bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial Homeostasis in VSMCs as a Central Hub in Vascular Remodeling
Authors: Xia Yi , Zhang Xu , An Peng , Luo Junjie , Luo Yongting
Published: February 2023

Vascular remodeling is a common pathological hallmark of many cardiovascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant cell type lining the tunica media and play a crucial role in maintaining aortic morphology, integrity, contraction and elasticity. Their abnormal proliferation, migration, apoptosis and other activities are tightly associated with a spectrum of structural and functional alterations in blood vessels. Emerging evidence suggests that mitochondria, the energy center of VSMCs, participate in vascular remodeling through multiple mechanisms. For example, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-mediated mitochondrial biogenesis prevents VSMCs from proliferation and senescence. The imbalance between mitochondrial fusion and fission controls the abnormal proliferation, migration and phenotypic transformation of VSMCs. Guanosine triphosphate-hydrolyzing enzymes, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy protein 1 (OPA1) and dynamin-related protein 1 (DRP1), are crucial for mitochondrial fusion and fission. In addition, abnormal mitophagy accelerates the senescence and apoptosis of VSMCs. PINK/Parkin and NIX/BINP3 pathways alleviate vascular remodeling by awakening mitophagy in VSMCs. Mitochondrial DNA (mtDNA) damage destroys the respiratory chain of VSMCs, resulting in excessive ROS production and decreased ATP levels, which are related to the proliferation, migration and apoptosis of VSMCs. Thus, maintaining mitochondrial homeostasis in VSMCs is a possible way to relieve pathologic vascular remodeling. This review aims to provide an overview of the role of mitochondria homeostasis in VSMCs during vascular remodeling and potential mitochondria-targeted therapies.
Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis
Authors: Hu Qiulei , Lai Jiayong , Chen Huamu , Cai Yong , Yue Zhihui , Lin Hongrong , Sun Liangzhong
Published: February 2023

Nephronophthisis (NPHP) is the most prevalent monogenic disease leading to end-stage renal failure in childhood. RhoA activation is involved in NPHP pathogenesis. This study explored the role of the RhoA activator guanine nucleotide exchange factor (GEF)-H1 in NPHP pathogenesis. We analyzed the expression and distribution of GEF-H1 in NPHP1 knockout (NPHP1KO) mice using Western blotting and immunofluorescence, followed by GEF-H1 knockdown. Immunofluorescence and renal histology were used to examine the cysts, inflammation, and fibrosis. A RhoA GTPase activation assay and Western blotting were used to detect the expression of downstream GTP-RhoA and p-MLC2, respectively. In NPHP1 knockdown (NPHP1KD) human kidney proximal tubular cells (HK2 cells), we detected the expressions of E-cadherin and α-smooth muscle actin (α-SMA). In vivo, increased expression and redistribution of GEF-H1, and higher levels of GTP-RhoA and p-MLC2 in renal tissue of NPHP1KO mice were observed, together with renal cysts, fibrosis, and inflammation. These changes were alleviated by GEF-H1 knockdown. In vitro, the expression of GEF-H1 and activation of RhoA were also increased, with increased expression of α-SMA and decreased E-cadherin. GEF-H1 knockdown reversed these changes in NPHP1KD HK2 cells. Thus, the GEF-H1/RhoA/MLC2 axis is activated in NPHP1 defects and may play a pivotal role in NPHP pathogenesis.
Meis1 Controls the Differentiation of Eye Progenitor Cells and the Formation of Posterior Poles during Planarian Regeneration
Authors: Wang Shaocong , Sun Yujia , Liu Xiaomai , Guo Yajun , Huang Yongding , Zhang Shoutao , Tian Qingnan
Published: February 2023

As a member of TALE family, Meis1 has been proven to regulate cell proliferation and differentiation during cell fate commitment; however, the mechanism is still not fully understood. The planarian, which has an abundance of stem cells (neoblasts) responsible for regenerating any organ after injury, is an ideal model for studying the mechanisms of tissue identity determination. Here, we characterized a planarian homolog of Meis1 from the planarian Dugesia japonica. Importantly, we found that knockdown of DjMeis1 inhibits the differentiation of neoblasts into eye progenitor cells and results in an eyeless phenotype with normal central nervous system. Furthermore, we observed that DjMeis1 is required for the activation of Wnt signaling pathway by promoting the Djwnt1 expression during posterior regeneration. The silencing of DjMeis1 suppresses the expression of Djwnt1 and results in the inability to reconstruct posterior poles. In general, our findings indicated that DjMeis1 acts as a trigger for the activation of eye and tail regeneration by regulating the differentiation of eye progenitor cells and the formation of posterior poles, respectively.
Structural and Functional Annotation of Hypothetical Proteins from the Microsporidia Species Vittaforma corneae ATCC 50505 Using in silico Approaches
Authors: Ang’ang’o Lilian Mbaisi , Herren Jeremy Keith , Tastan Bishop Özlem
Published: February 2023

