bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation Analysis of Riparian Plant Communities with Soil Ions in the Upper, Middle, and Lower Reaches of Heihe River Midstream in China
Authors: Wang Zhikai , Chen Guopeng , Li Jie , Jiao Jian
Published: August 2024

Our study examined the relationships between riparian plant communities and their soil properties along the midstream of the Heihe River in northwestern China’s arid region. Significant variations in species composition were observed across the upper, middle, and lower reaches of this midstream (adonis2 and anosim, p < 0.001). The lower reaches exhibited higher species diversity (Shannon index up to 2.12) compared to the other reaches. Gramineous plants, particularly Agropyron cristatum (L.) Gaertn. and Equisetum ramosissimum Desf., dominated all reaches, with relative abundances exceeding 50% in the upper reach sites. The soil ionic concentration showed distinct spatial heterogeneity, peaking at site 9 (upper reaches) and lowest at site 3 (lower reaches). Species diversity indices negatively correlated with SO42−, Mg2+, and Ca2+ concentrations, while salt-tolerant species like Agropyron cristatum (L.) Gaertn. and Phragmites australis Trin. positively correlated with Na+ and Cl− levels. Soil nutrients had weaker but notable effects on the distribution of Onopordum acanthium L. and Artemisia argyi H. Lév. and Vaniot. These findings suggest that riparian plant community distribution along the Heihe River is influenced by complex interactions between hydrological processes, salt dynamics, and soil physicochemical properties, such as anion and cation concentrations and electrical conductivity (EC). Our research provides valuable insights for understanding and managing riparian ecosystems in arid regions.
Effect of Supplementation of a Cryopreservation Extender with Pectoliv30 on Post-Thawing Semen Quality Parameters in Rooster Species
Authors: Díaz Ruiz Esther , Delgado Bermejo Juan Vicente , León Jurado José Manuel , Navas González Francisco Javier , Arando Arbulu Ander , Fernández-Bolaños Guzmán Juan , Bermúdez Oria Alejandra , González Ariza Antonio
Published: August 2024

Sperm cryopreservation is a fundamental tool for the conservation of avian genetic resources; however, avian spermatozoa are susceptible to this process. To cope with the high production of reactive oxygen species (ROS), the addition of exogenous antioxidants is beneficial. Pectoliv30 is a substance derived from alperujo, and in this study, its effect was analyzed on seminal quality after its addition to the cryopreservation extender of roosters at different concentrations. For this purpose, 16 Utrerana breed roosters were used, and seminal collection was performed in six replicates, creating a pool for each working day with ejaculates of quality. After cryopreservation, one sample per treatment and replicate was thawed, and several seminal quality parameters were evaluated. Statistical analysis revealed numerous correlations between these variables, both positive and negative according to the correlation matrix obtained. Furthermore, the chi-squared automatic interaction detection (CHAID) decision tree (DT) reported significant differences in the hypo-osmotic swelling test (HOST) variable between groups. Moreover, results for this parameter were more desirable at high concentrations of Pectoliv30. The application of this substance extracted from the by-product alperujo as an antioxidant allows the improvement of the post-thawing seminal quality in roosters and facilitates optimization of the cryopreservation process as a way to improve the conservation programs of different endangered poultry breeds.
ARE/Nrf2 Transcription System Involved in Carotenoid, Polyphenol, and Estradiol Protection from Rotenone-Induced Mitochondrial Oxidative Stress in Dermal Fibroblasts
Authors: Darawsha Aya , Trachtenberg Aviram , Sharoni Yoav
Published: August 2024

Skin aging is associated with the increased production of mitochondrial reactive oxygen species (mtROS) due to mitochondrial dysfunction, and various phytonutrients and estrogens have been shown to improve skin health. Thus, the aim of the current study was to examine damage to dermal fibroblasts by chemically induced mitochondrial dysfunction and to study the mechanism of the protective effects of carotenoids, polyphenols, and estradiol. Rotenone, a Complex I inhibitor, caused mitochondrial dysfunction in human dermal fibroblasts, substantially reducing respiration and ATP levels, followed by increased mitochondrial and cytosolic ROS, which resulted in apoptotic cell death, an increased number of senescent cells, increased matrix metalloproteinase-1 (MMP1) secretion, and decreased collagen secretion. Pre-treatment with carotenoid-rich tomato extracts, rosemary extract, and estradiol reversed these effects. These protective effects can be partially explained by a cooperative activation of antioxidant response element (ARE/Nrf2) transcriptional activity by the protective compounds and rotenone, which led to the upregulation of antioxidant proteins such as NQO1. To determine if ARE/Nrf2 activity is crucial for cell protection, we inhibited it using the Nrf2 inhibitors ML385 and ochratoxin A. This inhibition markedly reduced the protective effects of the test compounds by diminishing their effect to reduce cytosolic ROS. Our study results indicate that phytonutrients and estradiol protect skin cells from damage caused by mtROS, and thus may delay skin cell senescence and improve skin health.
Ribonuclease Inhibitor 1 (RNH1) Regulates Sperm tsRNA Generation for Paternal Inheritance through Interacting with Angiogenin in the Caput Epididymis
Authors: Ma Zhuoyao , Tang Ningyuan , Zhang Ruiyan , Deng Hanyu , Chen Kexin , Liu Yue , Ding Zhide
Published: August 2024

