bluuebunny/crossref_metadata_2025 huggingface dataset:
O-GlcNAcylation of Focal Adhesion Kinase Regulates Cell Adhesion, Migration, and Proliferation via the FAK/AKT Pathway
Authors: Zhang Zhiwei , Isaji Tomoya , Oyama Yoshiyuki , Liu Jianwei , Xu Zhiwei , Sun Yuhan , Fukuda Tomohiko , Lu Haojie , Gu Jianguo
Published: December 2024

Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase pivotal in cellular signal transduction, regulating cell adhesion, migration, growth, and survival. However, the regulatory mechanisms of FAK during tumorigenesis and progression still need to be fully understood. Our previous study demonstrated that O-GlcNAcylation regulates integrin-mediated cell adhesion. To further elucidate the underlying molecular mechanism, we focused on FAK in this study and purified it from 293T cells. Using liquid chromatography–mass spectrometry (LC-MS/MS), we identified the O-GlcNAcylation of FAK at Ser708, Thr739, and Ser886. Compared with wild-type FAK expressed in FAK-knockout 293T cells, the FAK mutant, in which Ser708, Thr739, and Ser886 were replaced with Ala, exhibited lower phosphorylation levels of Tyr397 and AKT. Cell proliferation and migration, assessed through MTT and wound healing assays, were significantly suppressed in the FAK mutant cells compared to the wild-type FAK cells. Additionally, the interaction among FAK, paxillin, and talin was enhanced, and cell adhesion was increased in the mutant cells. These data indicate that specific O-GlcNAcylation of FAK plays a critical regulatory role in integrin-mediated cell adhesion and migration. This further supports the idea that O-GlcNAcylation is essential for tumorigenesis and progression and that targeting the O-GlcNAcylation of FAK could offer a promising therapeutic strategy for cancer treatment.
Mutations of Key Functional Residues in CRM1/XPO1 Differently Alter Its Intranuclear Localization and the Nuclear Export of Endogenous Cargos
Authors: Omaetxebarria Miren Josu , Sendino Maria , Arrizabalaga Liher , Mota Irune , Zubiaga Ana Maria , Rodríguez José Antonio
Published: December 2024

CRM1 (XPO1) has been well-characterized as a shuttling receptor that mediates the export of protein and RNA cargos to the cytoplasm, and previous analyses have pinpointed several key residues (A541, F572, K568, S1055, and Q742) that modulate CRM1 export activity. CRM1 also has a less studied nuclear function in RNA biogenesis, which is reflected by its localization to the Cajal body and the nucleolus. Here, we have investigated how the mutation of these key residues affects the intranuclear localization of CRM1 and its ability to mediate export of endogenous cargos. We identify A541K as a separation-of-function mutant that reveals the independent nature of the Cajal body and nucleolar localizations of CRM1. We also show that the F572A mutation may have strikingly opposite effects on the export of specific cargos. Importantly, and in contrast to previous claims, our findings indicate that S1055 phosphorylation is not generally required for CRM1 function and that the Q742 is not a function-defining residue in human CRM1. Collectively, our findings provide new insights into an understudied aspect of CRM1 biology and highlight several important issues related to CRM1 function and regulation that need to be re-evaluated and addressed in more detail.
Increased Risk of Myositis-Specific and Myositis-Associated Autoantibodies After COVID-19 Pandemic and Vaccination: A Spanish Multicenter Collaborative Study
Authors: García-Bravo Laura , Prada Alvaro , Gutiérrez Larrañaga María , Espinosa Ros Eduardo , Almeida González Delia , Martín Martínez Dolores , Rodríguez Sánchez Telesforo , Mingorance Gámez Carlos Gustavo , Jurado Roger Aurora , Aguado Álvarez Rocío , Díaz Luna María De Las Mercedes , Rodríguez Hernández Carmen , de la Varga-Martínez Raquel , López-Cueto María , Julià Benique Maria Rosa , San José-Cascón Miriam , Quirant-Sánchez Bibiana , Martínez-Chamorro Alba , Marcaida-Benito Goitzane , Timoneda Timoneda Pilar Teresa , Fandos Sánchez Marta , Sacristán Enciso Beatriz , Mohamed Mohamed Kauzar , Guerra-Galán Teresa , Villegas Ángela , Roncancio-Clavijo Andrés , Rodríguez-Mahou Margarita , Sánchez-Ramón Silvia , Fernández-Arquero Miguel , Candelas-Rodríguez Gloria , Ochoa-Grullón Juliana ,   on behalf of the GEAI-SEI Group
Published: December 2024