Microsporidia are spore-forming eukaryotes that are related to fungi but have unique traits that set them apart. They have compact genomes as a result of evolutionary gene loss associated with their complete dependency on hosts for survival. Despite having a relatively small number of genes, a disproportionately high percentage of the genes in microsporidia genomes code for proteins whose functions remain unknown (hypothetical proteins—HPs). Computational annotation of HPs has become a more efficient and cost-effective alternative to experimental investigation. This research developed a robust bioinformatics annotation pipeline of HPs from Vittaforma corneae, a clinically important microsporidian that causes ocular infections in immunocompromised individuals. Here, we describe various steps to retrieve sequences and homologs and to carry out physicochemical characterization, protein family classification, identification of motifs and domains, protein–protein interaction network analysis, and homology modelling using a variety of online resources. Classification of protein families produced consistent findings across platforms, demonstrating the accuracy of annotation utilizing in silico methods. A total of 162 out of 2034 HPs were fully annotated, with the bulk of them categorized as binding proteins, enzymes, or regulatory proteins. The protein functions of several HPs from Vittaforma corneae were accurately inferred. This improved our understanding of microsporidian HPs despite challenges related to the obligate nature of microsporidia, the absence of fully characterized genes, and the lack of homologous genes in other systems.
Beneficial Effect of Polysaccharide Gel Made of Xanthan Gum and Locust Bean Gum on Bovine Oocytes
Authors: Hara Shunsuke , Inoue Yuki , Aoki Sogo , Tanaka Keisuke , Shirasuna Koumei , Iwata Hisataka
Published: February 2023

The present study examined the effect of polysaccharides gels made of xanthan gum and locust bean gum (gel culture system) on oocyte maturation and explored the molecules causing the beneficial effect of the gel culture system. Oocytes and cumulus cells complexes were collected from slaughterhouse-derived ovaries and cultured on a plastic plate or gel. The gel culture system improved the rate of development to the blastocyst stage. The oocytes that matured on the gel contained high lipid contents and F-actin formation, and the resultant 8-cell stage embryos had low DNA methylation levels compared to their plate counterparts. RNA sequencing of the oocytes and embryos revealed the differentially expressed genes between the gel and plate culture systems, and upstream regulator analysis revealed estradiol and TGFB1 as top activated upstream molecules. The medium of the gel culture system contained higher concentrations of estradiol and TGFB1 than that of the plate cultures system. Supplementation of the maturation medium with either estradiol or TGFB1 resulted in high lipid content in oocytes. In addition, TGFB1 improved the developmental ability of the oocytes and increased F-actin content while reducing DNA methylation levels in the 8-cell stage embryos. In conclusion, the gel culture system is useful for embryo production, potentially through the upregulation of TGFB1.
Characterization of De Novo Promoter Variants in Autism Spectrum Disorder with Massively Parallel Reporter Assays
Authors: Koesterich Justin , An Joon-Yong , Inoue Fumitaka , Sohota Ajuni , Ahituv Nadav , Sanders Stephan J. , Kreimer Anat
Published: February 2023

Autism spectrum disorder (ASD) is a common, complex, and highly heritable condition with contributions from both common and rare genetic variations. While disruptive, rare variants in protein-coding regions clearly contribute to symptoms, the role of rare non-coding remains unclear. Variants in these regions, including promoters, can alter downstream RNA and protein quantity; however, the functional impacts of specific variants observed in ASD cohorts remain largely uncharacterized. Here, we analyzed 3600 de novo mutations in promoter regions previously identified by whole-genome sequencing of autistic probands and neurotypical siblings to test the hypothesis that mutations in cases have a greater functional impact than those in controls. We leveraged massively parallel reporter assays (MPRAs) to detect transcriptional consequences of these variants in neural progenitor cells and identified 165 functionally high confidence de novo variants (HcDNVs). While these HcDNVs are enriched for markers of active transcription, disruption to transcription factor binding sites, and open chromatin, we did not identify differences in functional impact based on ASD diagnostic status.
MITF Downregulation Induces Death in Human Mast Cell Leukemia Cells and Impairs IgE-Dependent Degranulation
Authors: Proaño-Pérez Elizabeth , Ollé Laia , Guo Yanru , Aparicio Cristina , Guerrero Mario , Muñoz-Cano Rosa , Martin Margarita
Published: February 2023

Activating mutations in KIT (CD117) have been associated with several diseases, including gastrointestinal stromal tumors and mastocytosis. Rapidly progressing pathologies or drug resistance highlight the need for alternative treatment strategies. Previously, we reported that the adaptor molecule SH3 binding protein 2 (SH3BP2 or 3BP2) regulates KIT expression at the transcriptional level and microphthalmia-associated transcription factor (MITF) expression at the post-transcriptional level in human mast cells and gastrointestinal stromal tumor (GIST) cell lines. Lately, we have found that the SH3BP2 pathway regulates MITF through miR-1246 and miR-5100 in GIST. In this study, miR-1246 and miR-5100 were validated by qPCR in the SH3BP2-silenced human mast cell leukemia cell line (HMC-1). MiRNA overexpression reduces MITF and MITF-dependent target expression in HMC-1. The same pattern was observed after MITF silencing. In addition, MITF inhibitor ML329 treatment reduces MITF expression and affects the viability and cell cycle progression in HMC-1. We also examine whether MITF downregulation affected IgE-dependent mast cell degranulation. MiRNA overexpression, MITF silencing, and ML329 treatment reduced IgE-dependent degranulation in LAD2- and CD34+-derived mast cells. These findings suggest MITF may be a potential therapeutic target for allergic reactions and deregulated KIT mast-cell-mediated disorders.
Platelet-Derived Extracellular Vesicles Promote Tenogenic Differentiation of Stem Cells on Bioengineered Living Fibers
Authors: Graça Ana L. , Domingues Rui M. A. , Gomez-Florit Manuel , Gomes Manuela E.
Published: February 2023

