bluuebunny/crossref_metadata_2025 huggingface dataset:
Temperature Distribution in a Finite-Length Cylindrical Channel Filled with Biomass Transported by Electrically Heated Auger
Authors: Ledakowicz Stanisław , Piddubniak Olexa
Published: August 2023

The heat conduction problem for a cylindrical ring reactor of finite length, filled with biomass, which is transported at a constant speed by means of a rotating screw, is considered. The screw is assumed to be mounted on a circular shaft and is inductively heated by the Joule–Lenz effect. The surfaces of the channel and the shaft are thermally insulated. At the entrance and exit of the channel, boundary conditions of the third kind are formulated. The surface of the screw is replaced by uniformly distributed point heat sources. The problem is solved using the decomposition of the investigated temperature into Fourier–Bessel series over space variables and the integral Laplace transform over time. It is shown that the temperature has a quasi-stationary character with a short-term transient process. A numerical analysis of the spatio-temporal structure of temperature and its relationship with the thermophysical, kinematic and geometric parameters of the screw and biomass was carried out. In particular, it was found that the temperature along the reactor increases almost linearly starting from 400 K. It is shown that as in the case of an infinitely long channel, the condition of space–time resonance of the temperature field is fulfilled here.
Comparative Techno-Economic Evaluation of a Standalone Solar Power System for Scaled Implementation in Off-Grid Areas
Authors: Sadiq Muhammad , Kokchang Phimsupha , Kittipongvises Suthirat
Published: August 2023

The increasing environmental concerns and dependence on fossil fuel-based energy sectors necessitate a shift towards renewable energy. Off-grid communities can particularly benefit from standalone, scaled renewable power plants. This study developed a comprehensive techno-economic framework, analyzed the objective metrics, and assessed the influence of economies of scale in solar PV power plants to electrify off-grid communities, taking Baluchistan, Pakistan, as a pilot case. Simulations and analyses were performed using the System Advisor Model (SAM). The results indicate a noteworthy reduction in the levelized cost of energy (LCOE) with increased power generation capacity. It was observed that utilizing bi-facial modules with single-axis tracking leads to a more cost-effective LCOE compared to the relatively expensive dual-axis trackers. The main cost factors identified in the analysis were capital costs, installed balance of plant (BOP), mechanical, and electrical costs. Notably, the disparity between the highest and lowest LCOE values across the six different power generation pathways amounted to approximately 38.5%. The average LCOE was determined to be 2.14 USD/kWh for fixed-mounted plants, 1.79 USD/kWh for single-axis plants, and 1.74 USD/kWh for dual-axis plants across the examined power generation capacity range. The findings can serve as a valuable benchmark, specifically for regional key stakeholders, in making informed investment decisions, formulating effective policies, and devising appropriate strategies for off-grid electrification and the development of renewable energy value chains.
Divergent Decomposition Patterns of Leaf Litter and Fine Roots from an Urban Forest in Mid-Subtropical China
Authors: Chen Yuanqi , Chen Shengfu , Zhang Bohan , Ma Xiaotong , Liu Xiaotong , Huang Ying , Zhang Yu
Published: August 2023

Litter decomposition plays a pivotal role in carbon (C) and nutrient cycling in terrestrial ecosystems. However, little is known about the litter decomposition processes and nutrient dynamics in urban green space. In this study, the decomposition and nutrient dynamics of leaf litter and fine roots from Cinnamomum officinarum Nee ex Wall. and Elaeocarpus decipiens Hemsl. were studied in an urban forest in subtropical China. The results showed that the leaf litter mass loss, and nitrogen (N) and phosphorus (P) mineralization of E. decipiens were faster than that of C. officinarum in the first 180 days, but in the whole decomposition period, the leaf litter decomposition constant of C. officinarum was higher than that of E. decipiens. There was no difference in fine root decomposition constant and P mineralization, although the fine root N immobilization was higher relative to C. officinarum during the 90th to 270th days. Additionally, both the leaf litter mass loss, decomposition rate, and nutrient mineralization were faster than fine roots for these two tree species. The soil microbial biomass showed positive effects on leaf litter decomposition and negative effects on fine root decomposition. The correlation analysis indicated that initial litter quality, soil physicochemical properties, and microbial activity mainly affected early-stage litter decomposition and nutrient mineralization. Also, the leaf litter production and N and P storages of E. decipiens were higher than that of C. officinarum, suggesting faster decomposition rate and nutrient return for E. decipiens leaf litter. Consequently, we propose that tree species with fast nutrient return, such as E. decipiens, could be introduced to urban green space with pervious surfaces in respect of the nutrient balance. This work improves the understanding of litter decomposition and nutrient cycling and promotes the management for urban green space.
Comparing Algorithms for Estimation of Aboveground Biomass in Pinus yunnanensis
Authors: Huang Tianbao , Ou Guanglong , Xu Hui , Zhang Xiaoli , Wu Yong , Liu Zihao , Zou Fuyan , Zhang Chen , Xu Can
Published: August 2023

