bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Characterization Reveals Subclasses of 1q Gain in Intermediate Risk Wilms Tumors
Authors: van Belzen Ianthe A. E. M. , van Tuil Marc , Badloe Shashi , Strengman Eric , Janse Alex , Verwiel Eugène T. P. , van der Leest Douwe F. M. , de Vos Sam , Baker-Hernandez John , Groenendijk Alissa , de Krijger Ronald , Kerstens Hindrik H. D. , Drost Jarno , van den Heuvel-Eibrink Marry M. , Tops Bastiaan B. J. , Holstege Frank C. P. , Kemmeren Patrick , Hehir-Kwa Jayne Y.
Published: October 2022

Chromosomal alterations have recurrently been identified in Wilms tumors (WTs) and some are associated with poor prognosis. Gain of 1q (1q+) is of special interest given its high prevalence and is currently actively studied for its prognostic value. However, the underlying mutational mechanisms and functional effects remain unknown. In a national unbiased cohort of 30 primary WTs, we integrated somatic SNVs, CNs and SVs with expression data and distinguished four clusters characterized by affected biological processes: muscle differentiation, immune system, kidney development and proliferation. Combined genome-wide CN and SV profiles showed that tumors profoundly differ in both their types of 1q+ and genomic stability and can be grouped into WTs with co-occurring 1p−/1q+, multiple chromosomal gains or CN neutral tumors. We identified 1q+ in eight tumors that differ in mutational mechanisms, subsequent rearrangements and genomic contexts. Moreover, 1q+ tumors were present in all four expression clusters reflecting activation of various biological processes, and individual tumors overexpress different genes on 1q. In conclusion, by integrating CNs, SVs and gene expression, we identified subgroups of 1q+ tumors reflecting differences in the functional effect of 1q gain, indicating that expression data is likely needed for further risk stratification of 1q+ WTs.
PGC-1β and ERRα Promote Glutamine Metabolism and Colorectal Cancer Survival via Transcriptional Upregulation of PCK2
Authors: Frodyma Danielle E. , Troia Thomas C. , Rao Chaitra , Svoboda Robert A. , Berg Jordan A. , Shinde Dhananjay D. , Thomas Vinai C. , Lewis Robert E. , Fisher Kurt W.
Published: October 2022

Background: Previous studies have shown that Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Beta (PGC-1β) and Estrogen-Related Receptor Alpha (ERRα) are over-expressed in colorectal cancer and promote tumor survival. Methods: In this study, we use immunoprecipitation of epitope tagged endogenous PGC-1β and inducible PGC-1β mutants to show that amino acid motif LRELL on PGC-1β is responsible for the physical interaction with ERRα and promotes ERRα mRNA and protein expression. We use RNAsequencing to determine the genes regulated by both PGC-1β & ERRα and find that mitochondrial Phosphoenolpyruvate Carboxykinase 2 (PCK2) is the gene that decreased most significantly after depletion of both genes. Results: Depletion of PCK2 in colorectal cancer cells was sufficient to reduce anchorage-independent growth and inhibit glutamine utilization by the TCA cycle. Lastly, shRNA-mediated depletion of ERRα decreased anchorage-independent growth and glutamine metabolism, which could not be rescued by plasmid derived expression of PCK2. Discussion: These findings suggest that transcriptional control of PCK2 is one mechanism used by PGC-1β and ERRα to promote glutamine metabolism and colorectal cancer cell survival.
Liquid Biopsy-Derived DNA Sources as Tools for Comprehensive Mutation Profiling in Multiple Myeloma: A Comparative Study
Authors: Heestermans Robbe , De Brouwer Wouter , Maes Ken , Vande Broek Isabelle , Vaeyens Freya , Olsen Catharina , Caljon Ben , De Becker Ann , Bakkus Marleen , Schots Rik , Van Riet Ivan
Published: October 2022

The analysis of bone marrow (BM) samples in multiple myeloma (MM) patients can lead to the underestimation of the genetic heterogeneity within the tumor. Blood-derived liquid biopsies may provide a more comprehensive approach to genetic characterization. However, no thorough comparison between the currently available circulating biomarkers as tools for mutation profiling in MM has been published yet and the use of extracellular vesicle-derived DNA for this purpose in MM has not yet been investigated. Therefore, we collected BM aspirates and blood samples in 30 patients with active MM to isolate five different DNA types, i.e., cfDNA, EV-DNA, BM-DNA and DNA isolated from peripheral blood mononucleated cells (PBMNCs-DNA) and circulating tumor cells (CTC-DNA). DNA was analyzed for genetic variants with targeted gene sequencing using a 165-gene panel. After data filtering, 87 somatic and 39 germline variants were detected among the 149 DNA samples used for sequencing. cfDNA showed the highest concordance with the mutation profile observed in BM-DNA and outperformed EV-DNA, CTC-DNA and PBMNCs-DNA. Of note, 16% of all the somatic variants were only detectable in circulating biomarkers. Based on our analysis, cfDNA is the preferable circulating biomarker for genetic characterization in MM and its combined use with BM-DNA allows for comprehensive mutation profiling in MM.
DMA, a Small Molecule, Increases Median Survival and Reduces Radiation-Induced Xerostomia via the Activation of the ERK1/2 Pathway in Oral Squamous Cell Carcinoma
Authors: Parashar Palak , Das Monoj Kumar , Tripathi Pragya , Kataria Tejinder , Gupta Deepak , Sarin Deepak , Hazari Puja Panwar , Tandon Vibha
Published: October 2022