Environmental stressors can induce paternal epigenetic modifications that are a key determinant of the intergenerational inheritance of acquired phenotypes in mammals. Some of them can affect phenotypic expression through inducing changes in tRNA-derived small RNAs (tsRNAs), which modify paternal epigenetic regulation in sperm. However, it is unclear how these stressors can affect changes in the expression levels of tsRNAs and their related endonucleases in the male reproductive organs. We found that Ribonuclease inhibitor 1 (RNH1), an oxidation responder, interacts with ANG to regulate sperm tsRNA generation in the mouse caput epididymis. On the other hand, inflammation and oxidative stress induced by either lipopolysaccharide (LPS) or palmitate (PA) treatments weakened the RNH1-ANG interaction in the epididymal epithelial cells (EEC). Accordingly, ANG translocation increased from the nucleus to the cytoplasm, which led to ANG upregulation and increases in cytoplasmic tsRNA expression levels. In conclusion, as an antioxidant, RNH1 regulates tsRNA generation through targeting ANG in the mouse caput epididymis. Moreover, the tsRNA is an epigenetic factor in sperm that modulates paternal inheritance in offspring via the fertilization process.
Paraoxonase I Activity and Its Relationship with Nutrition in Amyotrophic Lateral Sclerosis
Authors: Proaño Belén , Benlloch María , Sancho-Castillo Sandra , Privado Jesús , Bargues-Navarro Guillermo , Sanchis-Sanchis Claudia Emmanuela , Martínez Bolós Palmira , Carriquí-Suárez Ana Belén , Cubero-Plazas Laura , Platero Armero Jose Luis , Escriva Dolores , Ceron Jose Joaquín , Tvarijonaviciute Asta , de la Rubia Ortí Jose Enrique
Published: August 2024

Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, with oxidative stress playing a key role. Paraoxonase 1 (PON1) is an antioxidant enzyme that may influence ALS progression. This study aimed to establish a predictive model for the influence of PON1 activity on functionality in ALS patients and explore its relationship with nutrition. Methods: In this observational cross-sectional study, 70 ALS patients underwent assessments of PON1 activity, lipid profile, functional capacity, respiratory function, and heart rate variability. A structural equation model was developed to determine the relationships between variables. Nutritional intake was analyzed in 65 patients. Results: The predictive model showed that PON1 activity and LDL levels positively influenced functionality, both directly and indirectly through respiratory capacity. Heart rate variability moderately predicted functionality independently. HDL levels were not significantly associated with functionality. Weak to moderate correlations were found between PON1 activity and intake of certain nutrients, with positive associations for monounsaturated fats and vitamin D, and negative associations for carbohydrates, proteins, and some micronutrients. Conclusions: PON1 activity appears to play an important role in ALS patient functionality, both directly and through effects on respiratory capacity. However, its relationship with nutritional intake was not strongly evident in this sample population.
Can Rice Growth Substrate Substitute Rapeseed Growth Substrate in Rapeseed Blanket Seedling Technology? Lesson from Reactive Oxygen Species Production and Scavenging Analysis
Authors: Yi Kaige , Ren Yun , Zhang Hui , Lin Baogang , Hao Pengfei , Hua Shuijin
Published: August 2024

Rapeseed (Brassica napus L.) seedlings suffering from inappropriate growth substrate stress will present poor seedling quality. However, the regulatory mechanism for the production and scavenging of reactive oxygen species (ROS) caused by this type of stress remains unclear. In the current study, a split plot experiment design was implemented with two crop growth substrates—a rice growth substrate (RIS) and rapeseed growth substrate (RAS)—as the main plot and two genotypes—a hybrid and an open-pollinated variety (Zheyouza 1510 and Zheyou 51, respectively)—as the sub-plot. The seedling quality was assessed, and the ROS production/scavenging capacity was evaluated. Enzymatic and non-enzymatic systems, including ascorbic acid and glutathione metabolism, and RNA-seq data were analyzed under the two growth substrate treatments. The results revealed that rapeseed seedling quality decreased under RIS, with the plant height, maximum leaf length and width, and aboveground dry matter being reduced by 187.7%, 64.6%, 73.2%, and 63.8% on average, respectively, as compared to RAS. The main type of ROS accumulated in rapeseed plants was hydrogen peroxide, which was 47.8% and 14.1% higher under RIS than under RAS in the two genotypes, respectively. The scavenging of hydrogen peroxide in Zheyouza 1510 was the result of a combination of enzymatic systems, with significantly higher peroxidase (POD) and catalase (CAT) activity as well as glutathione metabolism, with significantly higher reduced glutathione (GSH) content, under RAS, while higher oxidized glutathione (GSSH) was observed under RIS. However, the scavenging of hydrogen peroxide in Zheyou 51 was the result of a combination of elevated oxidized ascorbic acid (DHA) under RIS and higher GSH content under RAS. The identified gene expression levels were in accordance with the observed enzyme expression levels. The results suggest that the cost of substituting RAS with RIS is a reduction in rapeseed seedling quality contributing to excessive ROS production and a reduction in ROS scavenging capacity.
A Multi-Target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models
Authors: Gómez-Fernández David , Romero-González Ana , Suárez-Rivero Juan M. , Cilleros-Holgado Paula , Álvarez-Córdoba Mónica , Piñero-Pérez Rocío , Romero-Domínguez José Manuel , Reche-López Diana , López-Cabrera Alejandra , Ibáñez-Mico Salvador , Castro de Oliveira Marta , Rodríguez-Sacristán Andrés , González-Granero Susana , García-Verdugo José Manuel , Sánchez-Alcázar José A.
Published: August 2024