Comparing algorithms are crucial for enhancing the accuracy of remote sensing estimations of forest biomass in regions with high heterogeneity. Herein, Sentinel 2A, Sentinel 1A, Landsat 8 OLI, and Digital Elevation Model (DEM) were selected as data sources. A total of 12 algorithms, including 7 types of learners, were utilized for estimating the aboveground biomass (AGB) of Pinus yunnanensis forest. The results showed that: (1) The optimal algorithm (Extreme Gradient Boosting, XGBoost) was selected as the meta-model (referred to as XGBoost-stacking) of the stacking ensemble algorithm, which integrated 11 other algorithms. The R2 value was improved by 0.12 up to 0.61, and RMSE was decreased by 4.53 Mg/ha down to 39.34 Mg/ha compared to the XGBoost. All algorithms consistently showed severe underestimation of AGB in the Pinus yunnanensis forest of Yunnan Province when AGB exceeded 100 Mg/ha. (2) XGBoost-Stacking, XGBoost, BRNN (Bayesian Regularized Neural Network), RF (Random Forest), and QRF (Quantile Random Forest) have good sensitivity to forest AGB. QRNN (Quantile Regression Neural Network), GP (Gaussian Process), and EN (Elastic Network) have more outlier data and their robustness was poor. SVM-RBF (Radial Basis Function Kernel Support Vector Machine), k-NN (K Nearest Neighbors), and SGB (Stochastic Gradient Boosting) algorithms have good robustness, but their sensitivity was poor, and QRF algorithms and BRNN algorithm can estimate low values with higher accuracy. In conclusion, the XGBoost-stacking, XGBoost, and BRNN algorithms have shown promising application prospects in remote sensing estimation of forest biomass. This study could provide a reference for selecting the suitable algorithm for forest AGB estimation.
Preparation and Characterization of Wood Composites for Wood Restoration
Authors: Chen Tianyuan , Ma Qichao , Li Yudong , Li Guoliang
Published: August 2023

Given the widespread use of wood-based materials and that these materials are often damaged, an abundance of materials have been developed to repair and restore wood. Most of these materials treat the binder and filler as a single system; however, there is yet to be a system that has all the desired properties of an ideal wood-repair composite. Aiming for the goal of creating an ideal wood filler, this study proposed a wood-repair composite that combined epoxy resins, polyether amines, and poplar wood fibers. The materials were selected to mimic the hydrophobicity of lotus leaves and the strong adhesion of mussel proteins. The properties of the designed wood composites were characterized by various testing methods. The prepared fillers were then used to repair damaged poplar wood panels. The mechanical properties of the wood sample repaired with the optimal filler formulation reached 97% of those of the undamaged wood. In summary, the wood composites proposed in this study present a new means of repairing wooden relics, exposed outdoor wooden buildings, and household panels.
Application of a Soil Quality Index to a Mediterranean Mountain with Post-Fire Treatments
Authors: Andrés-Abellán Manuela , Picazo-Córdoba Marta I. , García-Saucedo Francisco , Wic-Baena Consolación , García-Morote Francisco A. , Rubio-Caballero Eva , Moreno Jose L. , Bastida Felipe , García Carlos , López-Serrano Francisco R.
Published: August 2023

In Mediterranean areas, fire has increased soil degradation and erosion. For this reason, the application of soil quality indices can help to determine soil recovery and degradation levels. By using a multiparameter soil quality index fitted to undisturbed forest soils, we can show the right information on soil functionality. In this study, the objectives were to evaluate soil functionality after suffering a fire, to subsequently treat with various soil treatments (wood mulching), and then check a soil quality index (SQI) to assess the soil quality recovery in burned Pinus nigra stands. For this purpose, a burned area was selected in the Cuenca Mountain range (Spain) under a Mediterranean climate. Experimental plots were established in the study area, with three slope gradients and applying three methods of covering soil using: (1) wood chips; (2) piles of branches; and (3) trunks of contour-felled logs. The experiment was conducted for 4 years. Results showed that the properties of soil were enhanced under wood chips and logs as a surface-covering material, and in a short time (less of 3 years). In consequence, the values of the SQI index were higher after applying these two treatments, thus reflecting the effectiveness of the SQI for monitoring post-fire recovery.
An Evolutionary Perspective of Codon Usage Pattern, Dinucleotide Composition and Codon Pair Bias in Prunus Necrotic Ringspot Virus
Authors: Wang Lingqi , Zhao Haiting , Wang Zhilei , Ding Shiwen , Qin Lang , Jiang Runzhou , Deng Xiaolong , He Zhen , Li Liangjun
Published: August 2023

Prunus necrotic ringspot virus (PNRSV) is a significant virus of ornamental plants and fruit trees. It is essential to study this virus due to its impact on the horticultural industry. Several studies on PNRSV diversity and phytosanitary detection technology were reported, but the content on the codon usage bias (CUB), dinucleotide preference and codon pair bias (CPB) of PNRSV is still uncertain. We performed comprehensive analyses on a dataset consisting of 359 coat protein (CP) gene sequences in PNRSV to examine the characteristics of CUB, dinucleotide composition, and CPB. The CUB analysis of PNRSV CP sequences showed that it was not only affected by natural selection, but also affected by mutations, and natural selection played a more significant role compared to mutations as the driving force. The dinucleotide composition analysis showed an over-expression of the CpC/GpA dinucleotides and an under-expression of the UpA/GpC dinucleotides. The dinucleotide composition of the PNRSV CP gene showed a weak association with the viral lineages and hosts, but a strong association with viral codon positions. Furthermore, the CPB of PNRSV CP gene is low and is related to dinucleotide preference and codon usage patterns. This research provides reference for future research on PNRSV genetic diversity and gene evolution mechanism.
Oxalate (dys)Metabolism: Person-to-Person Variability, Kidney and Cardiometabolic Toxicity
Authors: Baltazar Pedro , de Melo Junior Antonio Ferreira , Fonseca Nuno Moreira , Lança Miguel Brito , Faria Ana , Sequeira Catarina O. , Teixeira-Santos Luísa , Monteiro Emilia C. , Campos Pinheiro Luís , Calado Joaquim , Sousa Cátia , Morello Judit , Pereira Sofia A.
Published: August 2023

