bluuebunny/crossref_metadata_2025 huggingface dataset:
Family-Level Multimorbidity among Older Adults in India: Looking through a Syndemic Lens
Authors: Pati Sanghamitra , Sinha Abhinav , Ghosal Shishirendu , Kerketta Sushmita , Lee John Tayu , Kanungo Srikanta
Published: August 2022

Most evidence on multimorbidity is drawn from an individual level assessment despite the fact that multimorbidity is modulated by shared risk factors prevailing within the household environment. Our study reports the magnitude of family-level multimorbidity, its correlates, and healthcare expenditure among older adults using data from the Longitudinal Ageing Study in India (LASI), wave-1. LASI is a nationwide survey amongst older adults aged ≥45 years conducted in 2017–2018. We included (n = 22,526) families defined as two or more members coresiding in the same household. We propose a new term, “family-level multimorbidity”, defined as two or more members of a family having multimorbidity. Multivariable logistic regression was used to assess correlates, expressed as adjusted odds ratios with a 95% confidence interval. Family-level multimorbidity was prevalent among 44.46% families, whereas 41.8% had conjugal multimorbidity. Amongst siblings, 42.86% reported multimorbidity and intergenerational (three generations) was 46.07%. Family-level multimorbidity was predominantly associated with the urban and affluent class. Healthcare expenditure increased with more multimorbid individuals in a family. Our findings depict family-centred interventions that may be considered to mitigate multimorbidity. Future studies should explore family-level multimorbidity to help inform programs and policies in strategising preventive as well as curative services with the family as a unit.
Civic Engagement in Socially Excluded Young Adults Promotes Well-Being: The Mediation of Self-Efficacy, Meaning in Life, and Identity Exploration
Authors: Birger Sagiv Irit , Goldner Limor , Carmel Yifat
Published: August 2022

Civic engagement is thought to contribute to well-being among young adults. However, less is known about the ways in which civic engagement promotes well-being in general and in particular in socially excluded populations. This study investigated whether civic engagement contributes to life satisfaction and hope in a sample of 127 socially excluded young Israeli women who participated in social activism programs for a period of eight months. A mediation model incorporating self-efficacy, meaning in life, and identity exploration was used to examine the contribution of positive attitudes toward civic engagement, civic engagement skills, and political awareness to the participants’ life satisfaction and hope. Indirect effects were found between positive attitudes toward civic engagement, civic engagement skills, and political awareness and the participants’ life satisfaction and hope via self-efficacy. Positive attitudes toward civic engagement and political awareness also predicted the participants’ life satisfaction via meaning in life. A positive direct effect was found between political awareness and hope. However, contrary to the hypothesis, a negative direct effect was found between positive attitudes toward civic engagement and life satisfaction. Civic engagement skills and political awareness also predicted identity exploration. These findings underscore the need for clinicians to be aware of the potential benefits of civic engagement for the well-being of socially excluded populations.
Analysis of Rheumatic Heart Disease Mortality in the Chinese Population: A JoinPoint and Age–Period–Cohort Study
Authors: Cui Jiameng , Guo Xinru , Yuan Xin , Wu Hao , Yu Ge , Li Biao , Kou Changgui
Published: August 2022

(1) Background: We aimed to analyze rheumatic heart disease (RHD) mortality trends in China’s urban and rural areas and to determine the roles of age, period, and cohort effects. (2) Methods: Based on mortality data extracted from the China Health Statistics Yearbook, we calculated the crude mortality rate of RHD. Age–adjusted rates were computed by the direct method using the 2020 census as the standard population. The annual percentage change (APC) and average annual percentage change (AAPC) were determined by the JoinPoint regression model. The age–period–cohort model was used to estimate the effects of age, period, and cohort. (3) Results: From 2006 to 2020, the general trend in RHD standardized mortality declined. The RHD mortality rate was higher in rural than in urban areas and among females than males. The elderly (over 60 years old) were at high risk for RHD deaths in China. The age effect increased with age, and the cohort effect showed a declining trend as chronology grew, but the period effect was not significant. (4) Conclusions: China has achieved great success in RHD, but RHD mortality may increase with age. Compared with the period effect, age and cohort effects dominated the risk of RHD deaths.
Molecular Biomarkers in Glioblastoma: A Systematic Review and Meta-Analysis
Authors: Sareen Heena , Ma Yafeng , Becker Therese M. , Roberts Tara L. , de Souza Paul , Powter Branka
Published: August 2022