Background: Emerging evidence suggests that SARS-CoV-2 infection and vaccines may trigger autoimmune responses in predisposed individuals. Idiopathic inflammatory myopathies (IIMs) are diseases with diverse clinical manifestations, often associated with myositis autoantibodies (MAs). Diagnosing IIM is challenging due to limitations in classification criteria and diagnostic assays. This study aimed to describe the incidence of IIM following SARS-CoV-2 infection or vaccination and compare rates between exposures. Methods: A multicenter observational study was conducted with 788 patients from 11 Spanish referral centers. A total of 1209 autoantibodies including myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs), were analyzed using line blot immunoassay (LIA). Results: The study identified distinct patterns in aminoacyl-tRNA synthetase (ARS) antibody frequencies compared to pre-pandemic periods. Anti-PL-7 was the most prevalent ARS antibody (14.85%), while anti-Jo-1 was less frequent (7.23%). Anti-MDA5, commonly linked to SARS-CoV-2 infection, was detected in 11.68%. ANA positivity was observed in 60.66%, suggesting an autoimmune background. The most frequent diagnoses were anti-synthetase syndrome (ASSD) or IIM-non-ASSD (21.31%), followed by other systemic autoimmune diseases (SAIDs) (13.57%). Among the cohort, 91.13% received at least one dose of a messenger RNA (mRNA) COVID-19 vaccine, with a median of three doses per patient. Patients with prior SARS-CoV-2 infection or heterologous vaccination showed a higher frequency of multiple autoantibody positivity (p < 0.05), reflecting distinct immune signatures. Conclusions: This study provides valuable insights into the autoimmune risks and phenotypes associated with SARS-CoV-2 infection and vaccination, establishing a basis for further research on IIM and its link to MSAs and MAAs.
Dopamine-Sensitive Anterior Cingulate Cortical Glucose-Monitoring Neurons as Potential Therapeutic Targets for Gustatory and Other Behavior Alterations
Authors: Hormay Edina , László Bettina , Szabó István , Mintál Kitti , Berta Beáta , Ollmann Tamás , Péczely László , Nagy Bernadett , Tóth Attila , László Kristóf , Lénárd László , Karádi Zoltán
Published: December 2024

Background: The anterior cingulate cortex (ACC) is known for its involvement in various regulatory functions, including in the central control of feeding. Activation of local elements of the central glucose-monitoring (GM) neuronal network appears to be indispensable in these regulatory processes. Destruction of these type 2 glucose transporter protein (GLUT2)-equipped chemosensory cells results in multiple feeding-associated functional alterations. Methods: In order to examine this complex symptomatology, (1) dopamine sensitivity was studied in laboratory rats by means of the single-neuron-recording multibarreled microelectrophoretic technique, and (2) after local bilateral microinjection of the selective type 2 glucose transporter proteindemolishing streptozotocin (STZ), open-field, elevated plus maze, two-bottle and taste reactivity tests were performed. Results: A high proportion of the anterior cingulate cortical neurons changed their firing rate in response to microelectrophoretic administration of D-glucose, thus verifying them as local elements of the central glucose-monitoring network. Approximately 20% of the recorded cells displayed activity changes in response to microelectrophoretic application of dopamine, and almost 50% of the glucose-monitoring units here proved to be dopamine-sensitive. Moreover, taste stimulation experiments revealed even higher (80%) gustatory sensitivity dominance of these chemosensory cells. The anterior cingulate cortical STZ microinjections resulted in extensive behavioral and taste-associated functional deficits. Conclusions: The present findings provided evidence for the selective loss of glucose-monitoring neurons in the anterior cingulate cortex leading to motivated behavioral and gustatory alterations. This complex dataset also underlines the varied significance of the type 2 glucose transporter protein-equipped, dopamine-sensitive glucose-monitoring neurons as potential therapeutic targets. These units appear to be indispensable in adaptive control mechanisms of the homeostatic–motivational–emotional–cognitive balance for the overall well-being of the organism.
Numerical Simulation on Self-Propulsion Characteristics of Bionic Flexible Foil Considering Ground Wall Effect
Authors: Li Yongcheng , Zhang Nan , Tang Xinyuan , Pan Ziying , Xu Pengfei
Published: December 2024

In order to figure out the wall effect on the propulsive property of an auto-propelled foil, the commercial open-source code ANSYS Fluent was employed to numerically evaluate the fluid dynamics of flexible foil under various wall distances. A virtual model of NACA0015 foil undergoing travelling wavy motion was adopted, and the research object included 2D and 3D models. To capture the foil’s moving boundary, the dynamic grid technique coupled with the overlapping grid was utilized to realize the foil’s positive deformation and passive forward motion. The ground wall effect on fluid dynamics (thrust force, lift force and propulsive efficiency) and the flow structures of travelling wavy foil were analyzed. The numerical results show that the existence of the ground wall is beneficial for the propulsive property of foil. Specifically, the existence of the wall can improve the forward speed and efficiency of foil, with a maximum increase of 13% in moving velocity and a 10.5% increase in propulsive efficiency. The conclusions acquired in the current study are of great significance for the design of bionic UUV.
Cellular Compartmentalization as a Physical Regulatory Mechanism of Signaling Pathways
Authors: Fayad Ahmed N. , Mazo-Durán Diego , Míguez David G.
Published: December 2024