Survival, recurrence, and xerostomia are considerable problems in the treatment of oral squamous carcinoma patients. In this study, we investigated the role of DMA (5-(4-methylpiperazin-1-yl)-2-[2′-(3,4-dimethoxyphenyl)5″benzimidazoyl]benzimidazole) as a salivary gland cytoprotectant in a patient-derived xenograft mouse model. A significant increase in saliva secretion was observed in the DMA-treated xenograft compared to radiation alone. Repeated doses of DMA with a high dose of radiation showed a synergistic effect on mice survival and reduced tumor growth. The mean survival rate of tumor-bearing mice was significantly enhanced. The increased number of Ki-67-stained cells in the spleen, intestine, and lungs compared to the tumor suggests DMA ablates the tumor but protects other organs. The expression of aquaporin-5 was restored in tumor-bearing mice injected with DMA before irradiation. The reduced expression of αvβ3 integrin and CD44 in DMA alone and DMA with radiation-treated mice suggests a reduced migration of cells and stemness of cancer cells. DMA along with radiation treatment results in the activation of the Ras/Raf/MEK/ERK pathway in the tumor, leading to apoptosis through caspase upregulation. In conclusion, DMA has strong potential for use as an adjuvant in radiotherapy in OSCC patients.
Metabolic Biomarkers Affecting Cell Proliferation and Prognosis in Polycythemia Vera
Authors: Wang Ziqing , Lv Yan , Yang Erpeng , Li Yujin , Wang Dehao , Hu Guang , Li Yumeng , Wang Mingjing , Liu Weiyi , Sun Mingqian , Hu Xiaomei
Published: October 2022

Polycythemia vera (PV) is a malignant clonal hematological disease of hematopoietic stem cells characterized by the proliferation of peripheral blood cells, and JAK2 mutation is one of the main causes of PV peripheral blood cell proliferation. Abnormal cell metabolism is a new feature of malignant proliferation of tumor cells, but the role of metabolism in the pathogenesis and prognosis of PV remains unclear. We analyzed metabolic differences of peripheral blood sera between 32 PV patients and 20 healthy controls (HCs) by liquid chromatography–mass spectrometry (LC–MS) to investigate their relationship with cell proliferation and to screen for prognosis-related metabolic biomarkers. Compared to HC, 33 endogenous metabolites were significantly changed in PV and were involved in fatty acid metabolism, glucose metabolism, sphingolipid metabolism, and amino acid metabolism pathways. Among them, seven metabolites were closely associated with JAK2 mutations, 2 of which may contribute to the proliferation of peripheral blood cells in PV patients. A set of potential prognostic metabolic biomarkers containing four metabolites was identified by a receiver operating characteristic (ROC) curve according to the risk stratification of the PV patients and their combined AUC value of 0.952, with a sensitivity of 90.905% and specificity of 90.909% at the optimal cutoff point. Metabonomics is an important tool for the study of the pathogenesis of PV and the relationship between JAK2 gene mutation. Furthermore, the potential biomarkers of this study may provide a reference for the prognosis of PV.
Circulating Tumor DNA: Less Invasive, More Representative Method to Unveil the Genomic Landscape of Newly Diagnosed Multiple Myeloma Than Bone Marrow Aspirates
Authors: Liu Yang , Guo Jiapei , Yi Yuting , Gao Xuan , Wen Lei , Duan Wenbing , Wen Zhaohong , Liu Yaoyao , Guan Yanfang , Xia Xuefeng , Ma Ling , Fu Rong , Liu Lihong , Huang Xiaojun , Ge Qing , Lu Jin
Published: October 2022

Multiple myeloma (MM) is highly heterogenous and dynamic in its genomic abnormalities. Capturing a representative image of these alterations is essential in understanding the molecular pathogenesis and progression of the disease but was limited by single-site invasive bone marrow (BM) biopsy-based genomics studies. We compared the mutational landscapes of circulating tumor DNA (ctDNA) and BM in 82 patients with newly diagnosed MM. A 413-gene panel was used in the sequencing. Our results showed that more than 70% of MM patients showed one or more genes with somatic mutations and at least half of the mutated genes were shared between ctDNA and BM samples. Compared to the BM samples, ctDNA exhibited more types of driver mutations in the shared driver genes, higher numbers of uniquely mutated genes and subclonal clusters, more translocation-associated mutations, and higher frequencies of mutated genes enriched in the transcriptional regulation pathway. Multivariate Cox analysis showed that age, ctDNA mutations in the transcriptional regulation pathway and DNA repair pathway were independent predictors of progression-free survival (PFS). Our results demonstrated sequencing of ctDNA provides more thorough information on the genomic instability and is a potential representative biomarker for risk stratification and in newly diagnosed MM than bone marrow.
Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice
Authors: Capeloa Tania , Van de Velde Justine A. , d’Hose Donatienne , Lipari Sara G. , Derouane Françoise , Hamelin Loïc , Bedin Marie , Vazeille Thibaut , Duhoux François P. , Murphy Michael P. , Porporato Paolo E. , Gallez Bernard , Sonveaux Pierre
Published: October 2022