Background: Glioblastoma (GBM) is a highly aggressive cancer with poor prognosis that needs better treatment modalities. Moreover, there is a lack of reliable biomarkers to predict the response and outcome of current or newly designed therapies. While several molecular markers have been proposed as potential biomarkers for GBM, their uptake into clinical settings is slow and impeded by marker heterogeneity. Detailed assessment of prognostic and predictive value for biomarkers in well-defined clinical trial settings, if available, is scattered throughout the literature. Here we conducted a systematic review and meta-analysis to evaluate the prognostic and predictive significance of clinically relevant molecular biomarkers in GBM patients. Material and methods: A comprehensive literature search was conducted to retrieve publications from 3 databases (Pubmed, Cochrane and Embase) from January 2010 to December 2021, using specific terms. The combined hazard ratios (HR) and confidence intervals (95% CI) were used to evaluate the association of biomarkers with overall survival (OS) in GBM patients. Results: Twenty-six out of 1831 screened articles were included in this review. Nineteen articles were included in the meta-analyses, and 7 articles were quantitatively summarised. Fourteen studies with 1231 GBM patients showed a significant association of MGMT methylation with better OS with the pooled HR of 1.66 (95% CI 1.32–2.09, p < 0.0001, random effect). Five studies including 541 GBM patients analysed for the prognostic significance of IDH1 mutation showed significantly better OS in patients with IDH1 mutation with a pooled HR of 2.37 (95% CI 1.81–3.12; p < 0.00001]. Meta-analysis performed on 5 studies including 575 GBM patients presenting with either amplification or high expression of EGFR gene did not reveal any prognostic significance with a pooled HR of 1.31 (95% CI 0.96–1.79; p = 0.08). Conclusions: MGMT promoter methylation and IDH1 mutation are significantly associated with better OS in GBM patients. No significant associations were found between EGFR amplification or overexpression with OS.
Genome-Wide Expression Profiling Analysis of Kiwifruit GolS and RFS Genes and Identification of AcRFS4 Function in Raffinose Accumulation
Authors: Yang Jun , Ling Chengcheng , Liu Yunyan , Zhang Huamin , Hussain Quaid , Lyu Shiheng , Wang Songhu , Liu Yongsheng
Published: August 2022

The raffinose synthetase (RFS) and galactinol synthase (GolS) are two critical enzymes for raffinose biosynthesis, which play an important role in modulating plant growth and in response to a variety of biotic or abiotic stresses. Here, we comprehensively analyzed the RFS and GolS gene families and their involvement in abiotic and biotic stresses responses at the genome-wide scale in kiwifruit. A total of 22 GolS and 24 RFS genes were identified in Actinidia chinensis and Actinidia eriantha genomes. Phylogenetic analysis showed that the GolS and RFS genes were clustered into four and six groups, respectively. Transcriptomic analysis revealed that abiotic stresses strongly induced some crucial genes members including AcGolS1/2/4/8 and AcRFS2/4/8/11 and their expression levels were further confirmed by qRT-PCR. The GUS staining of AcRFS4Pro::GUS transgenic plants revealed that the transcriptionlevel of AcRFS4 was significantly increased by salt stress. Overexpression of AcRFS4 in Arabidopsis demonstrated that this gene enhanced the raffinose accumulation and the tolerance to salt stress. The co-expression networks analysis of hub transcription factors targeting key AcRFS4 genes indicated that there was a strong correlation between AcNAC30 and AcRFS4 expression under salt stress. Furthermore, the yeast one-hybrid assays showed that AcNAC30 could bind the AcRFS4 promoter directly. These results may provide insights into the evolutionary and functional mechanisms of GolS and RFS genes in kiwifruit.
Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model
Authors: Da’as Sahar Isa , Hasan Waseem , Salem Rola , Younes Nadine , Abdelrahman Doua , Mohamed Iman A. , Aldaalis Arwa , Temanni Ramzi , Mathew Lisa Sara , Lorenz Stephan , Yacoub Magdi , Nomikos Michail , Nasrallah Gheyath K. , Fakhro Khalid A.
Published: August 2022