Mutations in the lipoyltransferase 1 (LIPT1) gene are rare inborn errors of metabolism leading to a fatal condition characterized by lipoylation defects of the 2-ketoacid dehydrogenase complexes causing early-onset seizures, psychomotor retardation, abnormal muscle tone, severe lactic acidosis, and increased urine lactate, ketoglutarate, and 2-oxoacid levels. In this article, we characterized the disease pathophysiology using fibroblasts and induced neurons derived from a patient bearing a compound heterozygous mutation in LIPT1. A Western blot analysis revealed a reduced expression of LIPT1 and absent expression of lipoylated pyruvate dehydrogenase E2 (PDH E2) and alpha-ketoglutarate dehydrogenase E2 (α-KGDH E2) subunits. Accordingly, activities of PDH and α-KGDH were markedly reduced, associated with cell bioenergetics failure, iron accumulation, and lipid peroxidation. In addition, using a pharmacological screening, we identified a cocktail of antioxidants and mitochondrial boosting agents consisting of pantothenate, nicotinamide, vitamin E, thiamine, biotin, and α-lipoic acid, which is capable of rescuing LIPT1 pathophysiology, increasing the LIPT1 expression and lipoylation of mitochondrial proteins, improving cell bioenergetics, and eliminating iron overload and lipid peroxidation. Furthermore, our data suggest that the beneficial effect of the treatment is mainly mediated by SIRT3 activation. In conclusion, we have identified a promising therapeutic approach for correcting LIPT1 mutations.
Avicularin Attenuated Lead-Induced Ferroptosis, Neuroinflammation, and Memory Impairment in Mice
Authors: Guo Jun-Tao , Cheng Chao , Shi Jia-Xue , Zhang Wen-Ting , Sun Han , Liu Chan-Min
Published: August 2024

Lead (Pb) is a common environmental neurotoxicant that results in abnormal neurobehavior and impaired memory. Avicularin (AVL), the main dietary flavonoid found in several plants and fruits, exhibits neuroprotective and hepatoprotective properties. In the present study, the effects of AVL on Pb-induced neurotoxicity were evaluated using ICR mice to investigate the molecular mechanisms behind its protective effects. Our study has demonstrated that AVL treatment significantly ameliorated memory impairment induced by lead (Pb). Furthermore, AVL mitigated Pb-triggered neuroinflammation, ferroptosis, and oxidative stress. The inhibition of Pb-induced oxidative stress in the brain by AVL was evidenced by the reduction in malondialdehyde (MDA) levels and the enhancement of glutathione (GSH) and glutathione peroxidase (GPx) activities. Additionally, in the context of lead-induced neurotoxicity, AVL mitigated ferroptosis by increasing the expression of GPX4 and reducing ferrous iron levels (Fe2+). AVL increased the activities of glycogenolysis rate-limiting enzymes HK, PK, and PYG. Additionally, AVL downregulated TNF-α and IL-1β expression while concurrently enhancing the activations of AMPK, Nrf2, HO-1, NQO1, PSD-95, SNAP-25, CaMKII, and CREB in the brains of mice. The findings from this study suggest that AVL mitigates the memory impairment induced by Pb, which is associated with the AMPK/Nrf2 pathway and ferroptosis.
Localization and Aggregation of Honokiol in the Lipid Membrane
Authors: Villalaín José
Published: August 2024

Honokiol, a biphenyl lignan extracted from bark extracts belonging to Magnolia plant species, is a pleiotropic compound which exhibits a widespread range of antioxidant, antibacterial, antidiabetic, anti-inflammatory, antiaggregant, analgesic, antitumor, antiviral and neuroprotective activities. Honokiol, being highly hydrophobic, is soluble in common organic solvents but insoluble in water. Therefore, its biological effects could depend on its bioactive mechanism. Although honokiol has many impressive bioactive properties, its effects are unknown at the level of the biological membrane. Understanding honokiol’s bioactive mechanism could unlock innovative perspectives for its therapeutic development or for therapeutic development of molecules similar to it. I have studied the behaviour of the honokiol molecule in the presence of a plasma-like membrane and established the detailed relation of honokiol with membrane components using all-atom molecular dynamics. The results obtained in this work sustain that honokiol has a tendency to insert inside the membrane; locates near and below the cholesterol oxygen atom, amid the hydrocarbon membrane palisade; increases slightly hydrocarbon fluidity; does not interact specifically with any membrane lipid; and, significantly, forms aggregates. Significantly, aggregation does not impede honokiol from going inside the membrane. Some of the biological characteristics of honokiol could be accredited to its aptitude to alter membrane biophysical properties, but the establishment of aggregate forms in solution might hamper its clinical use.
Addition of a Polar, Porous Phase-Inversion-PVDF Membrane to Lithium–Sulfur Cells (LSBs) Already with a Microporous Polypropylene Separator Enhances the Battery Performance
Authors: Mohammad Irshad , Barter Luke D. J. , Crean Carol , Slade Robert C. T.
Published: August 2024