At diagnosis, about 35% of pancreatic cancers are at the locally invasive yet premetastatic stage. Surgical resection is not a treatment option, leaving patients with a largely incurable disease that often evolves to the polymetastatic stage despite chemotherapeutic interventions. In this preclinical study, we hypothesized that pancreatic cancer metastasis can be prevented by inhibiting mitochondrial redox signaling with MitoQ, a mitochondria-targeted antioxidant. Using four different cancer cell lines, we report that, at clinically relevant concentrations (100–500 nM), MitoQ selectively repressed mesenchymal pancreatic cancer cell respiration, which involved the inhibition of the expression of PGC-1α, NRF1 and a reduced expression of electron-transfer-chain complexes I to III. MitoQ consequently decreased the mitochondrial membrane potential and mitochondrial superoxide production by these cells. Phenotypically, MitoQ further inhibited pancreatic cancer cell migration, invasion, clonogenicity and the expression of stem cell markers. It reduced by ~50% the metastatic homing of human MIA PaCa-2 cells in the lungs of mice. We further show that combination treatments with chemotherapy are conceivable. Collectively, this study indicates that the inhibition of mitochondrial redox signaling is a possible therapeutic option to inhibit the metastatic progression of pancreatic cancer.
Auto-Combustion Synthesis of Mn1−xAgxCo2O4 Catalysts for Diesel Soot Combustion
Authors: Liu Huanrong , Chen Yanhong , Han Dongmin , Ma Weiwei , Dai Xiaodong , Yan Zifeng
Published: October 2022

The increase in diesel consumption has led to the proliferation of soot particles from diesel exhaust, resulting in pollution in the form of smog. To solve this problem, a series of Ag-doped Mn1−xAgxCo2O4 spinel catalysts were successfully prepared using an auto-combustion synthesis method that uses glucose as a fuel. X-ray diffraction and Fourier transform infrared spectroscopy analysis were used to analyse the phase structure of the as-prepared samples. The results reveal that the selected catalysts featured a spinel-type structure. Moreover, the catalytic activity of the catalysts for soot combustion was evaluated by temperature-programmed reaction analysis. The temperature required for soot combustion depended heavily on the Ag concentration in the Mn1−xAgxCo2O4 catalyst. The Mn0.8Ag0.2Co2O4 catalyst had a superior catalytic activity with a T90 of 399 °C and CO2 selectivity of 99.3%.
A Comprehensive Profiling of Cellular Sphingolipids in Mammalian Endothelial and Microglial Cells Cultured in Normal and High-Glucose Conditions
Authors: Mondal Koushik , Grambergs Richard C. , Gangaraju Rajashekhar , Mandal Nawajes
Published: October 2022

Sphingolipids (SPLs) play a diverse role in maintaining cellular homeostasis. Dysregulated SPL metabolism is associated with pathological changes in stressed and diseased cells. This study investigates differences in SPL metabolism between cultured human primary retinal endothelial (HREC) and murine microglial cells (BV2) in normal conditions (normal glucose, NG, 5 mM) and under high-glucose (HG, 25 mM)-induced stress by sphingolipidomics, immunohistochemistry, biochemical, and molecular assays. Measurable differences were observed in SPL profiles between HREC and BV2 cells. High-glucose treatment caused a >2.5-fold increase in the levels of Lactosyl-ceramide (LacCer) in HREC, but in BV2 cells, it induced Hexosyl-Ceramides (HexCer) by threefold and a significant increase in Sphingosine-1-phosphate (S1P) compared to NG. Altered SPL profiles coincided with changes in transcript levels of inflammatory and vascular permeability mediators in HREC and inflammatory mediators in BV2 cells. Differences in SPL profiles and differential responses to HG stress between endothelial and microglial cells suggest that SPL metabolism and signaling differ in mammalian cell types and, therefore, their pathological association with those cell types.
The Impact of Activity-Based Interventions on Neuropathic Pain in Experimental Spinal Cord Injury
Authors: Chen Jing , Weidner Norbert , Puttagunta Radhika
Published: October 2022

Physical activity-based rehabilitative interventions represent the main treatment concept for people suffering from spinal cord injury (SCI). The role such interventions play in the relief of neuropathic pain (NP) states is emerging, along with underlying mechanisms resulting in SCI-induced NP (SCI-NP). Animal models have been used to investigate the benefits of activity-based interventions (ABI), such as treadmill training, wheel running, walking, swimming, and bipedal standing. These activity-based paradigms have been shown to modulate inflammatory-related alterations as well as induce functional and structural changes in the spinal cord gray matter circuitry correlated with pain behaviors. Thus far, the research available provides an incomplete picture of the cellular and molecular pathways involved in this beneficial effect. Continued research is essential for understanding how such interventions benefit SCI patients suffering from NP and allow the development of individualized rehabilitative therapies. This article reviews preclinical studies on this specific topic, goes over mechanisms involved in SCI-NP in relation to ABI, and then discusses the effectiveness of different activity-based paradigms as they relate to different forms, intensity, initiation times, and duration of ABI. This article also summarizes the mechanisms of respective interventions to ameliorate NP after SCI and provides suggestions for future research directions.
A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family
Authors: Gauhar Zeeshan , Tejwani Leon , Abdullah Uzma , Saeed Sadia , Shafique Shagufta , Badshah Mazhar , Choi Jungmin , Dong Weilai , Nelson-Williams Carol , Lifton Richard P. , Lim Janghoo , Raja Ghazala K.
Published: October 2022

Autosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all cases. We studied a multiplex, consanguineous Pakistani family presenting with a slowly progressive gait ataxia, body imbalance, and dysarthria. Cerebellar atrophy was identified by magnetic resonance imaging of brain. Using whole exome sequencing, a novel homozygous missense mutation ERCC8:c.176T>C (p.M59T) was identified that co-segregated with the disease. Previous studies have identified homozygous mutations in ERCC8 as causal for Cockayne Syndrome type A (CSA), a UV light-sensitive syndrome, and several ARCAs. ERCC8 plays critical roles in the nucleotide excision repair complex. The p.M59T, a substitution mutation, is located in a highly conserved WD1 beta-transducin repeat motif. In silico modeling showed that the structure of this protein is significantly affected by the p.M59T mutation, likely impairing complex formation and protein-protein interactions. In cultured cells, the p.M59T mutation significantly lowered protein stability compared to wildtype ERCC8 protein. These findings expand the role of ERCC8 mutations in ARCAs and indicate that ERCC8-related mutations should be considered in the differential diagnosis of ARCAs.
Gut Microbiota in Nutrition and Health with a Special Focus on Specific Bacterial Clusters
Authors: Bresser Lucas R. F. , de Goffau Marcus C. , Levin Evgeni , Nieuwdorp Max
Published: October 2022

Health is influenced by how the gut microbiome develops as a result of external and internal factors, such as nutrition, the environment, medication use, age, sex, and genetics. Alpha and beta diversity metrics and (enterotype) clustering methods are commonly employed to perform population studies and to analyse the effects of various treatments, yet, with the continuous development of (new) sequencing technologies, and as various omics fields as a result become more accessible for investigation, increasingly sophisticated methodologies are needed and indeed being developed in order to disentangle the complex ways in which the gut microbiome and health are intertwined. Diseases of affluence, such as type 2 diabetes (T2D) and cardiovascular diseases (CVD), are commonly linked to species associated with the Bacteroides enterotype(s) and a decline of various (beneficial) complex microbial trophic networks, which are in turn linked to the aforementioned factors. In this review, we (1) explore the effects that some of the most common internal and external factors have on the gut microbiome composition and how these in turn relate to T2D and CVD, and (2) discuss research opportunities enabled by and the limitations of some of the latest technical developments in the microbiome sector, including the use of artificial intelligence (AI), strain tracking, and peak to trough ratios.
miR319-Regulated TCP3 Modulates Silique Development Associated with Seed Shattering in Brassicaceae
Authors: Cao Biting , Wang Hongfeng , Bai Jinjuan , Wang Xuan , Li Xiaorong , Zhang Yanfeng , Yang Suxin , He Yuke , Yu Xiang
Published: October 2022

Seed shattering is an undesirable trait that leads to crop yield loss. Improving silique resistance to shattering is critical for grain and oil crops. In this study, we found that miR319-targeted TEOSINTE BRANCHED 1, CYCLOIDEA, and PROLIFERATING CELL NUCLEAR ANTIGEN BINDING FACTOR (TCPs) inhibited the process of post-fertilized fruits (silique) elongation and dehiscence via regulation of FRUITFULL (FUL) expression in Arabidopsis thaliana and Brassica napus. AtMIR319a activation resulted in a longer silique with thickened and lignified replum, whereas overexpression of an miR319a-resistant version of AtTCP3 (mTCP3) led to a short silique with narrow and less lignified replum. Further genetic and expressional analysis suggested that FUL acted downstream of TCP3 to negatively regulate silique development. Moreover, hyper-activation of BnTCP3.A8, a B. napus homolog of AtTCP3, in rapeseed resulted in an enhanced silique resistance to shattering due to attenuated replum development. Taken together, our findings advance our knowledge of TCP-regulated silique development and provide a potential target for genetic manipulation to reduce silique shattering in Brassica crops.
Illustration of Gut–Thyroid Axis in Alcohol Use Disorder: Interplay of Gut Dysfunction, Pro-Inflammatory Responses, and Thyroid Function
Authors: Sagaram Manasa , Royer Amor J. , Hu Huirong , Rajhans Abhas , Parthasarathy Ranganathan , Krishnasamy Sathya Sridevi , Mokshagundam Sri Prakash , Kong Maiying , Schwandt Melanie L. , Parajuli Dipendra , Cave Matthew C. , Vatsalya Vatsalya
Published: October 2022

(1) Background: Heavy and chronic alcohol drinking leads to altered gut dysfunction, coupled with a pro-inflammatory state. Thyroid-associated hormones and proteins may be dysregulated by heavy and chronic alcohol intake; however, the mechanism for altered gut-derived changes in thyroid function has not been studied thus far. This study investigates the role of alcohol-induced gut dysfunction and pro-inflammatory cytokine profile in the thyroid function of patients with alcohol use disorder (AUD). (2) Methods: Male and female AUD patients (n = 44) were divided into Gr.1, patients with normal thyroid-stimulating hormone (TSH) levels (n = 28, 0.8 ≤ TSH ≤ 3 mIU/L); and Gr.2, patients with clinically elevated TSH levels (n = 16, TSH > 3 mIU/L). Demographics, drinking measures, comprehensive metabolic panels, and candidate thyroid markers (TSH, circulating triiodothyronine (T3), and free thyroxine (fT4)) were analyzed. Gut-dysfunction-associated markers (lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble LPS-induced pathogen-associated protein (sCD14)), and candidate pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8, MCP-1, PAI-1) were also evaluated. (3) Results: Patients in both groups presented with a borderline overweight BMI category. Gr.2 reported numerically higher indices of chronic and heavy drinking patterns than Gr.1. The fT4 levels were elevated, while T3 was within normal limits in both groups. The gut dysfunction markers LBP and sCD14 were numerically elevated in Gr.2 vs. Gr.1, suggesting subtle ongoing changes. Candidate pro-inflammatory cytokines were significantly elevated in Gr.2, including IL-1 β, MCP-1, and PAI-1. Gr.2 showed a strong and statistically significant effect on the gut–immune–thyroid response (r = 0.896, 36 p = 0.002) on TSH levels in a multivariate regression model with LBP, sCD14, and PAI-1 levels as upstream variables in the gut–thyroid pathway. In addition, AUROC analysis demonstrated that many of the cytokines strongly predicted TSH in Gr.2, including IL-6 (area = 0.774, 39 p < 0.001) and TNF-α (area = 0.708, p = 0.017), among others. This was not observed in Gr.1. Gr.2 demonstrated elevated fT4, as well as TSH, which suggests that there was subclinical thyroiditis with underlying CNS dysfunction and a lack of a negative feedback loop. (4) Conclusions: These findings reveal the toxic effects of heavy and chronic drinking that play a pathological role in thyroid gland dysregulation by employing the gut–brain axis. These results also emphasize potential directions to carefully evaluate thyroid dysregulation in the overall medical management of AUD.
Advances in Concentration Gradient Generation Approaches in a Microfluidic Device for Toxicity Analysis
Authors: Valle Nicole M. E. , Nucci Mariana P. , Alves Arielly H. , Rodrigues Luiz D. , Mamani Javier B. , Oliveira Fernando A. , Lopes Caique S. , Lopes Alexandre T. , Carreño Marcelo N. P. , Gamarra Lionel F.
Published: October 2022