Oxalate is a metabolic end-product whose systemic concentrations are highly variable among individuals. Genetic (primary hyperoxaluria) and non-genetic (e.g., diet, microbiota, renal and metabolic disease) reasons underlie elevated plasma concentrations and tissue accumulation of oxalate, which is toxic to the body. A classic example is the triad of primary hyperoxaluria, nephrolithiasis, and kidney injury. Lessons learned from this example suggest further investigation of other putative factors associated with oxalate dysmetabolism, namely the identification of precursors (glyoxylate, aromatic amino acids, glyoxal and vitamin C), the regulation of the endogenous pathways that produce oxalate, or the microbiota’s contribution to oxalate systemic availability. The association between secondary nephrolithiasis and cardiovascular and metabolic diseases (hypertension, type 2 diabetes, and obesity) inspired the authors to perform this comprehensive review about oxalate dysmetabolism and its relation to cardiometabolic toxicity. This perspective may offer something substantial that helps advance understanding of effective management and draws attention to the novel class of treatments available in clinical practice.
Gene Polymorphisms of Epithelial Cell-Derived Alarmins and Their Effects on Protein Levels and Disease Severity in Patients with COVID-19
Authors: Ranjbar Maral , Cusack Ruth P. , Whetstone Christiane E. , Nawaz Shiraz , Khoury Christopher , Wattie Jennifer , Wiltshire Lesley , Le Roux Jennifer , Cheng Eric , Srinathan Thivya , Ho Terence , Sehmi Roma , Duong MyLinh , Gauvreau Gail M.
Published: August 2023

Background: The immune response in COVID-19 is characterized by the release of alarmin cytokines, which play crucial roles in immune activation and inflammation. The interplay between these cytokines and genetic variations may influence disease severity and outcomes, while sex differences might further contribute to variations in the immune response. Methods: We measured the levels of alarmin cytokines in a cohort of COVID-19 and non-COVID-19 patients using a sensitive Meso Scale Discovery system. Additionally, we conducted an SNP analysis to identify genetic variations within the IL-33 and TSLP genes. The association between these genetic variations, cytokine production, and COVID-19 severity was examined. Results: Our findings revealed elevated levels of IL-33 and IL-25 in COVID-19-positive patients compared to COVID-19-negative patients (p < 0.05), indicating their potential as therapeutic targets for disease modulation. Moreover, a minor allele within the IL-33 gene (rs3939286) was found to be associated with a protective effect against severe COVID-19 (p < 0.05), and minor alleles of the TSLP gene (rs2289276 and rs13806933) were found to significantly reduce TSLP protein levels in serum (p < 0.05). Sex-specific effects of TSLP and IL-33 SNPs were observed, suggesting a potential influence of sex hormones and genetic variations on the regulation of cytokine production. Conclusion: The present study highlights the importance of alarmin cytokines and genetic variations in COVID-19 severity, providing valuable insights into personalized treatment approaches. Our results suggest that targeting alarmin cytokines may offer potential therapeutic benefits in managing COVID-19. Furthermore, the sex-specific effects of genetic variations emphasize the need to consider individual genetic profiles and sex differences when designing targeted interventions.
Soil Erosion in a British Watershed under Climate Change as Predicted Using Convection-Permitting Regional Climate Projections
Authors: Ciampalini Rossano , Kendon Elizabeth J. , Constantine José A. , Schindewolf Marcus , Hall Ian R.
Published: August 2023

Climate change can lead to significant environmental and societal impacts; for example, through increases in the amount and intensity of rainfall with the associated possibility of flooding. Twenty-first-century climate change simulations for Great Britain reveal an increase in heavy precipitation that may lead to widespread soil loss by rising the likelihood of surface runoff. Here, hourly high-resolution rainfall projections from a 1.5 km (‘convection-permitting’) regional climate model are used to simulate the soil erosion response for two periods of the century (1996–2009 and a 13-year future period at ~2100) in the “Rother” catchment, West Sussex, England. Modeling soil erosion with EROSION 3D, we found a general increase in sediment production (off-site erosion) for the end of the century of about 43.2%, with a catchment-average increase from 0.176 to 0.252 t ha−1 y−1 and large differences between areas with diverse land use. These results highlight the effectiveness of using high-resolution rainfall projections to better account for spatial variability in the assessment of long-term soil erosion than other current methods.
“Collapsing into Darkness”: An Exploratory Qualitative Thematic Analysis of the Experience of Workplace Reintegration among Nurses with Operational Stress Injuries
Authors: Jones Chelsea , Juby Brenda , Spencer Shaylee , Smith-MacDonald Lorraine , O’Greysik Elly , Vincent Michelle , Mooney Colleen , Bright Katherine S. , Sevigny Phillip R. , Burback Lisa , Greenshaw Andrew , Carleton R. Nicholas , Savage Raymond , Hayward Jake , Zhang Yanbo , Cao Bo , Brémault-Phillips Suzette
Published: August 2023