Cells compartmentalize biochemical processes using physical barriers in the form of membranes. Eukaryotes have a wide diversity of membrane-based compartments that can be used in this context, with the main ones being the extracellular membrane, which separates the inside from the outside of the cell, and the nuclear membrane, which separates the nucleus from the cytoplasm. The nuclear membrane not only isolates and protects the DNA and the transcription and replication processes from the other processes that are occurring in the cytoplasm but also has an active role in the regulation of cellular signaling. The TGF-β pathway is one of the most important and conserved signaling cascades, and it achieves compartmentalization using a well-tuned balance between the import and export rates of the active and inactive forms of key proteins. Thus, compartmentalization serves as an additional regulatory mechanism, physically isolating transcription factors from their targets, influencing the dynamics and strength of signal transduction. This contribution focuses on this biophysical layer of regulation, using the TGF-β pathway to illustrate the molecular mechanisms underlying this process, as well as the biological consequences of this compartmentalization. We also introduce a simplified mathematical formulation for studying the dynamics of this process using a generalized approach.
Electrochemical and Optical Multi-Detection of Escherichia coli Through Magneto-Optic Nanoparticles: A Pencil-on-Paper Biosensor
Authors: Soysaldı Furkan , Dincyurek Ekici Derya , Soylu Mehmet Çağrı , Mutlugun Evren
Published: December 2024

Escherichia coli (E. coli) detection suffers from slow analysis time and high costs, along with the need for specificity. While state-of-the-art electrochemical biosensors are cost-efficient and easy to implement, their sensitivity and analysis time still require improvement. In this work, we present a paper-based electrochemical biosensor utilizing magnetic core-shell Fe2O3@CdSe/ZnS quantum dots (MQDs) to achieve fast detection, low cost, and high sensitivity. Using electrochemical impedance spectroscopy (EIS) as the detection technique, the biosensor achieved a limit of detection of 2.7 × 102 CFU/mL for E. coli bacteria across a concentration range of 102–108 CFU/mL, with a relative standard deviation (RSD) of 3.5781%. From an optical perspective, as E. coli concentration increased steadily from 104 to 107 CFU/mL, quantum dot fluorescence showed over 60% lifetime quenching. This hybrid biosensor thus provides rapid, highly sensitive E. coli detection with a fast analysis time of 30 min. This study, which combines the detection advantages of electrochemical and optical biosensor systems in a graphite-based paper sensor for the first time, has the potential to meet the needs of point-of-care applications. It is thought that future studies that will aim to examine the performance of the production-optimized, portable, graphite-based sensor system on real food samples, environmental samples, and especially medical clinical samples will be promising.
On the Choice of the Characteristic Length in the NMMD Model for the Simulation of Brittle Fractures
Authors: Lu Guangda
Published: December 2024

The recently proposed nonlocal macro–meso-scale consistent damage (NMMD) model has been applied successfully to various static and dynamic fracture problems. The characteristic length in the NMMD model, although proven to be necessary for the mesh insensitivity of a strain-softening regime, remains to be estimated indirectly with considerable arbitrariness. Such an issue also exists in other nonlocal models, e.g., peridynamics and phase field models. To overcome this obstacle, a series of dog-bone specimens composed of polymethyl-methacrylate (PMMA) material with and without circular defects are investigated in this paper. It is found that the NMMD model with the appropriate influence radius can correctly capture the experimentally observed size effect of the defect, which challenges the conventional local criteria without involving the characteristic length. In addition to being directly measurable and identifiable in experiments, based on the two-scale mechanism of the NMMD model, the characteristic length is also theoretically calibrated to be related to the ratio of the fracture toughness to the tensile strength of the material. Comparisons with the predictions of other modified nonlocalized criteria involving some characteristic length demonstrate the superior ability of the NMMD model to simulate brittle crack initiation and propagation from a non-singular boundary. The revalidation of short bending beams demonstrates that theoretical calibration is also suitable for problems of mixed-mode fractures with stress singularity. Although limited to brittle materials like PMMA, the current work could be generalized to the analysis of quasi-brittle or even ductile fractures in the future.
Navigating Tensions in Green Building Certification: The Impact of Leadership and Collaboration in Temporary Multi-Organizations
Authors: Gomes Jorge Vareda , Barata Vasco , Romão Mário
Published: December 2024

The building sector has emerged as a crucial driver of innovation in the transition towards sustainability, gaining increased recognition at multiple levels of society. This shift is not occurring in isolation; it is being accelerated by mounting pressures from both governmental bodies and non-governmental organizations. These external forces are pushing the building industry to adopt more sustainable practices, leading to significant changes not only within individual organizations but also on a broader macroeconomic scale. Policies, regulations, and market demands are converging to create a landscape where sustainability is no longer optional but imperative. Considering these developments, this study set out to investigate the impact of Green Building Certificates (GBCs) on innovation processes within the construction industry. The research specifically focused on how GBCs influence both the technological advancements introduced in building projects and the collaborative dynamics among the various stakeholders involved. By employing a multiple case study approach, the study was able to capture real-world examples and offer a comparative analysis against established academic frameworks. One of the standout findings was the pivotal role played by the green project champion; a leadership figure whose influence extends across all stages of project development. This role is not merely administrative; it is strategic, as the green project champion helps to navigate the complexities of sustainable practices, fostering collaboration among architects, engineers, developers, and consultants. Their leadership is instrumental in ensuring that sustainability goals are integrated into the project’s objectives, while also managing the tensions that arise between the various actors involved. This study highlights the importance of effective leadership and collaboration in driving the successful implementation of GBCs, emphasizing the green project champion’s role as a key facilitator of innovation in the sustainable building sector.
Development of Limestone Calcined Clay Cement-Based Lightweight Bricks Incorporating Waste Rockwool: A Step into Leading the Way in Low-Carbon Bricks
Authors: Alghamdi Hussam , Shoukry Hamada , Abdel-Gawwad Hamdy A. , Hossain Md. Uzzal , Abadel Aref A. , Eltawil Khaled A. , Youssef Ahmed S.
Published: December 2024