Variants in cardiac myosin-binding protein C (cMyBP-C) are the leading cause of inherited hypertrophic cardiomyopathy (HCM), demonstrating the key role that cMyBP-C plays in the heart’s contractile machinery. To investigate the c-MYBPC3 HCM-related cardiac impairment, we generated a zebrafish mypbc3-knockout model. These knockout zebrafish displayed significant morphological heart alterations related to a significant decrease in ventricular and atrial diameters at systolic and diastolic states at the larval stages. Immunofluorescence staining revealed significant hyperplasia in the mutant’s total cardiac and ventricular cardiomyocytes. Although cardiac contractility was similar to the wild-type control, the ejection fraction was significantly increased in the mypbc3 mutants. At later stages of larval development, the mutants demonstrated an early cardiac phenotype of myocardium remodeling, concurrent cardiomyocyte hyperplasia, and increased ejection fraction as critical processes in HCM initiation to counteract the increased ventricular myocardial wall stress. The examination of zebrafish adults showed a thickened ventricular cardiac wall with reduced heart rate, swimming speed, and endurance ability in both the mypbc3 heterozygous and homozygous groups. Furthermore, heart transcriptome profiling showed a significant downregulation of the actin-filament-based process, indicating an impaired actin cytoskeleton organization as the main dysregulating factor associated with the early ventricular cardiac hypertrophy in the zebrafish mypbc3 HCM model.
The Effects of Hypoxic Preconditioned Murine Mesenchymal Stem Cells on Post-Infarct Arrhythmias in the Mouse Model
Authors: Ahmad Beschan , Skorska Anna , Wolfien Markus , Sadraddin Haval , Lemcke Heiko , Vasudevan Praveen , Wolkenhauer Olaf , Steinhoff Gustav , David Robert , Gaebel Ralf
Published: August 2022

Ventricular arrhythmias associated with myocardial infarction (MI) have a significant impact on mortality in patients following heart attack. Therefore, targeted reduction of arrhythmia represents a therapeutic approach for the prevention and treatment of severe events after infarction. Recent research transplanting mesenchymal stem cells (MSC) showed their potential in MI therapy. Our study aimed to investigate the effects of MSC injection on post-infarction arrhythmia. We used our murine double infarction model, which we previously established, to more closely mimic the clinical situation and intramyocardially injected hypoxic pre-conditioned murine MSC to the infarction border. Thereafter, various types of arrhythmias were recorded and analyzed. We observed a homogenous distribution of all types of arrhythmias after the first infarction, without any significant differences between the groups. Yet, MSC therapy after double infarction led to a highly significant reduction in simple and complex arrhythmias. Moreover, RNA-sequencing of samples from stem cell treated mice after re-infarction demonstrated a significant decline in most arrhythmias with reduced inflammatory pathways. Additionally, following stem-cell therapy we found numerous highly expressed genes to be either linked to lowering the risk of heart failure, cardiomyopathy or sudden cardiac death. Moreover, genes known to be associated with arrhythmogenesis and key mutations underlying arrhythmias were downregulated. In summary, our stem-cell therapy led to a reduction in cardiac arrhythmias after MI and showed a downregulation of already established inflammatory pathways. Furthermore, our study reveals gene regulation pathways that have a potentially direct influence on arrhythmogenesis after myocardial infarction.
Chemokines in Primary Liver Cancer
Authors: Zajkowska Monika , Mroczko Barbara
Published: August 2022