Background: Nurses are engaged in an unpredictable and dynamic work environment where they are exposed to events that may cause or contribute to physical and/or psychological injuries. Operational stress injury (OSI) may lead to an extended time away from work or nurses leaving the profession altogether. A deliberate focus on the workplace reintegration phase of the mental health recovery process may lead to the increased retention of nurses in their profession. Prior to the creation and implementation of potential solutions to address workplace reintegration, it is imperative to explore the experiences and perceptions of nurses affected by OSI. This qualitative study aims to investigate the experiences and perceptions of nurses (N = 7) employed within a Canadian provincial healthcare system who have attempted workplace reintegration after being off of work with an OSI. Methods: Nurses were recruited via social media, unit emails, and word of mouth. Data were collected through recorded semi-structured interviews conducted over videoconferencing. Once transcribed, the data were thematically analyzed using an inductive approach. Results: The resulting themes included (1) heroes to zeros, (2) changing the status quo, (3) connection is key, and (4) post-traumatic growth: advocacy and altruism. Study participants indicated both that nursing culture and a cumulation of events contributed to a need for a leave of absence from work and that a formalized process was desired by nurses to assist in returning to work. Conclusions: The development, implementation, and exploration of innovative policies, procedures, and initiatives to bridge the gap from clinical interventions to workplace reintegration are needed for nurses experiencing OSI. Further research is also needed regarding mental health impacts and appropriate resources to support nurses in their workplace reintegration process after experiencing psychological and/or physical injury.
Characterization of Volatile Organic Compounds in Five Celery (Apium graveolens L.) Cultivars with Different Petiole Colors by HS-SPME-GC-MS
Authors: Sun Yue , Li Mengyao , Li Xiaoyan , Du Jiageng , Li Weilong , Lin Yuanxiu , Zhang Yunting , Wang Yan , He Wen , Chen Qing , Zhang Yong , Wang Xiaorong , Luo Ya , Xiong Aisheng , Tang Haoru
Published: August 2023

Celery (Apium graveolens L.) is an important vegetable crop cultivated worldwide for its medicinal properties and distinctive flavor. Volatile organic compound (VOC) analysis is a valuable tool for the identification and classification of species. Currently, less research has been conducted on aroma compounds in different celery varieties and colors. In this study, five different colored celery were quantitatively analyzed for VOCs using HS-SPME, GC-MS determination, and stoichiometry methods. The result revealed that γ-terpinene, d-limonene, 2-hexenal,-(E)-, and β-myrcene contributed primarily to the celery aroma. The composition of compounds in celery exhibited a correlation not only with the color of the variety, with green celery displaying a higher concentration compared with other varieties, but also with the specific organ, whereby the content and distribution of volatile compounds were primarily influenced by the leaf rather than the petiole. Seven key genes influencing terpenoid synthesis were screened to detect expression levels. Most of the genes exhibited higher expression in leaves than petioles. In addition, some genes, particularly AgDXS and AgIDI, have higher expression levels in celery than other genes, thereby influencing the regulation of terpenoid synthesis through the MEP and MVA pathways, such as hydrocarbon monoterpenes. This study identified the characteristics of flavor compounds and key aroma components in different colored celery varieties and explored key genes involved in the regulation of terpenoid synthesis, laying a theoretical foundation for understanding flavor chemistry and improving its quality.
Multi-Anticancer Activities of Phytoestrogens in Human Osteosarcoma
Authors: Cimmino Alessio , Fasciglione Giovanni Francesco , Gioia Magda , Marini Stefano , Ciaccio Chiara
Published: August 2023

Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties. Their potential health benefits, especially in cancer prevention and treatment, have been a subject of considerable research in the past decade. Phytoestrogens exert their effects, at least in part, through interactions with estrogen receptors (ERs), mimicking or inhibiting the actions of natural estrogens. Recently, there has been growing interest in exploring the impact of phytoestrogens on osteosarcoma (OS), a type of bone malignancy that primarily affects children and young adults and is currently presenting limited treatment options. Considering the critical role of the estrogen/ERs axis in bone development and growth, the modulation of ERs has emerged as a highly promising approach in the treatment of OS. This review provides an extensive overview of current literature on the effects of phytoestrogens on human OS models. It delves into the multiple mechanisms through which these molecules regulate the cell cycle, apoptosis, and key pathways implicated in the growth and progression of OS, including ER signaling. Moreover, potential interactions between phytoestrogens and conventional chemotherapy agents commonly used in OS treatment will be examined. Understanding the impact of these compounds in OS holds great promise for developing novel therapeutic approaches that can augment current OS treatment modalities.
On the Intermolecular Interactions in Thiophene-Cored Single-Stacking Junctions
Authors: Czernek Jiří , Brus Jiří
Published: August 2023

There have been attempts, both experimental and based on density-functional theory (DFT) modeling, at understanding the factors that govern the electronic conductance behavior of single-stacking junctions formed by pi-conjugated materials in nanogaps. Here, a reliable description of relevant stacked configurations of some thiophene-cored systems is provided by means of high-level quantum chemical approaches. The minimal structures of these configurations, which are found using the dispersion-corrected DFT approach, are employed in calculations that apply the coupled cluster method with singles, doubles and perturbative triples [CCSD(T)] and extrapolations to the complete basis set (CBS) limit in order to reliably quantify the strength of intermolecular binding, while their physical origin is investigated using the DFT-based symmetry-adapted perturbation theory (SAPT) of intermolecular interactions. In particular, for symmetrized S-Tn dimers (where “S” and “T” denote a thiomethyl-containing anchor group and a thiophene segment comprising “n” units, respectively), the CCSD(T)/CBS interaction energies are found to increase linearly with n ≤ 6, and significant conformational differences between the flanking 2-thiophene group in S-T1 and S-T2 are described by the CCSD(T)/CBS and SAPT/CBS computations. These results are put into the context of previous work on charge transport properties of S-Tn and other types of supramolecular junctions.
Pathogenesis, Clinical Features, and Treatment of Patients with Myelin Oligodendrocyte Glycoprotein (MOG) Autoantibody-Associated Disorders Focusing on Optic Neuritis with Consideration of Autoantibody-Binding Sites: A Review
Authors: Tanaka Keiko , Kezuka Takeshi , Ishikawa Hitoshi , Tanaka Masami , Sakimura Kenji , Abe Manabu , Kawamura Meiko
Published: August 2023