Lithium–sulfur batteries (LSBs) are widely studied as an alternative to lithium-ion batteries, this emphasis being due to their high theoretical energy density and low cost, and to the high natural abundance of sulfur. Lithium polysulfide shuttling and lithium dendrite growth have limited their commercialization. Porous polyvinylidene fluoride (PVDF) separators have shown improved performance (relative to hydrocarbon separators) in lithium-ion batteries due to faster lithium-ion migration and higher Li+ transference number. A thin polar PVDF membrane has now been fabricated via phase inversion (an immersion-precipitation method) yielding a β (polar) phase concentration of 72%. Preparation from commercial PVDF used dimethylformamide (DMF) solvent at the optimized crystallizing temperature of 70 °C, and pores in the membrane were generated by exchange of DMF with deionized water as non-solvent. The polar PVDF film produced has the advantages of being ultrathin (15 µm), lightweight (1.15 mg cm−2), of high porosity (75%) and high wettability (84%), and it shows enhanced thermal stability relative to polypropylene (PP). The porous, polar PVDF membrane was combined with a commercially available PP membrane to give a hybrid, two-layer, separator combination for LSBs. A synergy was created in the two-layer separator, providing high sulfur utilization and curbing polysulfide shuttling. The electrochemical performance with the hybrid separator (PP–β-PVDF) was evaluated in LSB cells and showed good cyclability and rate capability: those LSB cells showed a stable capacity of 750 mA h g−1 after 100 cycles at 0.1 C, much higher than that for otherwise-identical cells using a commercial PP-only separator (480 mA h g−1).
The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression
Authors: Cuevas Diego , Amigo Roberto , Agurto Adolfo , Heredia Adan Andreu , Guzmán Catherine , Recabal-Beyer Antonia , González-Pecchi Valentina , Caprile Teresa , Haigh Jody J. , Farkas Carlos
Published: August 2024

Acute myeloid leukemia (AML) is a diverse malignancy originating from myeloid progenitor cells, with significant genetic and clinical variability. Modern classification systems like those from the World Health Organization (WHO) and European LeukemiaNet use immunophenotyping, molecular genetics, and clinical features to categorize AML subtypes. This classification highlights crucial genetic markers such as FLT3, NPM1 mutations, and MLL-AF9 fusion, which are essential for prognosis and directing targeted therapies. The MLL-AF9 fusion protein is often linked with therapy-resistant AML, highlighting the risk of relapse due to standard chemotherapeutic regimes. In this sense, factors like the ZEB, SNAI, and TWIST gene families, known for their roles in epithelial–mesenchymal transition (EMT) and cancer metastasis, also regulate hematopoiesis and may serve as effective therapeutic targets in AML. These genes contribute to cell proliferation, differentiation, and extramedullary hematopoiesis, suggesting new possibilities for treatment. Advancing our understanding of the molecular mechanisms that promote AML, especially how the bone marrow microenvironment affects invasion and drug resistance, is crucial. This comprehensive insight into the molecular and environmental interactions in AML emphasizes the need for ongoing research and more effective treatments.
Therapeutic Potential of a Biodynamic Supplement on Skin Pressure Ulcers: A Randomized Clinical Study
Authors: Ferorelli Pasquale , Doepp Manfred , Lenzi Stefano , Rovelli Roberto , Gisonna Gennaro , Maierà Giuseppe , Antonelli Francesco , Radaelli Massimo , Shevchenko Anna , Feriotto Giordana , Mischiati Carlo , Borromeo Ilaria , Beninati Simone
Published: August 2024

Pressure ulcers (PUs) are a debilitating and often painful condition. They are localized lesions on the skin and/or underlying tissues and are common in the elderly, people with mobility difficulties, diabetics, and vascular disease or malnutrition, as well as in those requiring intensive or palliative care. The prevention and treatment of PUs involve strategies to optimize hydration, circulation, and nutrition. Nutrition plays a key role in pressure ulcer care because wounds require macronutrients and micronutrients to heal. Reports relating to the effectiveness of “Complementary Enzyme Therapy” also in the vulnological field led us to this study, the aim of which was to test the activity of a biodynamic food supplement (Citozym®) rich in carbohydrates, vitamins, and amylase and lactase and characterized by marked antioxidant activity. Citozym® administered topically and/or systemically, and in particular in both administrations, in patients suffering from Pus, has shown a marked reduction in bedsores and, in many cases, complete healing. Furthermore, it was possible to observe a lower incidence of side effects compared to conventional therapies. The results obtained, confirmed by various tests and recognized by the scientific community, allow us to conclude that treatment with Citozym® could represent a new and effective strategy for the treatment of PUs.
Exploring Vitamin D Deficiency and IGF Axis Dynamics in Colorectal Adenomas
Authors: Ciulei George , Orășan Olga Hilda , Cozma Angela , Negrean Vasile , Alexescu Teodora Gabriela , Țărmure Simina , Casoinic Florin Eugen , Lucaciu Roxana Liana , Hangan Adriana Corina , Procopciuc Lucia Maria
Published: August 2024

