, on new perspectives and scientific gaps in this field.
Overexpression of KLF4 Suppresses Pulmonary Fibrosis through the HIF-1α/Endoplasmic Reticulum Stress Signaling Pathway
Authors: Wei Shanchen , Qi Fei , Wu Yanping , Liu Xinmin
Published: September 2023

The hypoxia-inducible factor-1α/endoplasmic reticulum stress signaling pathway (HIF-1α/ERS) has a crucial role in the pathogenetic mechanism of pulmonary fibrosis (PF). However, the upstream regulatory mediators of this pathway remain unclear. In the present study, by conducting bioinformatics analysis, we found that Krüppel-like factor 4 (KLF4) expression was decreased in the lung tissues of patients with idiopathic pulmonary fibrosis (IPF) as compared to that in patients with non-IPF. Furthermore, KLF4 expression was significantly reduced (p = 0.0331) in bleomycin-induced fibrotic HFL-1 cells. Moreover, in mice with bleomycin-induced PF, the degree of fibrosis was significantly reduced in mice overexpressing KLF4 as compared to that in wild-type mice. In mice and HFL-1 cells, KLF4 overexpression significantly reduced bleomycin-induced protein expression of HIF-1α (p = 0.0027) and ERS markers, particularly p-IRE1α (p = 0.0255) and ATF6 (p = 0.0002). By using the JASPAR database, we predicted that KLF4 has five binding sites for the HIF-1α promoter. The results of in vitro and in vivo studies suggest that KLF4 may inhibit PF through the HIF-1α/ERS pathway. This finding could guide the development of future therapies for PF and facilitate the identification of appropriate biomarkers for routine clinical diagnosis of PF.
Circulating Sphingolipids in Insulin Resistance, Diabetes and Associated Complications
Authors: Hammad Samar M. , Lopes-Virella Maria F.
Published: September 2023

Sphingolipids play an important role in the development of diabetes, both type 1 and type 2 diabetes, as well as in the development of both micro- and macro-vascular complications. Several reviews have been published concerning the role of sphingolipids in diabetes but most of the emphasis has been on the possible mechanisms by which sphingolipids, mainly ceramides, contribute to the development of diabetes. Research on circulating levels of the different classes of sphingolipids in serum and in lipoproteins and their importance as biomarkers to predict not only the development of diabetes but also of its complications has only recently emerged and it is still in its infancy. This review summarizes the previously published literature concerning sphingolipid-mediated mechanisms involved in the development of diabetes and its complications, focusing on how circulating plasma sphingolipid levels and the relative content carried by the different lipoproteins may impact their role as possible biomarkers both in the development of diabetes and mainly in the development of diabetic complications. Further studies in this field may open new therapeutic avenues to prevent or arrest/reduce both the development of diabetes and progression of its complications.
Static Cold Storage with Mitochondria-Targeted Hydrogen Sulfide Donor Improves Renal Graft Function in an Ex Vivo Porcine Model of Controlled Donation-after-Cardiac-Death Kidney Transplantation
Authors: Dugbartey George J. , Juriasingani Smriti , Richard-Mohamed Mahms , Rasmussen Andrew , Levine Max , Liu Winnie , Haig Aaron , Whiteman Matthew , Arp Jacqueline , Luke Patrick P.W. , Sener Alp
Published: September 2023

The global donor kidney shortage crisis has necessitated the use of suboptimal kidneys from donors-after-cardiac-death (DCD). Using an ex vivo porcine model of DCD kidney transplantation, the present study investigates whether the addition of hydrogen sulfide donor, AP39, to University of Wisconsin (UW) solution improves graft quality. Renal pedicles of male pigs were clamped in situ for 30 min and the ureters and arteries were cannulated to mimic DCD. Next, both donor kidneys were nephrectomized and preserved by static cold storage in UW solution with or without AP39 (200 nM) at 4 °C for 4 h followed by reperfusion with stressed autologous blood for 4 h at 37 °C using ex vivo pulsatile perfusion apparatus. Urine and arterial blood samples were collected hourly during reperfusion. After 4 h of reperfusion, kidneys were collected for histopathological analysis. Compared to the UW-only group, UW+AP39 group showed significantly higher pO2 (p < 0.01) and tissue oxygenation (p < 0.05). Also, there were significant increases in urine production and blood flow rate, and reduced levels of urine protein, serum creatinine, blood urea nitrogen, plasma Na+ and K+, as well as reduced intrarenal resistance in the UW+AP39 group compared to the UW-only group. Histologically, AP39 preserved renal structure by reducing the apoptosis of renal tubular cells and immune cell infiltration. Our finding could lay the foundation for improved graft preservation and reduce the increasingly poor outcomes associated with DCD kidney transplantation.
Molecular Mechanism of Mutational Disruption of DCLK1 Autoinhibition Provides a Rationale for Inhibitor Screening
Authors: Chen Weizhi , Liu Rui , Yu Yamei , Wei Dongqing , Chen Qiang , Xu Qin
Published: September 2023