Although there is a substantial amount of data on the clinical characteristics, diagnostic criteria, and pathogenesis of myelin oligodendrocyte glycoprotein (MOG) autoantibody-associated disease (MOGAD), there is still uncertainty regarding the MOG protein function and the pathogenicity of anti-MOG autoantibodies in this disease. It is important to note that the disease characteristics, immunopathology, and treatment response of MOGAD patients differ from those of anti-aquaporin 4 antibody-positive neuromyelitis optica spectrum disorders (NMOSDs) and multiple sclerosis (MS). The clinical phenotypes of MOGAD are varied and can include acute disseminated encephalomyelitis, transverse myelitis, cerebral cortical encephalitis, brainstem or cerebellar symptoms, and optic neuritis. The frequency of optic neuritis suggests that the optic nerve is the most vulnerable lesion in MOGAD. During the acute stage, the optic nerve shows significant swelling with severe visual symptoms, and an MRI of the optic nerve and brain lesion tends to show an edematous appearance. These features can be alleviated with early extensive immune therapy, which may suggest that the initial attack of anti-MOG autoantibodies could target the structures on the blood–brain barrier or vessel membrane before reaching MOG protein on myelin or oligodendrocytes. To understand the pathogenesis of MOGAD, proper animal models are crucial. However, anti-MOG autoantibodies isolated from patients with MOGAD do not recognize mouse MOG efficiently. Several studies have identified two MOG epitopes that exhibit strong affinity with human anti-MOG autoantibodies, particularly those isolated from patients with the optic neuritis phenotype. Nonetheless, the relations between epitopes on MOG protein remain unclear and need to be identified in the future.
Untousling the Role of Tousled-like Kinase 1 in DNA Damage Repair
Authors: Ghosh Ishita , De Benedetti Arrigo
Published: August 2023

DNA damage repair lies at the core of all cells’ survival strategy, including the survival strategy of cancerous cells. Therefore, targeting such repair mechanisms forms the major goal of cancer therapeutics. The mechanism of DNA repair has been tousled with the discovery of multiple kinases. Recent studies on tousled-like kinases have brought significant clarity on the effectors of these kinases which stand to regulate DSB repair. In addition to their well-established role in DDR and cell cycle checkpoint mediation after DNA damage or inhibitors of replication, evidence of their suspected involvement in the actual DSB repair process has more recently been strengthened by the important finding that TLK1 phosphorylates RAD54 and regulates some of its activities in HRR and localization in the cell. Earlier findings of its regulation of RAD9 during checkpoint deactivation, as well as defined steps during NHEJ end processing, were earlier hints of its broadly important involvement in DSB repair. All this has opened up new avenues to target cancer cells in combination therapy with genotoxins and TLK inhibitors.
Uncovering the Role of Natural and Synthetic Small Molecules in Counteracting the Burden of α-Synuclein Aggregates and Related Toxicity in Different Models of Parkinson’s Disease
Authors: Mohammed Salihu , Russo Isabella , Ramazzina Ileana
Published: August 2023

A proteostasis network represents a sophisticated cellular system that controls the whole process which leads to properly folded functional proteins. The imbalance of proteostasis determines a quantitative increase in misfolded proteins prone to aggregation and elicits the onset of different diseases. Among these, Parkinson’s Disease (PD) is a progressive brain disorder characterized by motor and non-motor signs. In PD pathogenesis, alpha-Synuclein (α-Syn) loses its native structure, triggering a polymerization cascade that leads to the formation of toxic inclusions, the PD hallmark. Because molecular chaperones represent a “cellular arsenal” to counteract protein misfolding and aggregation, the modulation of their expression represents a compelling PD therapeutic strategy. This review will discuss evidence concerning the effects of natural and synthetic small molecules in counteracting α-Syn aggregation process and related toxicity, in different in vitro and in vivo PD models. Firstly, the role of small molecules that modulate the function(s) of chaperones will be highlighted. Then, attention will be paid to small molecules that interfere with different steps of the protein-aggregation process. This overview would stimulate in-depth research on already-known small molecules or the development of new ones, with the aim of developing drugs that are able to modify the progression of the disease.
Relations between Structure/Composition and Mechanics in Osteoarthritic Regenerated Articular Tissue: A Machine Learning Approach
Authors: Berni Matteo , Veronesi Francesca , Fini Milena , Giavaresi Gianluca , Marchiori Gregorio
Published: August 2023

In the context of a large animal model of early osteoarthritis (OA) treated by orthobiologics, the purpose of this study was to reveal relations between articular tissues structure/composition and cartilage viscoelasticity. Twenty-four sheep, with induced knee OA, were treated by mesenchymal stem cells in various preparations—adipose-derived mesenchymal stem cells (ADSCs), stromal vascular fraction (SVF), and amniotic endothelial cells (AECs)—and euthanized at 3 or 6 months to evaluate the (i) biochemistry of synovial fluid; (ii) histology, immunohistochemistry, and histomorphometry of articular cartilage; and (iii) viscoelasticity of articular cartilage. After performing an initial analysis to evaluate the correlation and multicollinearity between the investigated variables, this study used machine learning (ML) models—Variable Selection Using Random Forests (VSURF) and Extreme Gradient Boosting (XGB)—to classify variables according to their importance and employ them for interpretation and prediction. The experimental setup revealed a potential relation between cartilage elastic modulus and cartilage thickness (CT), synovial fluid interleukin 6 (IL6), and prostaglandin E2 (PGE2), and between cartilage relaxation time and CT and PGE2. SVF treatment was the only limit on the deleterious OA effect on cartilage viscoelastic properties. This work provides indications to future studies aiming to highlight these and other relationships and focusing on advanced regeneration targets.
Extensive Angular Sampling Enables the Sensitive Localization of Macromolecules in Electron Tomograms
Authors: Chaillet Marten L. , van der Schot Gijs , Gubins Ilja , Roet Sander , Veltkamp Remco C. , Förster Friedrich
Published: August 2023