This study aimed to develop eco-friendly limestone calcined clay cement (LC3)-based lightweight bricks by reusing waste rockwool (RW) with the improvement of technical performances such as thermo-physical and mechanical, including fire-resistance performances. LC3 binder was blended with expanded clay (EC) aggregates at a ratio of binder-to-aggregate of 1:1.5 (vol%). EC was substituted by waste RW at different percentages, ranging from 5 to 15 vol%. Several technical properties such as density, compressive strength, total porosity, water absorption, thermal conductivity, and thermal diffusivity were investigated after 7 days of curing. The fire-resistance performance of the developed bricks was determined by assessing the residual compressive strength after exposure to standard fire for up to an hour. With dry bulk densities ranging from 1200 to 1360 kg/m3 and compressive strengths (>8.60 MPa), the developed brick met the acceptance criteria for non-load-bearing applications. Even at the highest dosage of RW, the results demonstrated a thermal conductivity as low as 0.36 W/mK, indicating that the developed brick is suitable for hot weather zones, as it reduces the heat flow into buildings. The partial replacement of EC by RW is very beneficial in enhancing the fire-resistance performance, and a residual strength of about 89.7% has been maintained by the bricks incorporating 5% waste RW after 1 h of fire exposure (employing a maximum applied temperature of 927 °C). Lifecycle assessment results indicated that up to 13% lower carbon emissions are associated with LC3-based lightweight bricks designed to reuse a higher amount of waste RW.
Stochastic Extension of Nonlocal Macro–Mesoscale Consistent Damage Model for Fracture Behaviors of Concrete Materials
Authors: Lu Guangda , Xie Jiankang
Published: December 2024

The nonlinearity and randomness in composite materials such as concrete present challenges regarding the safety analysis and reliability-based design of structures. Based on two-scale damage evolution and physically based geometry–energy conversion, the nonlocal macro–mesoscale consistent damage model (NMMD) shows a unique capability in dealing with the nonlinearity of crack evolution. In this paper, a stochastic extension of the NMMD model is proposed to analyze the stochastic fracture behaviors of concrete materials. The extended model uses the stochastic harmonic function (second kind) to represent the spatial variability in concrete properties and thus to investigate the influence of inhomogeneity in the cracking process. Numerical examples of three-point bending beams without defects and with initial cracks of various sizes demonstrate that the stochastic NMMD model is capable of not only capturing uncertain fluctuations in peak load but also simulating the random walk of the crack path with the instantaneous transition of fracture modes, as observed in experiments. In addition, the effectiveness of the stochastic NMMD model with only a single random field (i.e., Young’s modulus) also contradicts the conventional assertion that stochastic simulations of quasi-brittle fracture should contain at least two mechanical properties with spatial randomness. Finally, the investigation of fracture energy with stochastic fluctuations reveals that randomness resulting from heterogeneity can statistically improve the fracture toughness of concrete materials to some extent.
Comparisons of Intravesical Treatments with Mitomycin C, Gemcitabine, and Docetaxel for Recurrence and Progression of Non-Muscle Invasive Bladder Cancer: Updated Systematic Review and Meta-Analysis
Authors: Matloubieh Jubin E. , Hanelin David , Agalliu Ilir
Published: December 2024

Background: Non-muscle-invasive bladder cancer (NMIBC) comprises about 75% of all bladder cancers. Although NMIBC is treatable, it poses significant costs and burdens to patients due to high recurrence rates. We conducted an updated meta-analysis of studies that evaluated the efficacy of and outcomes after treatment with mitomycin C (MMC), gemcitabine (GEM), and docetaxel (DOCE) for NMIBC recurrence and progression. Methods: We searched the PubMed and Cochrane databases for observational cohort studies and randomized clinical trials (RCT) conducted between 2009 and 2022 that assessed the efficacy of GEM, DOCE, or MMC, alone or in combination, regarding NMIBC outcomes. A total of 49 studies that met the inclusion criteria were reviewed for their quality, sample size, outcomes, and potential for bias, and relevant data were extracted for the meta-analysis. Separate meta-analyses were performed to assess the risks of recurrence or progression when comparing GEM/DOCE or MMC vs. other treatments. Study heterogeneity was assessed by I2 statistics. Results: Among 31 studies comparing GEM or MMC to other treatments for NMIBC recurrence, there were statistically significant risk reductions of 24% for GEM (pooled relative risk (RR) of 0.76; 95% confidence interval (CI) 0.64–0.87) and 37% for MMC (pooled RR = 0.63; 95% CI 0.58–0.68). Recurrence-free survival (RFS) for GEM or MMC alone was 69.5% (95% CI 66.6–72.3%) and 67.2% (95% CI 66.2–68.2%), respectively. Studies assessing the combination of treatments had a pooled RFS of 44.6% (95% CI 40.4–48.7%). Fewer studies examined the risk of NMIBC progression, with large variability and inconclusive results across them. Conclusions: Our findings corroborate recent guidelines indicating that both GEM and MMC are effective treatments that reduce tumor recurrence and improve survival of NMIBC, although with large variability across the studies. Fewer studies evaluated DOCE treatment, with inconclusive results. Women and minorities were generally underrepresented, raising concerns about the generalizability of the findings and highlighting the importance of including a broader patient population in future RCTs.
The Use of Nutraceutical and Pharmacological Strategies in Murine Models of Autism Spectrum Disorder
Authors: Bonetti Matteo , Borsani Elisa , Bonomini Francesca
Published: December 2024