This systematic review aimed to analyze the development and functionality of microfluidic concentration gradient generators (CGGs) for toxicological evaluation of different biological organisms. We searched articles using the keywords: concentration gradient generator, toxicity, and microfluidic device. Only 33 of the 352 articles found were included and examined regarding the fabrication of the microdevices, the characteristics of the CGG, the biological model, and the desired results. The main fabrication method was soft lithography, using polydimethylsiloxane (PDMS) material (91%) and SU-8 as the mold (58.3%). New technologies were applied to minimize shear and bubble problems, reduce costs, and accelerate prototyping. The Christmas tree CGG design and its variations were the most reported in the studies, as well as the convective method of generation (61%). Biological models included bacteria and nematodes for antibiotic screening, microalgae for pollutant toxicity, tumor and normal cells for, primarily, chemotherapy screening, and Zebrafish embryos for drug and metal developmental toxicity. The toxic effects of each concentration generated were evaluated mostly with imaging and microscopy techniques. This study showed an advantage of CGGs over other techniques and their applicability for several biological models. Even with soft lithography, PDMS, and Christmas tree being more popular in their respective categories, current studies aim to apply new technologies and intricate architectures to improve testing effectiveness and reduce common microfluidics problems, allowing for high applicability of toxicity tests in different medical and environmental models.
The Emerging Role of Pericyte-Derived Extracellular Vesicles in Vascular and Neurological Health
Authors: Sharma Kushal , Zhang Yunpei , Paudel Keshav Raj , Kachelmeier Allan , Hansbro Philip M. , Shi Xiaorui
Published: October 2022

Pericytes (PCs), as a central component of the neurovascular unit, contribute to the regenerative potential of the central nervous system (CNS) and peripheral nervous system (PNS) by virtue of their role in blood flow regulation, angiogenesis, maintenance of the BBB, neurogenesis, and neuroprotection. Emerging evidence indicates that PCs also have a role in mediating cell-to-cell communication through the secretion of extracellular vesicles (EVs). Extracellular vesicles are cell-derived, micro- to nano-sized vesicles that transport cell constituents such as proteins, nucleic acids, and lipids from a parent originating cell to a recipient cell. PC-derived EVs (PC-EVs) play a crucial homeostatic role in neurovascular disease, as they promote angiogenesis, maintain the integrity of the blood-tissue barrier, and provide neuroprotection. The cargo carried by PC-EVs includes growth factors such as endothelial growth factor (VEGF), connecting tissue growth factors (CTGFs), fibroblast growth factors, angiopoietin 1, and neurotrophic growth factors such as brain-derived neurotrophic growth factor (BDNF), neuron growth factor (NGF), and glial-derived neurotrophic factor (GDNF), as well as cytokines such as interleukin (IL)-6, IL-8, IL-10, and MCP-1. The PC-EVs also carry miRNA and circular RNA linked to neurovascular health and the progression of several vascular and neuronal diseases. Therapeutic strategies employing PC-EVs have potential in the treatment of vascular and neurodegenerative diseases. This review discusses current research on the characteristic features of EVs secreted by PCs and their role in neuronal and vascular health and disease.
Network-Based Analysis to Identify Hub Genes Involved in Spatial Root Response to Mechanical Constrains
Authors: Dimitrova Anastazija , Sferra Gabriella , Scippa Gabriella Stefania , Trupiano Dalila
Published: October 2022