Tendon mimetic scaffolds that recreate the tendon hierarchical structure and niche have increasing potential to fully restore tendon functionality. However, most scaffolds lack biofunctionality to boost the tenogenic differentiation of stem cells. In this study, we assessed the role of platelet-derived extracellular vesicles (EVs) in stem cells’ tenogenic commitment using a 3D bioengineered in vitro tendon model. First, we relied on fibrous scaffolds coated with collagen hydrogels encapsulating human adipose-derived stem cells (hASCs) to bioengineer our composite living fibers. We found that the hASCs in our fibers showed high elongation and cytoskeleton anisotropic organization, typical of tenocytes. Moreover, acting as biological cues, platelet-derived EVs boosted the hASCs’ tenogenic commitment, prevented phenotypic drift, enhanced the deposition of the tendon-like extracellular matrix, and induced lower collagen matrix contraction. In conclusion, our living fibers provided an in vitro system for tendon tissue engineering, allowing us to study not only the tendon microenvironment but also the influence of biochemical cues on stem cell behavior. More importantly, we showed that platelet-derived EVs are a promising biochemical tool for tissue engineering and regenerative medicine applications that are worthy of further exploration, as paracrine signaling might potentiate tendon repair and regeneration.
7,8-Dihydroxyflavone Attenuates Inflammatory Response and Insulin Resistance Induced by the Paracrine Interaction between Adipocytes and Macrophages
Authors: Shin Ye-Eun , Choi Ji Won , Park Yong Il , Kim Hye-Kyeong
Published: February 2023

Obesity-induced inflammation and insulin resistance are mediated by macrophage infiltration into adipose tissue. We investigated the effects of 7,8-dihydroxyflavone (7,8-DHF), a flavone found in plants, on the inflammatory response and insulin resistance induced by the interaction between adipocytes and macrophages. Hypertrophied 3T3-L1 adipocytes were cocultured with RAW 264.7 macrophages and treated with 7,8-DHF (3.12, 12.5, and 50 μM). The inflammatory cytokines and free fatty acid (FFA) release were evaluated by assay kits, and signaling pathways were determined by immunoblotting. Coculture of adipocytes and macrophages increased inflammatory mediators, such as nitric oxide (NO), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) and FFA secretion but suppressed the production of anti-inflammatory adiponectin. 7,8-DHF counteracted the coculture-induced changes (p < 0.001). 7,8-DHF also inhibited c-Jun N-terminal kinase (JNK) activation and blocked nuclear factor kappa B (NF-κB) nuclear translocation in the coculture system (p < 0.01). In addition, adipocytes cocultured with macrophages did not increase glucose uptake and Akt phosphorylation in response to insulin. However, 7,8-DHF treatment recovered the impaired responsiveness to insulin (p < 0.01). These findings show that 7,8-DHF alleviates inflammation and adipocyte dysfunction in the coculture of hypertrophied 3T3-L1 adipocytes and RAW 264.7 macrophages, indicating its potential as a therapeutic agent for obesity-induced insulin resistance.
Diarylethene-Based Ionic Liquids: Synthesis and Photo-Driven Solution Properties
Authors: Soromenho Mário R. C. , Afonso Carlos A. M. , Esperança José M. S. S.
Published: February 2023

In this work, the design and synthesis of a series of photochromic gemini diarylethene-based ionic liquids (GDILs) with different cationic motifs is reported. Several synthetic pathways were optimized for the formation of cationic GDILs with chloride as the counterion. The different cationic motifs were achieved through the N-alkylation of the photochromic organic core unit with different tertiary amines, including different aromatic amines such as imidazole derivatives and pyridinium, and other non-aromatic amines. These novel salts present surprising water solubility with unexplored photochromic features that broaden their known applications. The covalent attachment of the different side groups dictates their water solubility and differences upon photocyclization. The physicochemical properties of GDILs in aqueous and in imidazolium-based ionic liquid (IL) solutions were investigated. Upon irradiation with ultraviolet (UV) light, we have observed changes in the physico-chemical properties of distinct solutions containing these GDILs, at very low concentrations. More specifically, in aqueous solution, the overall conductivity increased with the time of UV photoirradiation. In contrast, in IL solution, these photoinducible changes are dependent on the type of ionic liquid used. These compounds can improve non-ionic and ionic liquids’ solutions since we can change their properties, such as conductivity, viscosity or ionicity, only by UV photoirradiation. The electronic and conformational changes associated with these innovative stimuli GDILs may open new opportunities for their use as photoswitchable materials.
The Complex Interplay between Nevi and Melanoma: Risk Factors and Precursors
Authors: Shreberk-Hassidim Rony , Ostrowski Stephen M. , Fisher David E.
Published: February 2023

One effort to combat the rising incidence of malignant melanoma is focused on early detection by the clinical and dermoscopic screening of melanocytic nevi. However, the interaction between nevi, which are congenital or acquired benign melanocytic proliferations, and melanoma is still enigmatic. On the one hand, the majority of melanomas are thought to form de novo, as only a third of primary melanomas are associated with a histologically identifiable nevus precursor. On the other hand, an increased number of melanocytic nevi is a strong risk factor for developing melanoma, including melanomas that do not derive from nevi. The formation of nevi is modulated by diverse factors, including pigmentation, genetic risk factors, and environmental sun exposure. While the molecular alterations that occur during the progression of a nevus to melanoma have been well characterized, many unanswered questions remain surrounding the process of nevus to melanoma evolution. In this review, we discuss clinical, histological, molecular, and genetic factors that influence nevus formation and progression to melanoma.
Increased Expression of Hepatic Stearoyl-CoA Desaturase (SCD)-1 and Depletion of Eicosapentaenoic Acid (EPA) Content following Cytotoxic Cancer Therapy Are Reversed by Dietary Fish Oil
Authors: Monirujjaman Md , Renani Leila Baghersad , Isesele Peter , Dunichand-Hoedl Abha R. , Mazurak Vera C.
Published: February 2023