(1) Colorectal cancer is a major cause of cancer-related death, with colorectal adenomas (CRAs) serving as precursors. Identifying risk factors such as vitamin D deficiency and the insulin-like growth factor (IGF) axis is crucial for prevention. (2) This case–control study included 85 participants (53 CRA patients and 32 controls) who underwent colonoscopy. We measured serum vitamin D3 (cholecalciferol), calcidiol (vitamin D metabolite), calcitriol (active vitamin D metabolite), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) to explore their associations with CRA risk. (3) Results: We found that lower cholecalciferol levels were a significant risk factor for CRA (OR = 4.63, p = 0.004). Although no significant differences in calcidiol and calcitriol levels were observed between CRA patients and controls, calcidiol deficiency was common in the study population. IGF-1 levels inversely correlated with age, calcitriol, and IGFBP-3 in CRA patients. (4) This study highlights the potential of lower cholecalciferol levels to detect patients at risk of CRA when calcidiol values cannot, suggesting the importance of evaluating different vitamin D metabolites in cancer prevention research. Our findings underscore the need to further investigate the interactions between calcitriol, the active form of vitamin D, and the IGF axis in colorectal cancer development.
The Impact of Adenomyosis on Pregnancy
Authors: Tsikouras Panagiotis , Kritsotaki Nektaria , Nikolettos Konstantinos , Kotanidou Sonia , Oikonomou Efthymios , Bothou Anastasia , Andreou Sotiris , Nalmpanti Theopi , Chalkia Kyriaki , Spanakis Vlasios , Tsikouras Nikolaos , Chalil Melda , Machairiotis Nikolaos , Iatrakis George , Nikolettos Nikolaos
Published: August 2024

Adenomyosis is characterized by ectopic proliferation of endometrial tissue within the myometrium. Histologically, this condition is marked by the presence of islands of benign endometrial glands surrounded by stromal cells. The myometrium appears thinner, and cross-sectional analysis often reveals signs of recent or chronic hemorrhage. The ectopic endometrial tissue may respond to ovarian hormonal stimulation, exhibiting proliferative or secretory changes during the menstrual cycle, potentially leading to bleeding, uterine swelling, and pain. Adenomyosis can appear as either a diffuse or focal condition. It is crucial to understand that adenomyosis involves the infiltration of the endometrium into the myometrium, rather than its displacement. The surgical management of adenomyosis is contingent upon its anatomical extent. The high incidence of the disease and the myths that develop around it increase the need to study its characteristics and its association with pregnancy and potential obstetric complications. These complications often require quick decisions, appropriate diagnosis, and proper counseling. Therefore, knowing the possible risks associated with adenomyosis is key to decision making. Pregnancy has a positive effect on adenomyosis and its painful symptoms. This improvement is not only due to the inhibition of ovulation, which inhibits the bleeding of adenomyotic tissue, but also to the metabolic, hormonal, immunological, and angiogenic changes associated with pregnancy. Adenomyosis affects pregnancy through disturbances of the endocrine system and the body’s immune response at both local and systemic levels. It leads to bleeding from the adenomyotic tissue, molecular and functional abnormalities of the ectopic endometrium, abnormal placentation, and destruction of the adenomyotic tissue due to changes in the hormonal environment that characterizes pregnancy. Some of the obstetric complications that occur in women with adenomyosis in pregnancy include miscarriage, preterm delivery, placenta previa, low birth weight for gestational age, obstetric hemorrhage, and the need for cesarean section. These complications are an understudied field and remain unknown to the majority of obstetricians. These pathological conditions pose challenges to both the typical progression of pregnancy and the smooth conduct of labor in affected women. Further multicenter studies are imperative to validate the most suitable method for concluding labor following surgical intervention for adenomyosis.
Combination of Anti-CD40 and Anti-CD40L Antibodies as Co-Stimulation Blockade in Preclinical Cardiac Xenotransplantation
Authors: Bender Martin , Abicht Jan-Michael , Reichart Bruno , Neumann Elisabeth , Radan Julia , Mokelke Maren , Buttgereit Ines , Leuschen Maria , Wall Felicia , Michel Sebastian , Ellgass Reinhard , Steen Stig , Paskevicius Audrius , Lange Andreas , Kessler Barbara , Kemter Elisabeth , Klymiuk Nikolai , Denner Joachim , Godehardt Antonia W. , Tönjes Ralf R. , Burgmann Jonathan M. , Figueiredo Constança , Milusev Anastasia , Zollet Valentina , Salimi-Afjani Neda , Despont Alain , Rieben Robert , Ledderose Stephan , Walz Christoph , Hagl Christian , Ayares David , Wolf Eckhard , Schmoeckel Michael , Brenner Paolo , Binder Uli , Gebauer Michaela , Skerra Arne , Längin Matthias
Published: August 2024

The blockade of the CD40/CD40L immune checkpoint is considered essential for cardiac xenotransplantation. However, it is still unclear which single antibody directed against CD40 or CD40L (CD154), or which combination of antibodies, is better at preventing organ rejection. For example, the high doses of antibody administered in previous experiments might not be feasible for the treatment of humans, while thrombotic side effects were described for first-generation anti-CD40L antibodies. To address these issues, we conducted six orthotopic pig-to-baboon cardiac xenotransplantation experiments, combining a chimeric anti-CD40 antibody with an investigational long-acting PASylated anti-CD40L Fab fragment. The combination therapy effectively resulted in animal survival with a rate comparable to a previous study that utilized anti-CD40 monotherapy. Importantly, no incidence of thromboembolic events associated with the administration of the anti-CD40L PAS-Fab was observed. Two experiments failed early because of technical reasons, two were terminated deliberately after 90 days with the baboons in excellent condition and two were extended to 120 and 170 days, respectively. Unexpectedly, and despite the absence of any clinical signs, histopathology revealed fungal infections in all four recipients. This study provides, for the first time, insights into a combination therapy with anti-CD40/anti-CD40L antibodies to block this immune checkpoint.
Could the Early Detection of Atrial Fibrillation Reduce the Risk of Developing Dementia?
Authors: Demoniere Fabrice , Abdelli Rim , Rivard Léna
Published: August 2024