Previous studies report that the asymmetric response, observed along the main poplar woody bent root axis, was strongly related to both the type of mechanical forces (compression or tension) and the intensity of force displacement. Despite a large number of targets that have been proposed to trigger this asymmetry, an understanding of the comprehensive and synergistic effect of the antistress spatially related pathways is still lacking. Recent progress in the bioinformatics area has the potential to fill these gaps through the use of in silico studies, able to investigate biological functions and pathway overlaps, and to identify promising targets in plant responses. Presently, for the first time, a comprehensive network-based analysis of proteomic signatures was used to identify functions and pivotal genes involved in the coordinated signalling pathways and molecular activities that asymmetrically modulate the response of different bent poplar root sectors and sides. To accomplish this aim, 66 candidate proteins, differentially represented across the poplar bent root sides and sectors, were grouped according to their abundance profile patterns and mapped, together with their first neighbours, on a high-confidence set of interactions from STRING to compose specific cluster-related subnetworks (I–VI). Successively, all subnetworks were explored by a functional gene set enrichment analysis to identify enriched gene ontology terms. Subnetworks were then analysed to identify the genes that are strongly interconnected with other genes (hub gene) and, thus, those that have a pivotal role in the bent root asymmetric response. The analysis revealed novel information regarding the response coordination, communication, and potential signalling pathways asymmetrically activated along the main root axis, delegated mainly to Ca2+ (for new lateral root formation) and ROS (for gravitropic response and lignin accumulation) signatures. Furthermore, some of the data indicate that the concave side of the bent sector, where the mechanical forces are most intense, communicates to the other (neighbour and distant) sectors, inducing spatially related strategies to ensure water uptake and accompanying cell modification. This information could be critical for understanding how plants maintain and improve their structural integrity—whenever and wherever it is necessary—in natural mechanical stress conditions.
C9-ALS-Associated Proline-Arginine Dipeptide Repeat Protein Induces Activation of NLRP3 Inflammasome of HMC3 Microglia Cells by Binding of Complement Component 1 Q Subcomponent-Binding Protein (C1QBP), and Syringin Prevents This Effect
Authors: Fu Ru-Huei , Tsai Chia-Wen , Chiu Shao-Chih , Liu Shih-Ping , Chiang Yu-Ting , Kuo Yun-Hua , Shyu Woei-Cherng , Lin Shinn-Zong
Published: October 2022

Amyotrophic lateral sclerosis (ALS) is a fatal disease in which motor neurons gradually degenerate. The mutation of the C9orf72 gene is the main genetic cause of ALS (C9-ALS). One of its specific pathological features is the production of proline-arginine (PR) dipeptide repeat protein (DPR). In this study, we developed a PR-DPR (PR50)-expressing human HMC3 microglial cell model. We found that PR50 mainly aggregates into spots in the nucleus and induces significant NLRP3 inflammasome activity. Moreover, mouse NSC-34 motor neuron cells treated with a conditional medium of PR50-expressing HMC3 cells (PR-CM) caused cell damage and apoptosis activity. However, R50-expressing HMC cells treated with MCC950 (an NLRP3 inhibitor) reversed this result. Furthermore, we identified complement component 1 q subcomponent-binding protein (C1QBP) as one of the interaction partners of PR50. The downregulation of C1QBP in HMC3 cells induces NLRP3 inflammasome activity similar to PR50 expression. Finally, we found that syringin can block the interaction between PR50 and C1QBP, and effectively reduce the PR50-induced NLRP3 inflammasome activity in HMC3 cells. This improves the apoptosis of NSC-34 cells caused by PR-CM. This study is the first to link PR50, C1QBP, and NLRP3 inflammasome activity in microglia and develop potential therapeutic strategies for syringin intervention in C9-ALS.
ALG3 Promotes Peritoneal Metastasis of Ovarian Cancer through Increasing Interaction of α1,3-mannosylated uPAR and ADAM8
Authors: Cui Xinyuan , Pei Xiaosong , Wang Hao , Feng Ping , Qin Huamin , Liu Shuai , Yan Qiu , Liu Jiwei
Published: October 2022

Peritoneal metastasis is the main cause of poor prognoses and high mortality in ovarian cancer patients. Abnormal protein glycosylation modification is associated with cancer malignancy. Elevated α1,3-mannosyltransferase 3 (ALG3), which catalyzes the α1,3-mannosylation of glycoproteins, has been found in some malignant tumors. However, the pathological significance of ALG3 and its regulatory mechanism in ovarian cancer metastasis is unclear. The results showed that the level of ALG3/α1,3-mannosylation was higher in human ovarian cancer tissues compared with normal ovarian tissues, as measured by Lectin chip, Western blot and Lectin blot analyses, as well as ovarian tissue microarray analysis. ALG3 was also correlated with the poor prognosis of ovarian cancer patients, according to survival analysis. The downregulation of ALG3 decreased the proliferation, stemness and peritoneal metastasis of ovarian cancer cells. The increase in urokinase plasminogen activator receptor (uPAR) α1,3-mannosylation catalyzed by ALG3 enhanced urokinase plasminogen activator (uPA)/uPAR activation and the interaction of uPAR with a disintegrin and metalloproteinase 8 (ADAM8), which promoted ovarian cancer peritoneal metastasis via the ADAM8/Ras/ERK pathway. Furthermore, decreased ALG3 suppressed ascites formation and the peritoneal metastasis of ovarian cancer cells in mice. This study highlights ALG3 as a potential diagnostic biomarker and prospective therapeutic target for ovarian cancer.
Next Generation Immuno-Oncology Strategies: Unleashing NK Cells Activity
Authors: Mendoza-Valderrey Alberto , Alvarez Maite , De Maria Andrea , Margolin Kim , Melero Ignacio , Ascierto Maria Libera
Published: October 2022

In recent years, immunotherapy has become a powerful therapeutic option against multiple malignancies. The unique capacity of natural killer (NK) cells to attack cancer cells without antigen specificity makes them an optimal immunotherapeutic tool for targeting tumors. Several approaches are currently being pursued to maximize the anti-tumor properties of NK cells in the clinic, including the development of NK cell expansion protocols for adoptive transfer, the establishment of a favorable microenvironment for NK cell activity, the redirection of NK cell activity against tumor cells, and the blockage of inhibitory mechanisms that constrain NK cell function. We here summarize the recent strategies in NK cell-based immunotherapies and discuss the requirement to further optimize these approaches for enhancement of the clinical outcome of NK cell-based immunotherapy targeting tumors.
Novel Insight into the Role of the Kiss1/GPR54 System in Energy Metabolism in Major Metabolic Organs
Authors: Li Xuehan , Liang Chunyu , Yan Yi
Published: October 2022