Cancer treatment evokes impediments to liver metabolism that culminate in fatty liver. This study determined hepatic fatty acid composition and expression of genes and mediators involved in lipid metabolism following chemotherapy treatment. Female rats bearing the Ward colon tumor were administered Irinotecan (CPT-11) +5-fluorouracil (5-FU) and maintained on a control diet or a diet containing eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) (2.3 g/100 g fish oil). Healthy animals provided with a control diet served as a reference group. Livers were collected one week after chemotherapy. Triacylglycerol (TG), phospholipid (PL), ten lipid metabolism genes, leptin, and IL-4 were measured. Chemotherapy increased TG content and reduced EPA content in the liver. Expression of SCD1 was upregulated by chemotherapy, while dietary fish oil downregulated its expression. Dietary fish oil down-regulated expression of the fatty acid synthesis gene FASN, while restoring the long chain fatty acid converting genes FADS2 and ELOVL2, and genes involved in mitochondrial β-oxidation (CPT1α) and lipid transport (MTTP1), to values similar to reference animals. Neither leptin nor IL-4 were affected by chemotherapy or diet. Depletion of EPA is associated with pathways evoking enhanced TG accumulation in the liver. Restoring EPA through diet may pose a dietary strategy to attenuate chemotherapy-associated impediments in liver fatty acid metabolism.
Simultaneous Administration of Bevacizumab with Bee-Pollen Extract-Loaded Hybrid Protein Hydrogel NPs Is a Promising Targeted Strategy against Cancer Cells
Authors: Hanafy Nemany A. N. , Eltonouby Eman Ali Bakr , Salim Elsayed I. , Mahfouz Magdy E. , Leporatti Stefano , Hafez Ezar H.
Published: February 2023

Bevacizumab (Bev) a humanized monoclonal antibody that fights vascular endothelial growth factor A (VEGF-A). It was the first specifically considered angiogenesis inhibitor and it has now become the normative first-line therapy for advanced non-small-cell lung cancer (NSCLC). In the current study, polyphenolic compounds were isolated from bee pollen (PCIBP) and encapsulated (EPCIBP) inside moieties of hybrid peptide–protein hydrogel nanoparticles in which bovine serum albumin (BSA) was combined with protamine-free sulfate and targeted with folic acid (FA). The apoptotic effects of PCIBP and its encapsulation (EPCIBP) were further investigated using A549 and MCF-7 cell lines, providing significant upregulation of Bax and caspase 3 genes and downregulation of Bcl2, HRAS, and MAPK as well. This effect was synergistically improved in combination with Bev. Our findings may contribute to the use of EPCIBP simultaneously with chemotherapy to strengthen the effectiveness and minimize the required dose.
MicroRNAs and Gene Regulatory Networks Related to Cleft Lip and Palate
Authors: Iwaya Chihiro , Suzuki Akiko , Iwata Junichi
Published: February 2023

Cleft lip and palate is one of the most common congenital birth defects and has a complex etiology. Either genetic or environmental factors, or both, are involved at various degrees, and the type and severity of clefts vary. One of the longstanding questions is how environmental factors lead to craniofacial developmental anomalies. Recent studies highlight non-coding RNAs as potential epigenetic regulators in cleft lip and palate. In this review, we will discuss microRNAs, a type of small non-coding RNAs that can simultaneously regulate expression of many downstream target genes, as a causative mechanism of cleft lip and palate in humans and mice.
Mesenchymal Stromal Cell-Based Targeted Therapy Pancreatic Cancer: Progress and Challenges
Authors: Ma Zhilong , Hua Jie , Liu Jiang , Zhang Bo , Wang Wei , Yu Xianjun , Xu Jin
Published: February 2023

Pancreatic cancer is an aggressive malignancy with high mortality rates and poor prognoses. Despite rapid progress in the diagnosis and treatment of pancreatic cancer, the efficacy of current therapeutic strategies remains limited. Hence, better alternative therapeutic options for treating pancreatic cancer need to be urgently explored. Mesenchymal stromal cells (MSCs) have recently received much attention as a potential therapy for pancreatic cancer owing to their tumor-homing properties. However, the specific antitumor effect of MSCs is still controversial. To this end, we aimed to focus on the potential anti-cancer treatment prospects of the MSC-based approach and summarize current challenges in the clinical application of MSCs to treat pancreatic cancer.
Recognition of Differentially Expressed Molecular Signatures and Pathways Associated with COVID-19 Poor Prognosis in Glioblastoma Patients
Authors: Alzahrani Faisal A. , Khan Mohd Faheem , Ahmad Varish
Published: February 2023