Atrial fibrillation (AF) and dementia are major global public health issues and share common risk factors, especially after the age of 65 and regardless of the presence of stroke. Despite accounting for potential confounders, AF appears to be an independent risk factor for cognitive decline and dementia. The mechanisms are likely to be multifactorial and may include AF-related ischemic stroke, cerebral hypoperfusion, microbleeds, systemic inflammation, genetic factors, and small vessel disease, leading to brain atrophy and white matter damage. The early aggressive management of AF and comorbidities may reduce the risk of dementia. Indeed, the early detection of AF-related cognitive impairment should allow for the early implementation of measures to prevent the development of dementia, mainly through integrative approaches involving the correction of risk factors and maintenance of rhythm control. Well-designed prospective studies are needed to determine whether early detection and AF treatment can prevent dementia and identify whether optimal integrative measures are effective in preventing cognitive impairment and dementia.
Solid-Phase Electrochemiluminescence Enzyme Electrodes Based on Nanocage Arrays for Highly Sensitive Detection of Cholesterol
Authors: Ma Xinying , Zhang Zhe , Zheng Yanyan , Liu Jiyang
Published: August 2024

The convenient and sensitive detection of metabolites is of great significance for understanding human health status and drug development. Solid-phase electrochemiluminescence (ECL) enzyme electrodes show great potential in metabolite detection based on the enzyme-catalyzed reaction product hydrogen peroxide (H2O2). Herein, a solid-phase ECL enzyme sensor was fabricated based on a confined emitter and an immobilized enzyme using electrostatic nanocage array, constructing a platform for the sensitive detection of cholesterol. The electrostatic cage nanochannel consists of a bipolar and bilayer vertically aligned mesoporous silica film (bp-VMSF). The upper layer of bp-VMSF is an amino-modified, positively charged VMSF (p-VMSF), and the lower layer is a negatively charged VMSF (n-VMSF). The most commonly used ECL probe tris(bipyridine)ruthenium(II) (Ru(bpy)32+) is fixed in n-VMSF by electrostatic adsorption from n-VMSF and electrostatic repulsion from the upper p-VMSF, generating significantly enhanced and stable ECL signals. The successful preparation of the electrostatic cage was characterized by scanning electron microscopy (SEM) and electrochemical methods. After amino groups on the outer surface of bp-VMSF were derivatized with aldehyde, cholesterol oxidase (ChOx) molecules were covalently immobilized. The successful construction of the enzyme electrode was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). When the corresponding enzyme substrate, cholesterol, was present in the solution, the ECL signal of Ru(bpy)32+ was quenched by the enzyme-catalyzed reaction product H2O2, enabling the high-sensitivity detection of cholesterol. The linear range for detecting cholesterol was from 0.05 mM to 5.0 mM, with a limit of detection (LOD) of 1.5 μM.
Recent Advances in Nanomaterials for Modulation of Stem Cell Differentiation and Its Therapeutic Applications
Authors: Kim Chang-Dae , Koo Kyeong-Mo , Kim Hyung-Joo , Kim Tae-Hyung
Published: August 2024

Challenges in directed differentiation and survival limit the clinical use of stem cells despite their promising therapeutic potential in regenerative medicine. Nanotechnology has emerged as a powerful tool to address these challenges and enable precise control over stem cell fate. In particular, nanomaterials can mimic an extracellular matrix and provide specific cues to guide stem cell differentiation and proliferation in the field of nanotechnology. For instance, recent studies have demonstrated that nanostructured surfaces and scaffolds can enhance stem cell lineage commitment modulated by intracellular regulation and external stimulation, such as reactive oxygen species (ROS) scavenging, autophagy, or electrical stimulation. Furthermore, nanoframework-based and upconversion nanoparticles can be used to deliver bioactive molecules, growth factors, and genetic materials to facilitate stem cell differentiation and tissue regeneration. The increasing use of nanostructures in stem cell research has led to the development of new therapeutic approaches. Therefore, this review provides an overview of recent advances in nanomaterials for modulating stem cell differentiation, including metal-, carbon-, and peptide-based strategies. In addition, we highlight the potential of these nano-enabled technologies for clinical applications of stem cell therapy by focusing on improving the differentiation efficiency and therapeutics. We believe that this review will inspire researchers to intensify their efforts and deepen their understanding, thereby accelerating the development of stem cell differentiation modulation, therapeutic applications in the pharmaceutical industry, and stem cell therapeutics.
Digital-Twin-Based Operation and Maintenance Management Method for Large Underground Spaces
Authors: Wang Haitao , Yu Caizhao , Zheng Jiarong , Jia Yihong , Liu Zhansheng , Yang Kai
Published: August 2024