Autism spectrum disorder (ASD) is a common neurodevelopmental condition mainly characterized by both a scarce aptitude for social interactions or communication and engagement in repetitive behaviors. These primary symptoms can manifest with variable severity and are often paired with a heterogeneous plethora of secondary complications, among which include anxiety, ADHD (attention deficit hyperactivity disorder), cognitive impairment, sleep disorders, sensory alterations, and gastrointestinal issues. So far, no treatment for the core symptoms of ASD has yielded satisfactory results in a clinical setting. Consequently, medical and psychological support for ASD patients has focused on improving quality of life and treating secondary complications. Despite no single cause being identified for the onset and development of ASD, many genetic mutations and risk factors, such as maternal age, fetal exposure to certain drugs, or infections have been linked to the disorder. In preclinical contexts, these correlations have acted as a valuable basis for the development of various murine models that have successfully mimicked ASD-like symptoms and complications. This review aims to summarize the findings of the extensive literature regarding the pharmacological and nutraceutical interventions that have been tested in the main animal models for ASD, and their effects on core symptoms and the anatomical, physiological, or molecular markers of the disorder.
Astrocytic Alterations and Dysfunction in Down Syndrome: Focus on Neurogenesis, Synaptogenesis, and Neural Circuits Formation
Authors: Uguagliati Beatrice , Grilli Mariagrazia
Published: December 2024

Down syndrome (DS) is characterized by severe neurodevelopmental alterations that ultimately lead to the typical hallmark of DS: intellectual disability. In the DS brain, since the prenatal life stages, the number of astrocytes is disproportional compared to the healthy brain. This increase is due to a shift from neuron to astrocyte differentiation during brain development. Astrocytes are involved in numerous functions during brain development, including balancing pro-neurogenic and pro-gliogenic stimuli, sustaining synapse formation, regulating excitatory/inhibitory signal equilibrium, and supporting the maintenance and integration of functional neural circuits. The enhanced number of astrocytes in the brain of DS individuals leads to detrimental consequences for brain development. This review summarizes the mechanisms underlying astrocytic dysfunction in DS, and particularly the dysregulation of key signaling pathways, which promote astrogliogenesis at the expense of neurogenesis. It further examines the implications of astrocytic alterations on dendritic branching, spinogenesis and synaptogenesis, and the impact of the abnormal astrocytic number in neural excitability and in the maintenance of the inhibitory/excitatory balance. Identifying deregulated pathways and the consequences of astrocytic alterations in early DS brain development may help in identifying new therapeutic targets, with the ultimate aim of ameliorating the cognitive disability that affects individuals with DS.
SARS-CoV-2 Spike Protein Amplifies the Immunogenicity of Healthy Renal Epithelium in the Presence of Renal Cell Carcinoma
Authors: Somova Maryna , Simm Stefan , Ehrhardt Jens , Schoon Janosch , Burchardt Martin , Pinto Pedro Caetano
Published: December 2024

Renal cell carcinoma (RCC) is the most common form of kidney cancer, known for its immune evasion and resistance to chemotherapy. Evidence indicates that the SARS-CoV-2 virus may worsen outcomes for RCC patients, as well as patients with diminished renal function. Evidence suggests that the SARS-CoV-2 virus may exacerbate outcomes in RCC patients and those with impaired renal function. This study explored the unidirectional effects of RCC cells and the SARS-CoV-2 spike protein (S protein) on human renal proximal tubule epithelial cells (RPTECs) using a microphysiological approach. We co-cultured RCC cells (Caki-1) with RPTEC and exposed them to the SARS-CoV-2 S protein under dynamic 3D conditions. The impact on metabolic activity, gene expression, immune secretions, and S protein internalization was evaluated. The SARS-CoV-2 S protein was internalized by RPTEC but poorly interacted with RCC cells. RPTECs exposed to RCC cells and the S protein exhibited upregulated expression of genes involved in immunogenic pathways, particularly those related to antigen processing and presentation via the major histocompatibility complex I (MHCI). Additionally, increased TNF-α secretion suggested a pro-inflammatory response. Metabolic shifts toward glycolysis were observed in RCC co-culture, while the presence of the S protein led to minor changes. The presence of RCC cells amplified the immune-modulatory effects of the SARS-CoV-2 S protein on the renal epithelium, potentially exacerbating renal inflammation and fostering tumor-supportive conditions. These findings suggest that COVID-19 infections can impact renal function in the presence of kidney cancer.
Alzheimer’s Disease: In Vitro and In Vivo Evidence of Activation of the Plasma Bradykinin-Forming Cascade and Implications for Therapy
Authors: Kaplan Allen P. , Ghebrehiwet Berhane , Joseph Kusumam
Published: December 2024