Doublecortin-like kinase 1 (DCLK1) is a prominent kinase involved in carcinogenesis, serving as a diagnostic marker for early cancer detection and prevention, as well as a target for cancer therapy. Extensive research efforts have been dedicated to understanding its role in cancer development and designing selective inhibitors. In our previous work, we successfully determined the crystal structure of DCLK1 while it was bound to its autoinhibitory domain (AID) at the active site. By analyzing this structure, we were able to uncover the intricate molecular mechanisms behind specific cancer-causing mutations in DCLK1. Utilizing molecular dynamics simulations, we discovered that these mutations disrupt the smooth assembly of the AID, particularly affecting the R2 helix, into the kinase domain (KD). This disruption leads to the exposure of the D533 residue of the DFG (Asp-Phe-Gly) motif in the KD, either through steric hindrance, the rearrangement of electrostatic interactions, or the disruption of local structures in the AID. With these molecular insights, we conducted a screening process to identify potential small-molecule inhibitors that could bind to DCLK1 through an alternative binding mode. To assess the binding affinity of these inhibitors to the KD of DCLK1, we performed calculations on their binding energy and conducted SPR experiments. We anticipate that our study will contribute novel perspectives to the field of drug screening and optimization, particularly in targeting DCLK1.
The Importance of Aortic Valve Bicuspid Phenotype in Valvular Evolution in Pediatric Patients: A Case Report and Literature Mini-Review
Authors: Făgărășan Amalia , Gurzu Simona , Satala Catalin-Bogdan , Hagău Asmaa Carla
Published: September 2023

Bicuspid aortic valve (BAV) is the most commonly encountered congenital malformation in the pediatric population, associated with aortic leaflet degeneration and aortopathy. However, studies on BAV and its complications in children are limited. We present the case of a 16-year-old with type 1B BAV with a raphe with fusion between the right and non-coronary cusps who exhibited severe aortic stenosis, regurgitation, and progressive dilatation of the ascending aorta. Surgical intervention, including aortic valve and aortic root replacement, was performed due to the patient’s deteriorating condition. Histopathological examination revealed degenerative changes and calcifications in the aortic valve and mucoid fibrosis in the ascending aorta. The results are consistent with BAV patients being predisposed to aortic stenosis and regurgitation due to increased mechanical stress and hemodynamic abnormalities. Although more common in adults and a rare complication in pediatric patients, calcification was previously observed concurrently with rapid valve degeneration in our daily practice. Further studies are needed to improve our understanding of the mechanisms underlying BAV-related complications and refine treatment strategies for pediatric patients.
Notch Signaling in Insect Development: A Simple Pathway with Diverse Functions
Authors: Chen Yao , Li Haomiao , Yi Tian-Ci , Shen Jie , Zhang Junzheng
Published: September 2023

Notch signaling is an evolutionarily conserved pathway which functions between adjacent cells to establish their distinct identities. Despite operating in a simple mechanism, Notch signaling plays remarkably diverse roles in development to regulate cell fate determination, organ growth and tissue patterning. While initially discovered and characterized in the model insect Drosophila melanogaster, recent studies across various insect species have revealed the broad involvement of Notch signaling in shaping insect tissues. This review focuses on providing a comprehensive picture regarding the roles of the Notch pathway in insect development. The roles of Notch in the formation and patterning of the insect embryo, wing, leg, ovary and several specific structures, as well as in physiological responses, are summarized. These results are discussed within the developmental context, aiming to deepen our understanding of the diversified functions of the Notch signaling pathway in different insect species.
Therapeutic Peptide RF16 Derived from CXCL8 Inhibits MDA-MB-231 Cell Invasion and Metastasis
Authors: Chang Chun-Ming , Chang Chun-Chun , Lam Ho Yin Pekkle , Peng Shih-Yi , Lai Yi-Hsuan , Hsiang Bi-Da , Liao Yu-Yi , Hsu Hao-Jen , Jiang Shinn-Jong
Published: September 2023