Large underground spaces are complex and huge, with problems such as fragmented data that cannot be shared, outdated management methods, and high operation and maintenance costs. The digitization of building information and the use of digital twin technology can effectively improve the efficiency of building operation and maintenance. Using information technology to build a digital-twin-based operation and maintenance management system, the huge and discrete data and equipment system information are effectively integrated and explored for application. First, we analyze the shortcomings of the traditional delivery and operation and maintenance methods and introduce the necessity of a new method of operation and maintenance management based on digital twin; then, we divide the operation and maintenance information of the construction project into four major categories of spatial information and eight major categories of equipment information and complete the coding work, and the categorized data serve as the data basis for operation and maintenance; second, we develop a digital twin operation and maintenance management platform based on the operation and maintenance data of BIM; finally, we carry out case validation for the three major constructions. Finally, case validation is carried out for three major buildings and a large underground space and the practical application shows that the operation and maintenance management system based on digital twin technology provides technical guarantee for decentralized information and system integration management and the information management quality and efficiency of the operation and maintenance process are effectively improved. Through the practice of summarizing the experience, which is worth learning, we aim to create a large underground space operation and maintenance management method to provide a reference.
Research on Sustainable Spatial Governance in Rural Revitalization: A Case Study of the Most Beautiful Courtyard Design Competition and Renovation Practices in Fujian Province
Authors: Meng Leilei , Wu Jiajun , Liu Qianyi , Xu Wei
Published: August 2024

As a pivotal component of rural revitalization, effective management of rural courtyard spaces is crucial for improving environmental quality and economic development. Utilizing the 2023 “Most Beautiful Courtyard” design competition in Guangze County as a backdrop, this study investigates the specific circumstances and practical challenges encountered during the courtyard transformation process. Based on a comprehensive literature review, this research establishes a unified indicator evaluation system; investigates the perspectives of villagers, designers, and managers; and conducts an in-depth analysis of the challenges faced in rural courtyard transformation practice. The goal is to offer substantial reference points for policy formulation and practical implementation, alongside recommendations for effective courtyard transformation. At the construction management level, the government should develop detailed operational guidelines for rural courtyard transformation, closely monitor construction progress, manage funds scientifically, and ensure efficient communication among the three groups. At the localization level, villagers’ daily production and life should be integrated with village cultural symbols, respecting and exploring localization factors. Adequate consideration of the ecological environment and climatic conditions is crucial to promoting the sustainable development of rural courtyards.
Elevated GRHL2 Imparts Plasticity in ER-Positive Breast Cancer Cells
Authors: Zheng Christy , Allen Kaelyn O. , Liu Tianrui , Solodin Natalia M. , Meyer Mark B. , Salem Kelley , Tsourkas Phillipos K. , McIlwain Sean J. , Vera Jessica M. , Cromwell Erika R. , Ozers Mary Szatkowski , Fowler Amy M. , Alarid Elaine T.
Published: August 2024

Estrogen receptor (ER)-positive breast cancer is characterized by late recurrences following initial treatment. The epithelial cell fate transcription factor Grainyhead-like protein 2 (GRHL2) is overexpressed in ER-positive breast cancers and is linked to poorer prognosis as compared to ER-negative breast cancers. To understand how GRHL2 contributes to progression, GRHL2 was overexpressed in ER-positive cells. We demonstrated that elevated GRHL2 imparts plasticity with stem cell- and dormancy-associated traits. RNA sequencing and immunocytochemistry revealed that high GRHL2 not only strengthens the epithelial identity but supports a hybrid epithelial to mesenchymal transition (EMT). Proliferation and tumor studies exhibited a decrease in growth and an upregulation of dormancy markers, such as NR2F1 and CDKN1B. Mammosphere assays and flow cytometry revealed enrichment of stem cell markers CD44 and ALDH1, and increased self-renewal capacity. Cistrome analyses revealed a change in transcription factor motifs near GRHL2 sites from developmental factors to those associated with disease progression. Together, these data support the idea that the plasticity and properties induced by elevated GRHL2 may provide a selective advantage to explain the association between GRHL2 and breast cancer progression.
Neutrophil-to-Lymphocyte Ratio and Prognostic Nutritional Index Are Predictors for Overall Survival after Primary Pancreatic Resection of Pancreatic Ductal Adenocarcinoma: A Single Centre Evaluation
Authors: Hackner Danilo , Merkel Susanne , Weiß Andreas , Krautz Christian , Weber Georg F. , Grützmann Robert , Brunner Maximilian
Published: August 2024

Purpose: Prognostic inflammation-based parameters have been reported as useful tools in various oncologic diseases. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high mortality rate, making reliable prognostic markers highly desirable. However, there is still inconsistency in the literature regarding the efficacy of the different available scores. Methods: A total of 207 patients, who underwent primary resection of PDAC from January 2000 to December 2018 at the University Hospital of Erlangen, were included in this retrospective single-center study. Different biomarkers, including the preoperative neutrophil–lymphocyte ratio (NLR), the platelet–lymphocyte ratio (PLR), the c-reactive protein (CRP)–albumin ratio (CAR), the lymphocyte–CRP ratio (LCR), the prognostic nutritional index (PNI) and the modified Glasgow prognostic score (mGPS) were analyzed for their ability to predict overall survival (OS). Results: In our cohort, the median overall survival was 20.7 months. Among the investigated biomarkers, NLR and PNI were identified as independent prognostic markers (Hazard Ratio (HR) 1.6 (1.0–2.5), p = 0.048 and HR 0.6 (0.4–0.9), p = 0.018), whereas PLR, CAR, LCR and mGPS did not reach significance in the multivariate analysis. Subgroup analysis revealed that the prognostic value of NLR and PNI is particularly evident in locally advanced tumor stages (pT3/4 and pN+). Conclusions: The NLR and PNI could serve as valuable tools for estimating prognosis in patients with PDAC undergoing pancreatic resection in curative intention, especially in locally advanced tumor stages. However, conflicting results in the current literature highlight the need for further prospective studies to validate these findings.
Exploring the Horizon: Anti-Fibroblast Growth Factor Receptor Therapy in Pancreatic Cancer with Aberrant Fibroblast Growth Factor Receptor Expression—A Scoping Review
Authors: Orlandi Elena , Guasconi Massimo , Vecchia Stefano , Trubini Serena , Giuffrida Mario , Proietto Manuela , Anselmi Elisa , Capelli Patrizio , Romboli Andrea
Published: August 2024