The Kiss1/GPR54 system is a multifunctional genetic system with an essential role in regulating energy balance and metabolic homeostasis. In the mammalian hypothalamus, two major populations of neurons, the rostral periventricular region of the third ventricle (RP3V) and the arcuate nucleus (ARC), produced kisspeptin. Kiss1ARC neurons input kisspeptin and glutamate to feeding-associated neurons to regulate energy intake and expenditure balance. Kisspeptin in the peripheral circulation is involved in lipid accumulation in adipose tissue. In the hepatic and pancreatic circuits, kisspeptin signaling affects insulin secretion, suggesting the critical role of the Kiss1/GPR54 system in regulating glucose and lipid metabolism. In addition, this review also predicts the role of the Kiss1/GPRS4 system in skeletal muscle in association with exercise performance. Recent studies have focused on the link between kisspeptin signaling and energy homeostasis, further investigation of potential function is warranted. Therefore, this review summarizes the role of the Kiss1/GPRS4 system in the major metabolic organs in relation to energy metabolism homeostasis, aiming to endow the reader with a critical and updated view of the Kiss1/GPR54 system in energy metabolism.
Biomonitoring and Assessment of Dumpsites Soil Using Phospholipid Fatty Acid Analysis (PLFA) Method—Evaluation of Possibilities and Limitations
Authors: Halász Judit , Kotroczó Zsolt , Szabó Péter , Kocsis Tamás
Published: October 2022

Dumped waste is not only a problem from an aesthetic point of view, but also has an environmental polluting effect, or can even pose a direct danger if the waste is dumped in illegal landfills in an uncontrolled manner with unknown composition. In the case of soil pollution, the assessment of the changing microbial state can be used as an indicator of initial changes, since waste as a pollutant impacts the diversity of the landfill’s microbial community. The degree of change depends on the qualitative and quantitative composition of the pollutants, which can be measured through the microbial phospholipid fatty acid (PLFA) pattern. The aim was a comprehensive assessment of the soil microbiological and toxicological hazards of various illegal landfill. Cluster-analysis of the average principal component revealed significant differences between the experimental sites. In comparison with the control site, the percentage of fatty acid biomarkers of Gram-positive bacteria was significantly higher in the contaminated areas, as well as the ratio of trans/cis isomerization in the case of 16:1ω7 and 18:1ω7 fatty acids. The inverse tendency was observed in the relative quantities of fatty acid biomarkers of Gram-negative bacteria compared to Actinomycetes, and in the fungal-bacterial ratio.
Recent Advances in Metal-Organic Frameworks for Biomacromolecule Sensing
Authors: Lin Yanna , Huang Yong , Chen Xuwei
Published: October 2022

Metal-organic frameworks (MOFs) are emerging class of ordered porous materials consisting of metal clusters and organic ligands. High porosity, adjustable topology, composition and structural diversity have earned MOFs extensive popularity in various fields, including biosensing. This review focuses on understanding the role of MOFs in biosensing, mainly as efficient signal probes, nanozymes and nanocarriers. It also provides the recent advances of MOFs in sensing biomacromolecules such as protein, peptide, DNA, RNA and polysaccharide. In addition, the challenge, and perspectives, of MOFs in biosensing are presented, based on our opinion.
Cellular, Molecular and Proteomic Characteristics of Early Hepatocellular Carcinoma
Authors: Armakolas Athanasios , Dimopoulou Vasiliki , Nezos Adrianos , Stamatakis George , Samiotaki Martina , Panayotou George , Tampaki Maria , Stathaki Martha , Dourakis Spyridon , Koskinas John
Published: October 2022

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Early detection/diagnosis is vital for the prognosis of HCC, whereas diagnosis at late stages is associated with very low survival rate. Early diagnosis is based on 6-month surveillance of the patient and the use of at least two imaging modalities. The aim of this study was to investigate diagnostic markers for the detection of early HCC based on proteome analysis, microRNAs (miRNAs) and circulating tumor cells (CTCs) in the blood of patients with cirrhosis or early or advanced HCC. We studied 89 patients with HCC, of whom 33 had early HCC and 28 were cirrhotic. CTCs were detected by real-time quantitative reverse transcription PCR and immunofluorescence using the markers epithelial cell adhesion molecule (EPCAM), vimentin, alpha fetoprotein (aFP) and surface major vault protein (sMVP). Expression of the five most common HCC-involved miRNAs (miR-122, miR-200a, miR-200b, miR-221, miR-222) was examined in serum using quantitative real time PCR (qRT-PCR). Finally, patient serum was analyzed via whole proteome analysis (LC/MS). Of 53 patients with advanced HCC, 27 (51%) had detectable CTCs. Among these, 10/27 (37%) presented evidence of mesenchymal or intermediate stage cells (vimentin and/or sMVP positive). Moreover, 5/17 (29%) patients with early HCC and 2/28 (7%) cirrhotic patients had detectable CTCs. Patients with early or advanced HCC exhibited a significant increase in miR-200b when compared to cirrhotic patients. Our proteome analysis indicated that early HCC patients present a significant upregulation of APOA2, APOC3 proteins when compared to cirrhotic patients. When taken in combination, this covers the 100% of the patients with early HCC. miR-200b, APOA2 and APOC3 proteins are sensitive markers and can be potentially useful in combination for the early diagnosis of HCC.
Systematic Investigation of Silicon Content Effects on the PEO Coatings’ Properties on Al–Si Binary Alloys in Silicate-Based and Tungstate-Containing Electrolytes
Authors: Moshrefifar Masoud , Ebrahimifar Hadi , Hakimizad Amin
Published: October 2022