Glioblastoma (GBM) is a type of brain cancer that is typically very aggressive and difficult to treat. Glioblastoma cases have been reported to have increased during COVID-19. The mechanisms underlying this comorbidity, including genomic interactions, tumor differentiation, immune responses, and host defense, are not completely explained. Therefore, we intended to investigate the differentially expressed shared genes and therapeutic agents which are significant for these conditions by using in silico approaches. Gene expression datasets of GSE68848, GSE169158, and GSE4290 studies were collected and analyzed to identify the DEGs between the diseased and the control samples. Then, the ontology of the genes and the metabolic pathway enrichment analysis were carried out for the classified samples based on expression values. Protein–protein interactions (PPI) map were performed by STRING and fine-tuned by Cytoscape to screen the enriched gene module. In addition, the connectivity map was used for the prediction of potential drugs. As a result, 154 overexpressed and 234 under-expressed genes were identified as common DEGs. These genes were found to be significantly enriched in the pathways involved in viral diseases, NOD-like receptor signaling pathway, the cGMP-PKG signaling pathway, growth hormone synthesis, secretion, and action, the immune system, interferon signaling, and the neuronal system. STAT1, CXCL10, and SAMDL were screened out as the top 03 out of the top 10 most critical genes among the DEGs from the PPI network. AZD-8055, methotrexate, and ruxolitinib were predicted to be the possible agents for the treatment. The current study identified significant key genes, common metabolic signaling networks, and therapeutic agents to improve our perception of the common mechanisms of GBM–COVID-19.
Metabolic Profile Reflects Stages of Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease
Authors: Jambulingam Nila , Forlano Roberta , Preston Benjamin , Mullish Benjamin H. , Portone Greta , Baheer Yama , Yee Michael , Goldin Robert D. , Thursz Mark R. , Manousou Pinelopi
Published: February 2023

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide, with fibrosis stage being the main predictor for clinical outcomes. Here, we present the metabolic profile of NAFLD patients with regards to fibrosis progression. We included all consecutive new referrals for NAFLD services between 2011 and 2019. Demographic, anthropometric and clinical features and noninvasive markers of fibrosis were recorded at baseline and at follow-up. Significant and advanced fibrosis were defined using liver stiffness measurement (LSM) as LSM ≥ 8.1 kPa and LSM ≥ 12.1 kPa, respectively. Cirrhosis was diagnosed either histologically or clinically. Fast progressors of fibrosis were defined as those with delta stiffness ≥ 1.03 kPa/year (25% upper quartile of delta stiffness distribution). Targeted and untargeted metabolic profiles were analysed on fasting serum samples using Proton nuclear magnetic resonance (1H NMR). A total of 189 patients were included in the study; 111 (58.7%) underwent liver biopsy. Overall, 11.1% patients were diagnosed with cirrhosis, while 23.8% were classified as fast progressors. A combination of metabolites and lipoproteins could identify the fast fibrosis progressors (AUROC 0.788, 95% CI: 0.703–0.874, p < 0.001) and performed better than noninvasive markers. Specific metabolic profiles predict fibrosis progression in patients with nonalcoholic fatty liver disease. Algorithms combining metabolites and lipids could be integrated in the risk-stratification of these patients.
Effects of Adjunct Antifibrotic Treatment within a Regenerative Rehabilitation Paradigm for Volumetric Muscle Loss
Authors: Motherwell Jessica M. , Dolan Connor P. , Kanovka Sergey S. , Edwards Jorge B. , Franco Sarah R. , Janakiram Naveena B. , Valerio Michael S. , Goldman Stephen M. , Dearth Christopher L.
Published: February 2023

The use of a rehabilitation approach that promotes regeneration has the potential to improve the efficacy of pro-regenerative therapies and maximize functional outcomes in the treatment of volumetric muscle loss (VML). An adjunct antifibrotic treatment could further enhance functional gains by reducing fibrotic scarring. This study aimed to evaluate the potential synergistic effects of losartan, an antifibrotic pharmaceutical, paired with a voluntary wheel running rehabilitation strategy to enhance a minced muscle graft (MMG) pro-regenerative therapy in a rodent model of VML. The animals were randomly assigned into four groups: (1) antifibrotic with rehabilitation, (2) antifibrotic without rehabilitation, (3) vehicle treatment with rehabilitation, and (4) vehicle treatment without rehabilitation. At 56 days, the neuromuscular function was assessed, and muscles were collected for histological and molecular analysis. Surprisingly, we found that the losartan treatment decreased muscle function in MMG-treated VML injuries by 56 days, while the voluntary wheel running elicited no effect. Histologic and molecular analysis revealed that losartan treatment did not reduce fibrosis. These findings suggest that losartan treatment as an adjunct therapy to a regenerative rehabilitation strategy negatively impacts muscular function and fails to promote myogenesis following VML injury. There still remains a clinical need to develop a regenerative rehabilitation treatment strategy for traumatic skeletal muscle injuries. Future studies should consider optimizing the timing and duration of adjunct antifibrotic treatments to maximize functional outcomes in VML injuries.
Towards Marker-Assisted Breeding for Black Rot Bunch Resistance: Identification of a Major QTL in the Grapevine Cultivar ‘Merzling’
Authors: Bettinelli Paola , Nicolini Daniela , Costantini Laura , Stefanini Marco , Hausmann Ludger , Vezzulli Silvia
Published: February 2023