Interleukin (IL)-8 plays a vital role in regulating inflammation and breast cancer formation by activating CXCR1/2. We previously designed an antagonist peptide, (RF16), to inhibits the activation of downstream signaling pathways by competing with IL-8 in binding to CXCR1/2, thereby inhibiting IL-8-induced chemoattractant monocyte binding. To evaluate the effect of the RF16 peptide on breast cancer progression, triple-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cells were used to investigate whether RF16 can inhibit the IL-8-induced breast cancer metastasis. Using growth, proliferation, and invasiveness assays, the results revealed that RF16 reduced cell proliferation, migration, and invasiveness in MDA-MB-231 cells. The RF16 peptide also regulated the protein and mRNA expressions of epithelial–mesenchymal transition (EMT) markers in IL-8-stimulated MDA-MB-231 cells. It also inhibited downstream IL-8 signaling and the IL-8-induced inflammatory response via the mitogen-activated protein kinase (MAPK) and Phosphoinositide 3-kinase (PI3K) pathways. In the xenograft tumor mouse model, RF16 synergistically reinforces the antitumor efficacy of docetaxel by improving mouse survival and retarding tumor growth. Our results indicate that RF16 significantly inhibited IL-8-stimulated cell growth, migration, and invasion in MDA-MB-231 breast cancer cells by blocking the activation of p38 and AKT cascades. It indicated that the RF16 peptide may serve as a new supplementary drug for breast cancer.
Sm/Co Magnetic Materials: A Recycling Strategy Using Modifiable Hydrophobic Deep Eutectic Solvents Based on Trioctylphosphine Oxide
Authors: Milevskii Nikita A. , Zinov’eva Inna V. , Kozhevnikova Arina V. , Zakhodyaeva Yulia A. , Voshkin Andrey A.
Published: September 2023

Hydrophobic deep eutectic solvents (HDES) are widely used as extractants. Usually, when preparing HDES, only the extraction ability of one component is taken into account, with the second serving as an “inert” component, whose effect on the extraction process is not taken into account. The present study demonstrates the possibility of controlling the selectivity of a hydrophobic deep eutectic solvent based on trioctylphosphine oxide (TOPO) by varying the substance that acts as a hydrogen bond donor, but which does not have an extractive ability. In the course of the work, the influence of the “inert” component on the physicochemical and extraction properties of HDES was confirmed by experimental, spectroscopic, and also calculation methods. A number of phenols with different structural features were chosen as the HDES’ hydrogen bond donors to modify: phenol (Ph), para-tert-butylphenol (PTBP) and thymol (Th). Using the example of separation of the Sm/Co pair, the influence of the structure of a hydrogen bond donor on the extraction ability of a hydrophobic deep eutectic solvent was established, where the degree of extraction of Sm (III) increased in the series Th:TOPO < PTBP:TOPO < Ph:TOPO. HDES based on TOPO and phenols can potentially be used to separate Sm and Co from the process leach solutions generated during the hydrometallurgical processing of waste SmCo magnets.
GMM-Based Expanded Feature Space as a Way to Extract Useful Information for Rare Cell Subtypes Identification in Single-Cell Mass Cytometry
Authors: Suwalska Aleksandra , Polanska Joanna
Published: September 2023