The liver is responsible for extremely important functions in the human body. In the liver’s structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver—hepatocytes. There are many factors, that negatively affect the liver cells, contributing to their damage. This may lead to fibrosis, liver failure and, in consequence, primary liver cancer, which is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Chemokines are a large family of secreted proteins. Their main role is to direct the recruitment and migration of cells to sites of inflammation or injury. Some authors suggest that these proteins might play a potential role in the development of many malignancies, including primary liver cancer. The aim of this study was to evaluate and summarize the knowledge regarding liver diseases, especially primary liver cancer (HCC) and the participation of chemokines in the development of this malignancy. Chemokines involved in the initiation of this type of tumor belong mainly to the CC and CXC chemokines. Their significant role in the course of hepatocellular carcinoma proves their usefulness in detecting and monitoring the course and treatment in patients with this disease.
Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview
Authors: Avram Vlad Florian , Merce Adrian Petru , Hâncu Iasmina Maria , Bătrân Alina Doruța , Kennedy Gabrielle , Rosca Mariana Georgeta , Muntean Danina Mirela
Published: August 2022

Mitochondrial dysfunction has emerged as a central pathomechanism in the setting of obesity and diabetes mellitus, linking these intertwined pathologies that share insulin resistance as a common denominator. High-resolution respirometry (HRR) is a state-of-the-art research method currently used to study mitochondrial respiration and its impairment in health and disease. Tissue samples, cells or isolated mitochondria are exposed to various substrate-uncoupler-inhibitor-titration protocols, which allows the measurement and calculation of several parameters of mitochondrial respiration. In this review, we discuss the alterations of mitochondrial bioenergetics in the main dysfunctional organs that contribute to the development of the obese and diabetic phenotypes in both animal models and human subjects. Herein we review data regarding the impairment of oxidative phosphorylation as integrated mitochondrial function assessed by means of HRR. We acknowledge the critical role of this method in determining the alterations in oxidative phosphorylation occurring in the early stages of metabolic pathologies. We conclude that there is a mutual two-way relationship between mitochondrial dysfunction and insulin insensitivity that characterizes these diseases.
TMAO Suppresses Megalin Expression and Albumin Uptake in Human Proximal Tubular Cells Via PI3K and ERK Signaling
Authors: Kapetanaki Stefania , Kumawat Ashok Kumar , Persson Katarina , Demirel Isak
Published: August 2022

Trimethylamine-N-oxide (TMAO) is a uremic toxin, which has been associated with chronic kidney disease (CKD). Renal tubular epithelial cells play a central role in the pathophysiology of CKD. Megalin is an albumin-binding surface receptor on tubular epithelial cells, which is indispensable for urine protein reabsorption. To date, no studies have investigated the effect of TMAO on megalin expression and the functional properties of human tubular epithelial cells. The aim of this study was first to identify the functional effect of TMAO on human renal proximal tubular cells and second, to unravel the effects of TMAO on megalin-cubilin receptor expression. We found through global gene expression analysis that TMAO was associated with kidney disease. The microarray analysis also showed that megalin expression was suppressed by TMAO, which was also validated at the gene and protein level. High glucose and TMAO was shown to downregulate megalin expression and albumin uptake similarly. We also found that TMAO suppressed megalin expression via PI3K and ERK signaling. Furthermore, we showed that candesartan, dapagliflozin and enalaprilat counteracted the suppressive effect of TMAO on megalin expression. Our results may further help us unravel the role of TMAO in CKD development and to identify new therapeutic targets to counteract TMAOs effects.
Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis
Authors: Sigalov Alexander B.
Published: August 2022