Pancreatic cancer is a highly lethal disease, often diagnosed at advanced stages, with a 5-year overall survival rate of around 10%. Current treatments have limited effectiveness, underscoring the need for new therapeutic options. This scoping review aims to identify and summarize preclinical and clinical studies on FGFR (Fibroblast Growth Factor Receptor) inhibitors, including tyrosine kinase inhibitors (TKIs) and FGFR-specific inhibitors, in pancreatic cancer with FGFR alterations. We included studies analyzing efficacy, safety, and survival outcomes in various populations. A comprehensive search across major databases identified 73 relevant studies: 32 preclinical, 16 clinical, and 25 from gray literature. The clinical trials focused primarily on efficacy (20 studies) and safety (14 studies), with fewer studies addressing survival outcomes. FGFR1 was the most studied alteration, followed by FGFR2 and FGFR4. Although FGFR alterations are relatively rare in pancreatic cancer, the available data, including promising real-life outcomes, suggest significant potential for FGFR inhibitors. However, more extensive research is needed to identify the correct genetic drivers and gather robust survival data. Ongoing and future trials are expected to provide more comprehensive insights, potentially leading to improved targeted therapies for pancreatic cancer patients with FGFR alterations.
Overcoming Resistance to Checkpoint Inhibitors with Combination Strategies in the Treatment of Non-Small Cell Lung Cancer
Authors: Reyes Amanda , Muddasani Ramya , Massarelli Erminia
Published: August 2024

Lung cancer continues to contribute to the highest percentage of cancer-related deaths worldwide. Advancements in the treatment of non-small cell lung cancer like immune checkpoint inhibitors have dramatically improved survival and long-term disease response, even in curative and perioperative settings. Unfortunately, resistance develops either as an initial response to treatment or more commonly as a progression after the initial response. Several modalities have been utilized to combat this. This review will focus on the various combination treatments with immune checkpoint inhibitors including the addition of chemotherapy, various immunotherapies, radiation, antibody–drug conjugates, bispecific antibodies, neoantigen vaccines, and tumor-infiltrating lymphocytes. We discuss the status of these agents when used in combination with immune checkpoint inhibitors with an emphasis on lung cancer. The early toxicity signals, tolerability, and feasibility of implementation are also reviewed. We conclude with a discussion of the next steps in treatment.
Clinical Implications of Circulating Tumor Cells in Patients with Esophageal Squamous Cell Carcinoma: Cancer-Draining Blood Versus Peripheral Blood
Authors: Joo Dong Chan , Kim Gwang Ha , I Hoseok , Park Su Jin , Lee Moon Won , Lee Bong Eun
Published: August 2024

Circulating tumor cells (CTCs) in cancer-draining veins have diagnostic and prognostic value. However, studies on esophageal squamous cell carcinoma (ESCC) are limited. This study aimed to compare CTCs obtained from different sampling sites (peripheral vein vs. cancer-draining azygos vein) and to investigate their association with the clinicopathological characteristics of ESCC patients. Blood samples were collected preoperatively from both veins in 40 ESCC patients at Pusan National University Hospital from June 2020 to April 2022. CTCs were detected using a centrifugal microfluidic method with fluid-assisted separation. CTCs and TWIST (+) CTCs were detected more frequently in the azygos vein blood than in the peripheral vein blood; however, the difference was not statistically significant (85.0% [34/40] vs. 77.5% [31/40], p = 0.250 and 82.5% [33/40] vs. 75.0% [30/40], p = 0.586, respectively). CTC and TWIST (+) CTC counts were significantly higher in the azygos vein blood than in the peripheral vein blood (7 vs. 3, p < 0.001, and 6 vs. 2, p < 0.001, respectively). CTCs and TWIST (+) CTCs from peripheral and azygos veins showed no association with clinicopathological characteristics. Further large-scale studies are needed to clarify their role as predictive biomarkers for prognosis and chemotherapy responses in ESCC patients.
Pathological Features Associated with Lymph Node Disease in Patients with Appendiceal Neuroendocrine Tumors
Authors: Rodriguez Franco Salvador , Ghaffar Sumaya Abdul , Jin Ying , Weiss Reed , Hamermesh Mona , Khomiak Andrii , Sugawara Toshitaka , Franklin Oskar , Leal Alexis D. , Lieu Christopher H. , Schulick Richard D. , Del Chiaro Marco , Ahrendt Steven , McCarter Martin D. , Gleisner Ana L.
Published: August 2024

This study aimed to evaluate the role of pathological features beyond tumor size in the risk of lymph node metastasis in appendiceal neuroendocrine tumors. Analyzing data from the national cancer database, we found that among 5353 cases, 18.8% had lymph node metastasis. Focusing on tumors smaller than 2 cm, a subject of considerable debate in treatment strategies, we identified lymphovascular invasion as one of the strongest predictors of lymph node disease. Interestingly, extension into the subserosa and beyond, a current factor in the staging system, was not a strong predictor. These findings suggest that careful interpretation of pathological features is needed when selecting therapeutic approaches using current staging systems.