The plaques associated with Alzheimer’s disease are formed as a result of the aggregation of Aβ peptides, which vary in length from 38 to 43 amino acids. The 1-40 peptide is the most abundant, while the 1-42 peptide appears to be the most destructive to neurons and/or glial cells in a variety of assays. We have demonstrated that aggregated Aβ, a state prior to plaque formation, will activate the plasma bradykinin-forming pathway when tested in vitro. Aggregation is zinc-dependent, optimal at 25–50 µM, and the rate of aggregation is paralleled by the rate of activation of the bradykinin-forming pathway as assessed by plasma kallikrein formation. The aggregation of Aβ 1-38, 1-40, and 1-42 is optimal after incubation for 3 days, 3 h, and under 1 min, respectively. The cascade is initiated by the autoactivation of factor XII upon binding to aggregated Aβ; then, prekallikrein is converted to kallikrein, which cleaves high-molecular-weight kininogen (HK) to release bradykinin. Studies by a variety of other researchers have demonstrated the presence of each “activation-step” in either the plasma or spinal fluid of patients with Alzheimer’s disease, including activated factor XII, kallikrein, and bradykinin itself. There is also evidence that activation is more prominent as dementia worsens. We now have medications that can block each step of the bradykinin-forming pathway as currently employed for the therapy of hereditary angioedema. Given the current state of therapy for Alzheimer’s disease, which includes monoclonal antibodies that retard the rate of progression by 30% at most and have significant side effects, it seems imperative to explore prophylaxis using one of the long-acting agents that target plasma kallikrein or factor XIIa. There is a long-acting bradykinin antagonist in development, and techniques to target kallikrein mRNA to lower levels or knock out the prekallikrein gene are being developed.
KSRP Deficiency Attenuates the Course of Pulmonary Aspergillosis and Is Associated with the Elevated Pathogen-Killing Activity of Innate Myeloid Immune Cells
Authors: Bolduan Vanessa , Palzer Kim-Alicia , Ries Frederic , Busch Nora , Pautz Andrea , Bros Matthias
Published: December 2024

The mRNA-binding protein KSRP (KH-type splicing regulatory protein) is known to modulate immune cell functions post-transcriptionally, e.g., by reducing the mRNA stability of cytokines. It is known that KSRP binds the AU-rich motifs (ARE) that are often located in the 3′-untranslated part of mRNA species, encoding dynamically regulated proteins as, for example, cytokines. Innate myeloid immune cells, such as polymorphonuclear neutrophils (PMNs) and macrophages (MACs), eliminate pathogens by multiple mechanisms, including phagocytosis and the secretion of chemo- and cytokines. Here, we investigated the role of KSRP in the phenotype and functions of both innate immune cell types in the mouse model of invasive pulmonary aspergillosis (IPA). Here, KSRP−/− mice showed lower levels of Aspergillus fumigatus conidia (AFC) and an increase in the frequencies of PMNs and MACs in the lungs. Our results showed that PMNs and MACs from KSRP−/− mice exhibited an enhanced phagocytic uptake of AFC, accompanied by increased ROS production in PMNs upon stimulation. A comparison of RNA sequencing data revealed that 64 genes related to inflammatory and immune responses were shared between PMNs and MACs. The majority of genes upregulated in PMNs were involved in metabolic processes, cell cycles, and DNA repair. Similarly, KSRP-deficient PMNs displayed reduced levels of apoptosis. In conclusion, our results indicate that KSRP serves as a critical negative regulator of PMN and MAC anti-pathogen activity.
The Unsung Heroes: The Profile of the Donor at a Southern Italian Milk Bank and Driving Factors in Human Milk Donation
Authors: Quitadamo Pasqua Anna , Comegna Laura , Zambianco Federica , Palumbo Giuseppina , Copetti Massimiliano , Gentile Maria Assunta , Mondelli Antonio , Beghetti Isadora , Corvaglia Luigi
Published: December 2024