Black rot (BR), caused by Guignardia bidwellii, is an emergent fungal disease threatening viticulture and affecting several mildew-tolerant varieties. However, its genetic bases are not fully dissected yet. For this purpose, a segregating population derived from the cross ‘Merzling’ (hybrid, resistant) × ‘Teroldego’ (V. vinifera, susceptible) was evaluated for BR resistance at the shoot and bunch level. The progeny was genotyped with the GrapeReSeq Illumina 20K SNPchip, and 7175 SNPs were combined with 194 SSRs to generate a high-density linkage map of 1677 cM. The QTL analysis based on shoot trials confirmed the previously identified Resistance to Guignardia bidwellii (Rgb)1 locus on chromosome 14, which explained up to 29.2% of the phenotypic variance, reducing the genomic interval from 2.4 to 0.7 Mb. Upstream of Rgb1, this study revealed a new QTL explaining up to 79.9% of the variance for bunch resistance, designated Rgb3. The physical region encompassing the two QTLs does not underlie annotated resistance (R)-genes. The Rgb1 locus resulted enriched in genes belonging to phloem dynamics and mitochondrial proton transfer, while Rgb3 presented a cluster of pathogenesis-related Germin-like protein genes, promoters of the programmed cell death. These outcomes suggest a strong involvement of mitochondrial oxidative burst and phloem occlusion in BR resistance mechanisms and provide new molecular tools for grapevine marker-assisted breeding.
Analysis of Experimental Data on Changes in Various Structures and Functions of the Rat Brain following Intranasal Administration of Fe2O3 Nanoparticles
Authors: Minigalieva Ilzira A. , Ryabova Yuliya V. , Shelomencev Ivan G. , Amromin Lev A. , Minigalieva Regina F. , Sutunkova Yuliya M. , Privalova Larisa I. , Sutunkova Marina P.
Published: February 2023

Particulate matter, including iron nanoparticles, is one of the constituents of ambient air pollution. We assessed the effect of iron oxide (Fe2O3) nanoparticles on the structure and function of the brain of rats. Electron microscopy showed Fe2O3 nanoparticles in the tissues of olfactory bulbs but not in the basal ganglia of the brain after their subchronic intranasal administration. We observed an increase in the number of axons with damaged myelin sheaths and in the proportion of pathologically altered mitochondria in the brains of the exposed animals against the background of almost stable blood parameters. We conclude that the central nervous system can be a target for toxicity of low-dose exposure to Fe2O3 nanoparticles.
New Histoprognostic Factors to Consider for the Staging of Colon Cancers: Tumor Deposits, Invasive Tumor Infiltration and High-Grade Budding
Authors: Riffet Marc , Dupont Benoît , Faisant Maxime , Cerasuolo Damiano , Menahem Benjamin , Alves Arnaud , Dubois Fatémeh , Levallet Guénaëlle , Bazille Céline
Published: February 2023

Colorectal cancer is a major public health issue due to its high incidence and mortality. It is, therefore, essential to identify histological markers for prognostic purposes and to optimize the therapeutic management of patients. The main objective of our study was to analyze the impact of new histoprognostic factors, such as tumor deposits, budding, poorly differentiated clusters, mode of infiltration, the intensity of inflammatory infiltrate and the type of tumor stroma, on the survival of patients with colon cancer. Two hundred and twenty-nine resected colon cancers were fully histologically reviewed, and survival and recurrence data were collected. Survival was analyzed using Kaplan–Meier curves. A univariate and multivariate Cox model was constructed to identify prognostic factors for overall survival and recurrence-free survival. The median overall survival of the patients was 60.2 months and the median recurrence-free survival was 46.9 months. Overall survival and recurrence-free survival were significantly worse in the presence of isolated tumor deposits (log rank = 0.003 and 0.001, respectively) and for an infiltrative type of tumor invasion (log rank = 0.008 and 0.02, respectively). High-grade budding was associated with a poor prognosis, with no significant difference. We did not find a significant prognostic impact of the presence of poorly differentiated clusters, the intensity of the inflammatory infiltrate or the stromal type. In conclusion, the analysis of these recent histoprognostic factors, such as tumor deposits, mode of infiltration, and budding, could be integrated into the results of pathological reports of colon cancers. Thus, the therapeutic management of patients could be adjusted by providing more aggressive treatments in the presence of some of these factors.
3D-Structured and Blood-Contact-Safe Graphene Materials
Authors: Kaczmarek-Szczepańska Beata , Michalska-Sionkowska Marta , Binkowski Pawel , Lukaszewicz Jerzy P. , Kamedulski Piotr
Published: February 2023

Graphene is a promising material that may be potentially used in biomedical applications, mainly for drug delivery applications. In our study, we propose an inexpensive 3D graphene preparation method by wet chemical exfoliation. The morphology of the graphene was studied by SEM and HRTEM. Moreover, the volumetric elemental composition (C, N, and H) of the materials was analyzed, and Raman spectra of prepared graphene samples were obtained. X-ray photoelectron spectroscopy, relevant isotherms, and specific surface area were measured. Survey spectra and micropore volume calculations were made. In addition, the antioxidant activity and hemolysis rate in contact with blood were determined. Activity against free radicals of graphene samples before and after thermal modification was tested using the DPPH method. The RSA of the material increased after graphene modification, which suggests that antioxidant properties were improved. All tested graphene samples caused hemolysis in the range of 0.28–0.64%. The results showed that all tested 3D graphene samples might be classified as nonhemolytic.
Structural Characteristics of High-Mobility Group Proteins HMGB1 and HMGB2 and Their Interaction with DNA
Authors: Starkova Tatiana , Polyanichko Alexander , Artamonova Tatiana , Tsimokha Anna , Tomilin Alexey , Chikhirzhina Elena
Published: February 2023