Cryo-electron tomography provides 3D images of macromolecules in their cellular context. To detect macromolecules in tomograms, template matching (TM) is often used, which uses 3D models that are often reliable for substantial parts of the macromolecules. However, the extent of rotational searches in particle detection has not been investigated due to computational limitations. Here, we provide a GPU implementation of TM as part of the PyTOM software package, which drastically speeds up the orientational search and allows for sampling beyond the Crowther criterion within a feasible timeframe. We quantify the improvements in sensitivity and false-discovery rate for the examples of ribosome identification and detection. Sampling at the Crowther criterion, which was effectively impossible with CPU implementations due to the extensive computation times, allows for automated extraction with high sensitivity. Consequently, we also show that an extensive angular sample renders 3D TM sensitive to the local alignment of tilt series and damage induced by focused ion beam milling. With this new release of PyTOM, we focused on integration with other software packages that support more refined subtomogram-averaging workflows. The automated classification of ribosomes by TM with appropriate angular sampling on locally corrected tomograms has a sufficiently low false-discovery rate, allowing for it to be directly used for high-resolution averaging and adequate sensitivity to reveal polysome organization.
Antiplatelet Effects of Selected Xanthine-Based Adenosine A2A and A2B Receptor Antagonists Determined in Rat Blood
Authors: Kubacka Monika , Mogilski Szczepan , Bednarski Marek , Pociecha Krzysztof , Świerczek Artur , Nicosia Noemi , Schabikowski Jakub , Załuski Michał , Chłoń-Rzepa Grażyna , Hockemeyer Jörg , Müller Christa E. , Kieć-Kononowicz Katarzyna , Kotańska Magdalena
Published: August 2023

The platelet aggregation inhibitory activity of selected xanthine-based adenosine A2A and A2B receptor antagonists was investigated, and attempts were made to explain the observed effects. The selective A2B receptor antagonist PSB-603 and the A2A receptor antagonist TB-42 inhibited platelet aggregation induced by collagen or ADP. In addition to adenosine receptor blockade, the compounds were found to act as moderately potent non-selective inhibitors of phosphodiesterases (PDEs). TB-42 showed the highest inhibitory activity against PDE3A along with moderate activity against PDE2A and PDE5A. The antiplatelet activity of PSB-603 and TB-42 may be due to inhibition of PDEs, which induces an increase in cAMP and/or cGMP concentrations in platelets. The xanthine-based adenosine receptor antagonists were found to be non-cytotoxic for platelets. Some of the compounds showed anti-oxidative properties reducing lipid peroxidation. These results may provide a basis for the future development of multi-target xanthine derivatives for the treatment of inflammation and atherosclerosis and the prevention of heart infarction and stroke.
Vitamin D Receptor Gene Polymorphism Predicts the Outcome of Multidisciplinary Rehabilitation in Multiple Sclerosis Patients
Authors: Guerini Franca Rosa , Agliardi Cristina , Oreni Letizia , Groppo Elisabetta , Bolognesi Elisabetta , Zanzottera Milena , Caputo Domenico , Rovaris Marco , Clerici Mario
Published: August 2023

Better knowledge about the possible role of genetic factors in modulating the response to multiple sclerosis (MS) treatment, including rehabilitation, known to promote neural plasticity, could improve the standard of care for this disease. Vitamin D receptor (VDR) gene polymorphisms are associated with MS risk, probably because of the role played by vitamin D in regulating inflammatory and reparative processes. The aim of this study was to evaluate the association of the most important functional VDR SNPs (TaqI (T/C), ApaI (A/C), and FokI (C/T)) with functional outcome in MS patients undergoing multidisciplinary inpatient rehabilitation (MDR) treatment, in order to determine whether genetic profiling might be useful to identify subjects with a higher chance of recovery. To this end, 249 MS inpatients with a diagnosis of either progressive (pMS; n = 155) or relapsing remitting (RRMS; n = 94) disease who underwent MDR treatment (average duration = 5.1 weeks) were genotyped for VDR SNPs by real-time allelic discrimination. The rehabilitation outcome was assessed using the modified Barthel Index (mBI), Expanded Disability Status Scale (EDSS), and pain numerical rating scores (NRS) at the beginning and the end of MDR treatment. A positive correlation was observed in RRMS patients between the VDR TaqI major allele (TT) and mBI increase (i.e., better functional recovery), as assessed by the linear and logistic regression analysis adjusted for gender, age, disease duration, time of hospitalization, HLA-DRB1*15.01 positivity, and number of rehabilitative interventions (Beta = 6.35; p = 0.0002). The VDR-1 TaqI, ApaI, FokI: TCC haplotype was also associated with mBI increase in RRMS patients (Beta = 3.24; p = 0.007), whereas the VDR-2: CAC haplotype was correlated with a lower mBI increase (Beta = −2.18 p = 0.04) compared with the other haplotypes. VDR TaqI major allele (TT), as well as the VDR-1 TaqI, ApaI, FokI: TCC haplotype could be associated with a better rehabilitation outcome in RRMS patients.
Modulation of Plasmatic Matrix Metalloprotease 9: A Promising New Tool for Understanding the Variable Clinical Responses of Patients with Cystic Fibrosis to Cystic Fibrosis Transmembrane Conductance Regulator Modulators
Authors: Capraro Michela , Pedrazzi Marco , De Tullio Roberta , Manfredi Marcello , Cresta Federico , Castellani Carlo , Averna Monica
Published: August 2023