Background/Objectives: One of the most effective strategies to mitigate morbidity associated with preterm birth is the use of human milk. The first choice is the mother’s milk; if that is not available, human milk donated to milk banks is the second choice. The recruitment of milk donors is essential for enhancing the effectiveness and efficiency of donation. This study aims to profile the donors of a southern Italian milk bank, examine how maternal and neonatal factors impacted the volume and duration of donation and analyze the trend over the last ten years. Materials and Methods: Data were collected from the milk bank database and hospitalization medical records, encompassing 593 donors and 13 years of activity of the Human Milk Bank from 2010 to 2022. Several variables were assessed: maternal characteristics—maternal age, employment status and the type of profession; pre and perinatal characteristics—type of delivery, parity, previous breastfeeding experience, birth weight and gestational age; milk donation characteristics—volume of milk donated and duration of donation. The trend of the characteristics was studied over time. Statistical correlations were conducted to assess the relationships between variables and the volume and duration of the milk donation. Results: In our cohort of donors, the most prevalent category consists of women over 30 years of age who are multiparous, have prior breastfeeding experience, are workers and have given birth to full-term babies. Maternal age and gestational age significantly influence both the volume and duration of milk donation. The type of delivery and occupation impact the volume of donated milk. There has been a decline in the number of donors over time. However, the trends in both the quantity and duration of milk donations have remained stable over the past decade, with the exception of the year immediately following the COVID-19 pandemic. Conclusions: We have outlined the prevailing average profile of the milk donor to a milk bank in Southern Italy. Factors impacting the volume and duration of donation, such as maternal age, occupation, type of delivery and gestational age, were identified. The volume and duration of donations have remained largely stable, with the exception of 2021, when the pandemic significantly reduced milk donations to the milk bank.
Gender and Educational Stage Differences in Motivation, Basic Psychological Needs and Enjoyment: Evidence from Physical Education Classes
Authors: Navarro-Patón Rubén , Rodríguez-Negro Josune , Muíño-Piñeiro María , Mecías-Calvo Marcos
Published: December 2024

Background/Objectives: There is evidence that shows an association between basic psychological needs, motivation, and enjoyment in the context of school physical education. However, there are no studies that have included all of them in a single study. Therefore, the objective of this research was to determine if there are differences in motivation, basic psychological needs, and enjoyment in physical education classes between primary and secondary education students and between boys and girls. Methods: A total of 740 schoolchildren (410 girls, 55.4%) from primary education (n = 310; 41.9%) and secondary education (n = 430; 58.1%) between the ages of 10 and 17 participated (M = 13.60; SD = 2.03). The Perceived Locus of Causality in Physical Education Scale (PLOC Scale), the Basic Psychological Needs in Exercise Scale (BPNES), and the Physical Activity Enjoyment Measurement Scale (PACES) were administered. Results: Statistically significant differences were found in the educational stage factor with higher scores in primary education students in intrinsic regulation (p < 0.001), identified regulation (p < 0.001), introjected regulation (p = 0.004), perceived competence (p < 0.001), relatedness (p < 0.001), and enjoyment (p < 0.001). In terms of the gender factor, there were significant differences in intrinsic regulation (p = 0.005), identified regulation (p = 0.007), and enjoyment (p = 0.010), with higher scores in boys. Conclusions: Primary education students present greater self-determined motivation (intrinsic, identified, and introjected regulation), as well as a greater sense of competition, relatedness, and enjoyment than secondary education students. Boys have greater regulation and intrinsic enjoyment than girls in physical education classes.
Transcriptome Analysis Provides Insights into the Safe Overwintering of Local Peach Flower Buds
Authors: Niu Ruxuan , Cheng Yongjuan , Wang Falin , Zhang Yiwen , Wang Chenbing
Published: December 2024

During the dormant period of peach trees in winter, flower buds exhibit weak cold resistance and are susceptible to freezing at low temperatures. Understanding the physiological and molecular mechanisms underlying the response of local peach buds to low-temperature adversity is crucial for ensuring normal flowering, fruiting, and yield. In this study, the experimental materials included the conventional cultivar ‘Xia cui’ (XC) and the cold-resistant local resources ‘Ding jiaba’ (DJB) peach buds. The antioxidant enzyme activity, levels of malondialdehyde (MDA), proline (Pro), and hydrogen peroxide content (H2O2) were determined in peach buds at different dormancy periods. Transcriptome sequencing was performed at three dormancy stages: the dormancy entry stage (FD), deep dormancy release stage (MD), and dormancy release stage (RD). Additionally, transcriptome sequencing was conducted to analyze gene expression profiles during these stages. Our findings revealed that compared with XC cultivars, DJB peach buds exhibited decreased MDA and H2O2 contents but increased superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities as well as Pro content during the dormancy period. These findings suggest that cold-resistant cultivars possess significantly stronger antioxidant capacity than conventional cultivars under low-temperature stress. A total of 10,168 differential genes were annotated through transcriptome sequencing. Among them, 4975 were up-regulated while 5193 were down-regulated. The differentially expressed genes associated with low-temperature response in peach buds are primarily enriched in plant hormone signal transduction pathway and phenylpropane synthesis pathway. Key differentially expressed genes related to cold resistance include ARF2, GH3, and SAPK2, and differentially expressed transcription factors mainly belong to the AP2/ERF-ERF, bHLH, and C2H2 families. This study provides a theoretical foundation for understanding the key genes involved.
Multi-Secular Trend of Drought Indices in Padua, Italy
Authors: Becherini Francesca , Stefanini Claudio , della Valle Antonio , Rech Francesco , Zecchini Fabio , Camuffo Dario
Published: December 2024