Non-histone nuclear proteins HMGB1 and HMGB2 (High Mobility Group) are involved in many biological processes, such as replication, transcription, and repair. The HMGB1 and HMGB2 proteins consist of a short N-terminal region, two DNA-binding domains, A and B, and a C-terminal sequence of glutamic and aspartic acids. In this work, the structural organization of calf thymus HMGB1 and HMGB2 proteins and their complexes with DNA were studied using UV circular dichroism (CD) spectroscopy. Post-translational modifications (PTM) of HMGB1 and HMGB2 proteins were determined with MALDI mass spectrometry. We have shown that despite the similar primary structures of the HMGB1 and HMGB2 proteins, their post-translational modifications (PTMs) demonstrate quite different patterns. The HMGB1 PTMs are located predominantly in the DNA-binding A-domain and linker region connecting the A and B domains. On the contrary, HMGB2 PTMs are found mostly in the B-domain and within the linker region. It was also shown that, despite the high degree of homology between HMGB1 and HMGB2, the secondary structure of these proteins is also slightly different. We believe that the revealed structural properties might determine the difference in the functioning of the HMGB1 and HMGB2 as well as their protein partners.
Alterations in Antioxidant Micronutrient Concentrations in Placental Tissue, Maternal Blood and Urine and the Fetal Circulation in Pre-eclampsia
Authors: Kurlak Lesia O. , Scaife Paula J. , Briggs Louise V. , Broughton Pipkin Fiona , Gardner David S. , Mistry Hiten D.
Published: February 2023

Trace elements such as selenium and zinc are vital components of many enzymes, including endogenous antioxidants, and can interact with each other. Women with pre-eclampsia, the hypertensive disease of pregnancy, have been reported as having changes in some individual antioxidant trace elements during pregnancy, which are related to maternal and fetal mortality and morbidity. We hypothesised that examination of the three compartments of (a) maternal plasma and urine, (b) placental tissue and (c) fetal plasma in normotensive and hypertensive pregnant women would allow identification of biologically significant changes and interactions in selenium, zinc, manganese and copper. Furthermore, these would be related to changes in the angiogenic markers, placental growth factor (PlGF) and Soluble Fms-Like Tyrosine Kinase-1 (sFlt-1) concentrations. Venous plasma and urine were collected from healthy non-pregnant women (n = 30), normotensive pregnant controls (n = 60) and women with pre-eclampsia (n = 50) in the third trimester. Where possible, matched placental tissue samples and umbilical venous (fetal) plasma were also collected. Antioxidant micronutrient concentrations were measured by inductively coupled plasma mass-spectrometry. Urinary levels were normalised to creatinine concentration. Plasma active PlGF and sFlt-1 concentrations were measured by ELISA. Maternal plasma selenium, zinc and manganese were all lower in women with pre-eclampsia (p < 0.05), as were fetal plasma selenium and manganese (p < 0.05 for all); maternal urinary concentrations were lower for selenium and zinc (p < 0.05). Conversely, maternal and fetal plasma and urinary copper concentrations were higher in women with pre-eclampsia (p < 0.05). Differences in placental concentrations varied, with lower overall levels of selenium and zinc (p < 0.05) in women with pre-eclampsia. Maternal and fetal PlGF were lower and sFlt-1 higher in women with pre-eclampsia; maternal plasma zinc was positively correlated with maternal plasma sFlt-1 (p < 0.05). Because of perceptions that early- and late-onset pre-eclampsia have differing aetiologies, we subdivided maternal and fetal data accordingly. No major differences were observed, but fetal sample sizes were small following early-onset. Disruption in these antioxidant micronutrients may be responsible for some of the manifestations of pre-eclampsia, including contributing to an antiangiogenic state. The potential benefits of mineral supplementation, in women with deficient intakes, during pregnancy to reduce pre-eclampsia remain an important area for experimental and clinical research.
The SAH7 Homologue of the Allergen Ole e 1 Interacts with the Putative Stress Sensor SBP1 (Selenium-Binding Protein 1) in Arabidopsis thaliana
Authors: Dervisi Irene , Petropoulos Orfeas , Agalou Adamantia , Podia Varvara , Papandreou Nikolaos , Iconomidou Vassiliki A. , Haralampidis Kosmas , Roussis Andreas
Published: February 2023

In this study, we focused on a member of the Ole e 1 domain-containing family, AtSAH7, in Arabidopsis thaliana. Our lab reports for the first time on this protein, AtSAH7, that was found to interact with Selenium-binding protein 1 (AtSBP1). We studied by GUS assisted promoter deletion analysis the expression pattern of AtSAH7 and determined that the sequence 1420 bp upstream of the transcription start can act as a minimal promoter inducing expression in vasculature tissues. Moreover, mRNA levels of AtSAH7 were acutely increased under selenite treatment in response to oxidative stress. We confirmed the aforementioned interaction in vivo, in silico and in planta. Following a bimolecular fluorescent complementation approach, we determined that the subcellular localization of the AtSAH7 and the AtSAH7/AtSBP1 interaction occur in the ER. Our results indicate the participation of AtSAH7 in a biochemical network regulated by selenite, possibly associated with responses to ROS production.
Impact Resistance Enhancement of Sustainable Geopolymer Composites Using High Volume Tile Ceramic Wastes
Authors: Huseien Ghasan Fahim , Kubba Ziyad , Mhaya Akram M. , Malik Noshaba Hassan , Mirza Jahangir
Published: February 2023