Cell subtype identification from mass cytometry data presents a persisting challenge, particularly when dealing with millions of cells. Current solutions are consistently under development, however, their accuracy and sensitivity remain limited, particularly in rare cell-type detection due to frequent downsampling. Additionally, they often lack the capability to analyze large data sets. To overcome these limitations, a new method was suggested to define an extended feature space. When combined with the robust clustering algorithm for big data, it results in more efficient cell clustering. Each marker’s intensity distribution is presented as a mixture of normal distributions (Gaussian Mixture Model, GMM), and the expanded space is created by spanning over all obtained GMM components. The projection of the initial flow cytometry marker domain into the expanded space employs GMM-based membership functions. An evaluation conducted on three established cellular identification algorithms (FlowSOM, ClusterX, and PARC) utilizing the most substantial publicly available annotated dataset by Samusik et al. demonstrated the superior performance of the suggested approach in comparison to the standard. Although our approach identified 20 cell clusters instead of the expected 24, their intra-cluster homogeneity and inter-cluster differences were superior to the 24-cluster FlowSOM-based solution.
Transcriptomics of Canine Inflammatory Mammary Cancer Treated with Empty Cowpea Mosaic Virus Implicates Neutrophils in Anti-Tumor Immunity
Authors: Barreno Lucia , Sevane Natalia , Valdivia Guillermo , Alonso-Miguel Daniel , Suarez-Redondo María , Alonso-Diez Angela , Fiering Steven , Beiss Veronique , Steinmetz Nicole F. , Perez-Alenza Maria Dolores , Peña Laura
Published: September 2023

Canine inflammatory mammary cancer (IMC) is a highly aggressive and lethal cancer in dogs serving as a valuable animal model for its human counterpart, inflammatory breast cancer (IBC), both lacking effective therapies. Intratumoral immunotherapy (IT-IT) with empty cowpea mosaic virus (eCPMV) nanoparticles has shown promising results, demonstrating a reduction in tumor size, longer survival rates, and improved quality of life. This study compares the transcriptomic profiles of tumor samples from female dogs with IMC receiving eCPMV IT-IT and medical therapy (MT) versus MT alone. Transcriptomic analyses, gene expression profiles, signaling pathways, and cell type profiling of immune cell populations in samples from four eCPMV-treated dogs with IMC and four dogs with IMC treated with MT were evaluated using NanoString Technologies using a canine immune-oncology panel. Comparative analyses revealed 34 differentially expressed genes between treated and untreated samples. Five genes (CXCL8, S100A9, CCL20, IL6, and PTGS2) involved in neutrophil recruitment and activation were upregulated in the treated samples, linked to the IL17-signaling pathway. Cell type profiling showed a significant increase in neutrophil populations in the tumor microenvironment after eCPMV treatment. These findings highlight the role of neutrophils in the anti-tumor response mediated by eCPMV IT-IT and suggest eCPMV as a novel therapeutic approach for IBC/IMC.
PDD-ET: Parkinson’s Disease Detection Using ML Ensemble Techniques and Customized Big Dataset
Authors: Chatterjee Kalyan , Kumar Ramagiri Praveen , Bandyopadhyay Anjan , Swain Sujata , Mallik Saurav , Li Aimin , Ray Kanad
Published: September 2023

Parkinson’s disease (PD) is a neurological disorder affecting the nerve cells. PD gives rise to various neurological conditions, including gradual reduction in movement speed, tremors, limb stiffness, and alterations in walking patterns. Identifying Parkinson’s disease in its initial phases is crucial to preserving the well-being of those afflicted. However, accurately identifying PD in its early phases is intricate due to the aging population. Therefore, in this paper, we harnessed machine learning-based ensemble methodologies and focused on the premotor stage of PD to create a precise and reliable early-stage PD detection model named PDD-ET. We compiled a tailored, extensive dataset encompassing patient mobility, medication habits, prior medical history, rigidity, gender, and age group. The PDD-ET model amalgamates the outcomes of various ML techniques, resulting in an impressive 97.52% accuracy in early-stage PD detection. Furthermore, the PDD-ET model effectively distinguishes between multiple stages of PD and accurately categorizes the severity levels of patients affected by PD. The evaluation findings demonstrate that the PDD-ET model outperforms the SVR, CNN, Stacked LSTM, LSTM, GRU, Alex Net, [Decision Tree, RF, and SVR], Deep Neural Network, HOG, Quantum ReLU Activator, Improved KNN, Adaptive Boosting, RF, and Deep Learning Model techniques by the approximate margins of 37%, 30%, 20%, 27%, 25%, 18%, 19%, 27%, 25%, 23%, 45%, 40%, 42%, and 16%, respectively.