The aim of this work is to investigate drought variability in Padua, northern Italy, over a nearly 300-year period, from 1725 to 2023. Two well-established and widely used indices are calculated, the standardized precipitation index (SPI) and the standardized precipitation evapotranspiration index (SPEI). They are compatible with a data series starting in the early instrumental period, as both can be estimated using only temperature and precipitation data. The Padua daily precipitation and temperature series from the early 18th century, which were recovered and homogenized with current observations, are used as datasets. The standard approach to estimate SPI and SPEI based on gamma and log-logistic probability distribution functions, respectively, is questioned, assessing the fitting performance of different distributions applied to monthly precipitation data. The best-performing distributions are identified for each index and accumulation period at annual and monthly scales, and their normality is evaluated. In general, they detect more extreme drought events than the standard functions. Moreover, the main statistical values of SPI are very similar, regardless of the approach type, as opposed to SPEI. The difference between SPI and SPEI time series calculated with the best-fit approach has increased since the mid-20th century, in particular in spring and summer, and can be related to ongoing global warming, which SPEI takes into account. The innovative trend analysis applied to SPEI12 indicates a general increasing trend in droughts, while for SPI12, it is significant only for severe events. Summer and fall are the most affected seasons. The critical drought intensity–duration–frequency curves provide an easily understandable relationship between the intensity, duration and frequency of the most severe droughts and allow for the calculation of return periods for the critical events of a certain duration. Moreover, the longest and most severe droughts over the 1725–2023 period are identified.
Relationship Between Sleep Disturbances and Chronic Pain: A Narrative Review
Authors: Jain Sejal V. , Panjeton Geoffrey D. , Martins Yuri Chaves
Published: December 2024

Sleep disturbances and chronic pain are prevalent and interrelated conditions that have significant impact on individuals’ quality of life. Understanding the intricate dynamics between sleep and pain is crucial for developing effective treatments that enhance the well-being of affected individuals and reduce the economic burden of these debilitating conditions. This narrative review examines the complex relationship between sleep disturbances and chronic pain. We describe the prevalence and types of sleep disturbances and sleep disorders in chronic pain patients. Posteriorly, we critically review the clinical and experimental evidence, investigating the relationship between sleep disturbances and chronic pain, aiming to clarify the impact of chronic pain on sleep and, conversely, the impact of sleep disturbances on pain perception. In conclusion, the literature largely agrees on the existence of a bidirectional relationship between chronic pain and sleep disturbances, though the strength of each direction in this association remains uncertain. Current evidence suggests that sleep impairment more strongly predicts pain than pain does sleep impairment. Additionally, addressing sleep disturbances in chronic pain patients is crucial, as poor sleep has been linked to higher levels of disability, depression, and pain-related catastrophizing.
Efficient Explainable Models for Alzheimer’s Disease Classification with Feature Selection and Data Balancing Approach Using Ensemble Learning
Authors: Dubey Yogita , Bhongade Aditya , Palsodkar Prachi , Fulzele Punit
Published: December 2024

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia. Early diagnosis of Alzheimer’s disease is critical for better management and treatment outcomes, but it remains a challenging task due to the complex nature of the disease. Clinical data, including a range of cognitive, functional, and demographic variables, play a crucial role in Alzheimer’s disease classification. Also, challenges such as data imbalance and high-dimensional feature sets often hinder model performance. Objective: This paper aims to propose a computationally efficient, reliable, and transparent machine learning-based framework for the classification of Alzheimer’s disease patients. This framework is interpretable and helps medical practitioners learn complex patterns in patients. Method: This study addresses these issues by employing boosting algorithms, for enhanced classification accuracy. To mitigate data imbalance, a random sampling technique is applied, ensuring a balanced representation of Alzheimer’s and healthy cases. Extensive feature analysis was conducted to identify the most impactful clinical features followed by feature reduction techniques to focus on the most informative clinical features, reducing model complexity and overfitting risks. Explainable AI tools, such as SHAP, LIME, ALE, and ELI5 are integrated to provide transparency into the model’s decision-making process, highlighting key features influencing the classification and allowing clinicians to understand and trust the key features driving the predictions. Results: This approach results in a robust, interpretable, and clinically relevant framework for Alzheimer’s disease diagnosis. The proposed approach achieved the best accuracy of 95%, demonstrating its effectiveness and potential for reliable early diagnosis of Alzheimer’s disease. Conclusions: This study demonstrates that integrating ensemble learning algorithms and explainable AI, while using a balanced dataset with feature selection, improves quantitative results and interpretability. This approach offers a promising method for early and better-informed clinical decisions.
Supplemental Security Income (SSI) Receipt and Access to Homeownership for People with Disabilities
Authors: Henly Megan
Published: December 2024

People with disabilities disproportionately face barriers to homeownership, many of which are associated with costs. One related, but unexplored barrier to homeownership in the United States (U.S.) is the role of Supplemental Security Income (SSI) policy. SSI is a means-tested federal program in the U.S. that provides monthly income to those who are blind or disabled. Recipients may not own assets totaling more than USD 2000 (or 3000 per married couple). While homes are excluded from this assessment, the strict cap on savings generally means that SSI recipients who do not already own a home when they begin to receive benefits cannot accrue sufficient savings to qualify for a mortgage. Using data from the 2019 American Community Survey, this analysis explores the relative importance of SSI receipt in predicting rate of homeownership by using logistic regression to examine the effect of having a disability and receiving SSI on the odds of homeownership. Marginal effects identify the average predicted probabilities of homeownership to demonstrate the extent to which SSI receipt is related to each category of disability and race differently, suggesting that this policy may be related to a lower rate of homeownership for people with disabilities.