The need for sustainable concrete with low carbon dioxide emissions and exceptional performance has recently increased in the building industry. Many distinct types of industrial byproducts and ecologically safe wastes have shown promise as ingredients for this kind of concrete. Meanwhile, as industrialization and lifestyle modernization continue to rise, ceramic waste becomes an increasingly serious threat to the natural environment. It is well known that free cement binder that incorporates tile ceramic wastes (TCWs) can significantly improve the material’s sustainability. We used this information to create a variety of geopolymer mortars by mixing TCWs with varied proportions of ground blast furnace slag (GBFS) and fly ash (FA). Analytical techniques were used to evaluate the mechanical properties and impact resistance (IR) of each designed mixture. TCWs were substituted for binders at percentages between 50 and 70 percent, and the resultant mixes were strong enough for real-world usage. Evidence suggests that the IR and ductility of the proposed mortars might be greatly improved by the addition of TCWs to a geopolymer matrix. It was found that there is a trend for both initial and failure impact energy to increase with increasing TCWs and FA content in the matrix. The results show that the raising of TCWs from 0% to 50, 60 and 70% significantly led to an increase in the failure impact energy from 397.3 J to 456.8, 496.6 and 595.9 J, respectively.
Continuous Long Time Series Monitoring of Urban Construction Land in Supporting the SDG 11.3.1—A Case Study of Nanning, Guangxi, China
Authors: Ling Ziyan , Jiang Weiguo , Lu Yuan , Ling Yurong , Zhang Ze , Liao Chaoming
Published: February 2023

Enhancing the spatio-temporal dynamic monitoring of the construction land of emerging major cities provides the basis for understanding the effects of human activities on the earth’s ecological environment changes, which is regarded as an important way to improve human wellbeing and to achieve the UN SDGs. This paper, which uses Nanning as an example, adopts 30 m annual remote sensing land cover datasets from 1990–2021 to elaborately analyze the temporal evolution and spatial expansion of construction land and to evaluate the sustainable development level based on SDG 11.3.1. The conclusions of this paper are as follows: (1) For Nanning City, during 1990–2021, construction land area increased from 54.77 km2 to 326.33 km2—a nearly five-fold increase. Spreading expansion and finger-like expansion along roads played a leading role during the development of the construction land in Nanning. Liangqing and Yongning are the future directions of urban development. The LCRPGR of Nanning declined with one peak period around 1995, and the LCRPGR was relatively stable with a high intensity of land use. (2) For the other emerging major cities, continuous long duration data are more suitable for urban construction land monitoring compared with traditional sparse time-series monitoring. The rich information derived from continuous long duration data can help decision makers to formulate and implement more comprehensive measures. The research paradigm adopted in this study can be applied in other cities. The newly developed urban districts will have foreseeable high sustainable development risks, and urban development strategies at the international, national, and urban levels could reduce those risks and promote the realization of UN SDGs from different angles and with different intensities.
Logistics Service Providers and Industry 4.0: A Systematic Literature Review
Authors: da Silva Ricardo Moreira , Frederico Guilherme Francisco , Garza-Reyes Jose Arturo
Published: February 2023

Background: Industry 4.0 is one of the topics related to manufacturing, supply chain and logistics that has received great interest from the academic community, organizations and governments in the last decade. Problem statement: Several published articles discuss and seek to conceptualize what the fourth industrial revolution is, but no research relates Industry 4.0 in the context of logistics service providers (LSPs) in a clear and structured way. Objectives: This study aims to fill this research gap, proposing a conceptual framework and addressing the challenges, barriers and organizational dimensions that need adaptation to insert LSPs in the new Industry 4.0 environment. Methods: This theoretical and conceptual study uses the Systematic Literature Review (SLR) as a research method to understand the Industry 4.0 phenomenon in the context of LSPs. Contributions: The relevant constructs identified in this research will help professionals and organizations that provide logistics services to develop strategies and encourage new research in the field of Industry 4.0 from the perspective of LSPs. Results: In addition, this research identified and generally consolidated six dimensions, as a result of this innovative study a conceptual framework is presented.
Exact Formulation for the Curvature of Gothic Arch Ball Screw Profiles and New Approximated Solution Based on Simplified Groove Geometry
Authors: Bertolino Antonio Carlo , De Martin Andrea , Mauro Stefano , Sorli Massimo
Published: February 2023

The correct evaluation of the curvatures of ball screw grooves allows the accurate design of the constructive parameters of this mechanism and enhancing its performance. The formulation commonly used in the literature, however, refers to ball bearing geometry, ignoring the shape of the section’s profile and the helix angle. In this paper, the exact formulae for calculating the principal curvature radii of the screw shaft and the nut grooves are analytically derived and presented. These equations, obtained through a rigorous differential geometry approach, consider the helix angle and a gothic arch profile. An approximated formulation is proposed simplifying the exact solution under the assumption of a circular groove profile. These new simple formulae accurately reproduce the exact curvature radii values with a mean relative error of approximatively 0.51% and 0.40%, respectively, for the screw shaft and nut grooves, against the value of more than 50% obtained by using the literature formulae for common off-the-shelf ball screws, especially those with high helix angles. Furthermore, they allow a computational time saving of 98%, making them suitable for being incorporated in high-fidelity dynamic models of ball. Finally, two MATLAB functions are provided to easily evaluate the complex curvature exact solution.