The present study evaluates the effect of a substrate’s silicon content on the coatings’ morphology, structure, and properties in an electrolyte containing sodium tungstate on Al–xSi alloys. The PEO-coated samples demonstrated the structure of the pancake and crater with irregular micro-cracks and micro-pores. The incorporation of the element W in the coatings decreased the surface roughness and porosity due to increasing the electrolyte conductivity and, hence, decreasing the breakdown voltage and intensity of micro-discharges. The friction coefficient of all the coatings stayed constant during the wear test due to the contact of the ball with the inner layer with less porosity and higher micro-hardness. The track depth to the thickness ratio of the coatings was found to be 0.60–0.75 for those without additive coatings and 0.55–0.65 for those with additive coatings. As a result, the higher wear rates, volume losses, track widths, and depths in the specimens with a lower silicon content of the substrate were found due to the greater thickness of the coating and the outer sublayer for both specimens with and without Na2WO4. The coatings formed using the W-containing electrolyte showed a higher micro-hardness and a lower wear rate in comparison with the coatings produced in the silicate-based electrolyte.
Enhanced Mechanical and Anti-Wear Properties of Magnesium by Alloying and Subsequent Extrusion–Aging Treatment
Authors: Lv Youjie , Li Shaoqing , Guo Feng , Xie Zhiwen
Published: October 2022

In this work, the microstructure, mechanical, and anti-wear properties of the alloyed-extruded-aged Mg-8.3Gd-4.5Y-1.4Zn-0.3Zr (wt%) alloys were investigated by X-ray diffraction (XRD), scanning electron microscope (SEM), nanoindentation, and wear tests. Results showed that the alloying—extrusion processing induced a significant grain refinement of magnesium resulting in the formation of bulk Mg24(GdYZn)5 at the grain boundaries. The grain size decreased from 116 μm in pure magnesium to 17 μm in alloyed-extruded magnesium, while the grain refinement, solid solution and second phase strengthening led to a hardness enhancement from 0.67 GPa in pure magnesium to 1.64 GPa in alloyed-extruded magnesium. Aging treatment further drove the structural homogenization of the alloyed-extruded magnesium resulting in an enhanced hardness of 1.83 GPa. During the sliding wear tests, a large-area plastic deformation layer formed on the wear track surface of pure magnesium, leading to an unstable friction coefficient and a high wear rate of 2.64 × 10−3 mm3·N−1·m−1. The alloying—extrusion—aging treatments effectively inhibited the formation of the plastic deformation layer. The wear rate of the alloyed-extruded material decreased to 1.60 × 10−3 mm3·N−1·m−1. In contrast, the alloyed-extruded-aged material showed a lower wear rate of 1.16 × 10−3 mm3·N−1·m−1. The wear failure mechanisms of all fabricated materials were further discussed according to the characterization results.
Effect of Floor Coatings on Slip-Resistance of Safety Shoes
Authors: Gupta Shubham , Sidhu Sarabjeet , Chatterjee Subhodip , Malviya Ayush , Singh Gurpreet , Chanda Arnab
Published: October 2022

Slippery flooring often leads to unintentional slips and falls, which results in traumatic injuries. To reduce slipping risks, adequate traction at the shoe and flooring contact is essential. In addition, viscous slippery contaminants like water or oil reduce a floor’s traction performance and increase slipping hazards. In this work, the effect of commonly available protective floor coatings on the traction performance of safety-labelled shoes was extensively studied. The study included three floor coatings, namely acid-based etchant coating, epoxy floor paint, and polyurethane, which were tested across five safety shoes. The coated floorings were tested using a robotic slip-testing device in dry and in the presence of water and machine oil—as separate contaminants. The application of floor coatings produced varying surface roughness for the flooring. Significant traction was generated by the etchant coating for the dry flooring, epoxy coating for the wet flooring, and polyurethane coating for all flooring conditions. A comparison of uncoated and coated floorings showed a high effectiveness of generating traction with epoxy coating on wet flooring and polyurethane coating on both wet and oily conditions. The study results are novel and are anticipated to provide valuable guidelines for the selection of slip-resistant coatings for different slippery floorings, and to reduce risks related to slips and falls.
Progress on New Preparation Methods, Microstructures, and Protective Properties of High-Entropy Alloy Coatings
Authors: Lu Kefeng , Zhu Jian , Ge Wenqing , Hui Xidong
Published: October 2022

Currently, the preparations of high-entropy alloy (HEA) coatings have developed into new methods such as thermal spraying, electrospark deposition technology, and magnetron sputtering. The microstructures and protective properties of HEA coatings prepared by different methods are bound to be different. Moreover, because HEAs have a wide range of composition systems, the difference in composition will inevitably lead to a change in process parameters and post-treatment methods, and then affect the microstructures and protective properties. This paper introduces the working mechanism of thermal spraying, electrospark deposition technology, and magnetron sputtering, compares the advantages and disadvantages of each method, and focuses on the influences of the compositions, process parameters, and post-treatment process on the microstructures and properties of the coating. Furthermore, this paper outlines the correlation between preparation methods, process parameters, microstructures, and properties, which will provide a reference for further development of the application of high-entropy alloy coatings. On this basis, the future development direction of HEA coatings is prospected.