Background: The most recent modulator combination, elexacaftor/tezacaftor/ivacaftor (Trikafta®), has been shown to improve clinical outcomes in most patients with cystic fibrosis (PwCF). Unfortunately, the clinical benefits are sometimes variable; thus, improving our knowledge of the possible causes of this variability can help reduce it. Methods: Circulating mononuclear cells (CMCs) and plasma were collected from 16 PwCF (including those on Trikafta® therapy) and 4 non-CF subjects. Cystic fibrosis transmembrane conductance regulator (CFTR) activity and matrix metalloprotease 9 (MMP9) expression were monitored before and after therapy, together with some clinical parameters. The relationship between MMP9 expression and the modulation of the extracellular-regulated 1/2 (ERK1/2) and nuclear factor-kB (NF-kB) pathways was also analyzed. Results: MMP9, markedly expressed in the CMCs and plasma of all the patients included in the study, was downregulated in the clinically responsive PwCF. In the non-responder, the MMP9 levels remained high. The modulation of MMP9 following treatment with Trikafta® may be controlled by the NF-kB pathway. Conclusions: These data strongly suggest that MMP9 downregulation is a potential biomarker of therapy efficacy and that it could be useful in understanding the molecular events underlying the variable clinical responses of patients to Trikafta®. This knowledge could be helpful for future studies of personalized medicine and thereby ensure improvements in individual responses to therapies.
Targeting Inhibitor of Apoptosis Proteins to Overcome Chemotherapy Resistance—A Marriage between Targeted Therapy and Cytotoxic Chemotherapy
Authors: Barroso Tiago , Melo-Alvim Cecília , Ribeiro Leonor Abreu , Casimiro Sandra , Costa Luís
Published: August 2023

Precision oncology is the ultimate goal of cancer treatment, i.e., to treat cancer and only cancer, leaving all the remaining cells and tissues as intact as possible. Classical chemotherapy and radiotherapy, however, are still effective in many patients with cancer by effectively inducing apoptosis of cancer cells. Cancer cells might resist apoptosis via the anti-apoptotic effects of the inhibitor of apoptosis proteins. Recently, the inhibitors of those proteins have been developed with the goal of enhancing the cytotoxic effects of chemotherapy and radiotherapy, and one of them, xevinapant, has already demonstrated effectiveness in a phase II clinical trial. This class of drugs represents an example of synergism between classical cytotoxic chemo- and radiotherapy and new targeted therapy.
Solving the Puzzle: Molecular Research in Inflammatory Bowel Diseases
Authors: Krug Susanne M.
Published: August 2023

Inflammatory bowel disease (IBD) encompasses chronic idiopathic relapsing and remitting gastrointestinal autoimmune diseases characterized by chronic inflammatory disorders of complex etiology, posing clinical challenges due to their often therapy-refractory nature [...]
Detection and Monitoring of Tumor-Derived Mutations in Circulating Tumor DNA Using the UltraSEEK Lung Panel on the MassARRAY System in Metastatic Non-Small Cell Lung Cancer Patients
Authors: Leest Paul van der , Janning Melanie , Rifaela Naomi , Azpurua Maria L. Aguirre , Kropidlowski Jolanthe , Loges Sonja , Lozano Nicolas , Sartori Alexander , Irwin Darryl , Lamy Pierre-Jean , Hiltermann T. Jeroen N. , Groen Harry J. M. , Pantel Klaus , Kempen Léon C. van , Wikman Harriet , Schuuring Ed
Published: August 2023

Analysis of circulating tumor DNA (ctDNA) is a potential minimally invasive molecular tool to guide treatment decision-making and disease monitoring. A suitable diagnostic-grade platform is required for the detection of tumor-specific mutations with high sensitivity in the circulating cell-free DNA (ccfDNA) of cancer patients. In this multicenter study, the ccfDNA of 72 patients treated for advanced-stage non-small cell lung cancer (NSCLC) was evaluated using the UltraSEEK® Lung Panel on the MassARRAY® System, covering 73 hotspot mutations in EGFR, KRAS, BRAF, ERBB2, and PIK3CA against mutation-specific droplet digital PCR (ddPCR) and routine tumor tissue NGS. Variant detection accuracy at primary diagnosis and during disease progression, and ctDNA dynamics as a marker of treatment efficacy, were analyzed. A multicenter evaluation using reference material demonstrated an overall detection rate of over 90% for variant allele frequencies (VAFs) > 0.5%, irrespective of ccfDNA input. A comparison of UltraSEEK® and ddPCR analyses revealed a 90% concordance. An 80% concordance between therapeutically targetable mutations detected in tumor tissue NGS and ccfDNA UltraSEEK® analysis at baseline was observed. Nine of 84 (11%) tumor tissue mutations were not covered by UltraSEEK®. A decrease in ctDNA levels at 4–6 weeks after treatment initiation detected with UltraSEEK® correlated with prolonged median PFS (46 vs. 6 weeks; p < 0.05) and OS (145 vs. 30 weeks; p < 0.01). Using plasma-derived ccfDNA, the UltraSEEK® Lung Panel with a mid-density set of the most common predictive markers for NSCLC is an alternative tool to detect mutations both at diagnosis and during disease progression and to monitor treatment response.
Bioelectrical State of Bacteria Is Linked to Growth Dynamics and Response to Neurotransmitters: Perspectives for the Investigation of the Microbiota–Brain Axis
Authors: Muñoz-Rodríguez David , Bourqqia-Ramzi Marwane , García-Esteban Maria Teresa , Murciano-Cespedosa Antonio , Vian Alejandro , Lombardo-Hernández Juan , García-Pérez Pablo , Conejero Francisco , Mateos González Álvaro , Geuna Stefano , Herrera-Rincon Celia
Published: August 2023

Inter-cellular communication is mediated by a sum of biochemical, biophysical, and bioelectrical signals. This might occur not only between cells belonging to the same tissue and/or animal species but also between cells that are, from an evolutionary point of view, far away. The possibility that bioelectrical communication takes place between bacteria and nerve cells has opened exciting perspectives in the study of the gut microbiota–brain axis. The aim of this paper is (i) to establish a reliable method for the assessment of the bioelectrical state of two bacterial strains: Bacillus subtilis (B. subtilis) and Limosilactobacillus reuteri (L. reuteri); (ii) to monitor the bacterial bioelectrical profile throughout its growth dynamics; and (iii) to evaluate the effects of two neurotransmitters (glutamate and γ-aminobutyric acid-GABA) on the bioelectrical signature of bacteria. Our results show that membrane potential (Vmem) and the proliferative capacity of the population are functionally linked in B. subtilis in each phase of the cell cycle. Remarkably, we demonstrate that bacteria respond to neural signals by changing Vmem properties. Finally, we show that Vmem changes in response to neural stimuli are present also in a microbiota-related strain L. reuteri. Our proof-of-principle data reveal a new methodological approach for the better understanding of the relation between bacteria and the brain, with a special focus on gut microbiota. Likewise, this approach will open exciting perspectives in the study of the inter-cellular mechanisms which regulate the bi-directional communication between bacteria and neurons and, ultimately, for designing gut microbiota–brain axis-targeted treatments for neuropsychiatric diseases.
SP1-Induced Upregulation of LncRNA AFAP1-AS1 Promotes Tumor Progression in Triple-Negative Breast Cancer by Regulating mTOR Pathway
Authors: Li Fangyuan , Xian Daheng , Huang Junying , Nie Longzhu , Xie Ting , Sun Qiang , Zhang Xiaohui , Zhou Yidong
Published: August 2023

The long non-coding RNA (lncRNA) actin fiber-associated protein-1 antisense RNA 1 (AFAP1-AS1) exerted oncogenic activity in triple-negative breast cancer (TNBC). We designed this study and conducted it to investigate the upstream regulation mechanism of AFAP1-AS1 in TNBC tumorigenesis. In this work, we proved the localization of AFAP1-AS1 in the cytoplasm. We elucidated the mechanism by which the transcription factor specificity protein 1 (SP1) modulated AFAP1-AS1 in TNBC progression, which has yet to be thoroughly studied. Dual luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay revealed a strong affinity of SP1 toward the promoter regions P3 of AFAP1-AS1, proving the gene expression regulation of AFAP1-AS1 via SP1 in TNBC. Additionally, SP1 could facilitate the tumorigenesis of TNBC cells in vitro and in vivo by regulating the AFAP1-AS1 expression. Furthermore, silenced AFAP1-AS1 suppressed the expression of genes in the mTOR pathway, such as eukaryotic translation initiation factor 4B (EIF4B), mitogen-activated protein kinase-associated protein 1 (MAPKAP1), SEH1-like nucleoporin (SEH1L), serum/glucocorticoid regulated kinase 1 (SGK1), and its target NEDD4-like E3 ubiquitin protein ligase (NEDD4L), and promoted the gene expression of s-phase kinase-associated protein 2 (SKP2). Overall, this study emphasized the oncogenic role of SP1 and AFAP1-AS1 in TNBC and illustrated the AFAP1-AS1 upstream interaction with SP1 and the downstream modulatory of mTOR signaling, thus offering insights into the tumorigenesis mechanism in TNBC.
Upregulation of Orai Channels Contributes to Aging-Related Vascular Alterations in Rat Coronary Arteries
Authors: Angulo Javier , Fernández Argentina , Sevilleja-Ortiz Alejandro , Sánchez-Ferrer Alberto , Rodríguez-Mañas Leocadio , El Assar Mariam
Published: August 2023

Vascular territories display heterogeneous sensitivity to the impacts of aging. The relevance of the STIM/Orai system to vascular function depends on the vascular bed. We aimed to evaluate the contribution of the STIM/Orai system to aging-related vascular dysfunction in rat coronary circulation. Vascular function was evaluated according to myography in coronary arteries from young (three-month-old) and older (twenty-month-old) rats. The effects of aging and STIM/Orai inhibition on the contraction and relaxation of the coronary arteries and on the protein expression of STIM-1, Orai1, and Orai3 in these vessels were determined. Aging-related hypercontractility to serotonin and endothelin-1 in arteries from male rats was reversed by STIM/Orai inhibition with YM-58483 or by specifically blocking the Orai1 channel with Synta66. The inhibitory effects of Synta66 on coronary vasoconstriction were also observed in older female rats. YM-58483 relaxed serotonin- but not KCl-contracted arteries from males. STIM/Orai inhibition improved defective endothelial vasodilations in aged arteries, even in the presence of NO synthase and cyclooxygenase inhibitors, but not in KCl-contracted segments. YM-58483 significantly enhanced relaxations to calcium-activated potassium channel stimulation in aged vessels. Increased protein expression of Orai1 and Orai3 was detected in arterial homogenates and sections from older rats. Upregulation of the Orai channel contributes to aging-related coronary dysfunction, revealing a potential target in reducing CVD risk.