The triggering receptors expressed on myeloid cells (TREMs) are a family of activating immune receptors that regulate the inflammatory response. TREM-1, which is expressed on monocytes and/or macrophages and neutrophils, functions as an inflammation amplifier and plays a role in the pathogenesis of rheumatoid arthritis (RA). Unlike TREM-1, the role in RA of TREM-2, which is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, remains unclear and controversial. TREM-2 ligands are still unknown, adding further uncertainty to our understanding of TREM-2 function. Previously, we demonstrated that TREM-1 blockade, using a ligand-independent TREM-1 inhibitory peptide sequence GF9 rationally designed by our signaling chain homooligomerization (SCHOOL) model of cell signaling, ameliorates collagen-induced arthritis (CIA) severity in mice. Here, we designed a TREM-2 inhibitory peptide sequence IA9 and tested it in the therapeutic CIA model, either as a free 9-mer peptide IA9, or as a part of a 31-mer peptide IA31 incorporated into lipopeptide complexes (IA31-LPC), for targeted delivery. We demonstrated that administration of IA9, but not a control peptide, after induction of arthritis diminished release of proinflammatory cytokines and dramatically suppressed joint inflammation and damage, suggesting that targeting TREM-2 may be a promising approach for the treatment of RA.
Omeprazole Suppresses Oxaliplatin-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database
Authors: Mine Keisuke , Kawashiri Takehiro , Inoue Mizuki , Kobayashi Daisuke , Mori Kohei , Hiromoto Shiori , Kudamatsu Hibiki , Uchida Mayako , Egashira Nobuaki , Koyanagi Satoru , Ohdo Shigehiro , Shimazoe Takao
Published: August 2022

(1) Background: Oxaliplatin is used as first-line chemotherapy not only for colorectal cancer but also for gastric and pancreatic cancers. However, it induces peripheral neuropathy with high frequency as an adverse event, and there is no effective preventive or therapeutic method. (2) Methods: The effects of omeprazole, a proton pump inhibitor (PPI), on oxaliplatin-induced peripheral neuropathy (OIPN) was investigated using an in vivo model and a real-world database. (3) Results: In a rat model, oxaliplatin (4 mg/kg, i.p., twice a week for 4 weeks) caused mechanical hypersensitivity accompanied by sciatic nerve axonal degeneration and myelin sheath disorder. Repeated injection of omeprazole (5–20 mg/kg, i.p., five times per week for 4 weeks) ameliorated these behavioral and pathological abnormalities. Moreover, omeprazole did not affect the tumor growth inhibition of oxaliplatin in tumor bearing mice. Furthermore, clinical database analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) suggests that the group using omeprazole has a lower reporting rate of peripheral neuropathy of oxaliplatin-treated patients than the group not using (3.06% vs. 6.48%, p < 0.001, reporting odds ratio 0.44, 95% confidence interval 0.32–0.61). (4) Conclusions: These results show the preventing effect of omeprazole on OIPN.
Comparative Evaluation of Different Surface Coatings of Fe3O4-Based Magnetic Nano Sorbent for Applications in the Nucleic Acids Extraction
Authors: Szymczyk Anna , Drozd Marcin , Kamińska Agnieszka , Matczuk Magdalena , Trzaskowski Maciej , Mazurkiewicz-Pawlicka Marta , Ziółkowski Robert , Malinowska Elżbieta
Published: August 2022

Nucleic acid extraction and purification are crucial steps in sample preparation for multiple diagnostic procedures. Routine methodologies of DNA isolation require benchtop equipment (e.g., centrifuges) and labor-intensive steps. Magnetic nanoparticles (MNPs) as solid-phase sorbents could simplify this procedure. A wide range of surface coatings employs various molecular interactions between dsDNA and magnetic nano-sorbents. However, a reliable, comparative evaluation of their performance is complex. In this work, selected Fe3O4 modifications, i.e., polyethyleneimine, gold, silica, and graphene derivatives, were comprehensively evaluated for applications in dsDNA extraction. A family of single batch nanoparticles was compared in terms of morphology (STEM), composition (ICP-MS/MS and elemental analysis), surface coating (UV-Vis, TGA, FTIR), and MNP charge (ζ-potential). ICP-MS/MS was also used to unify MNPs concentration allowing a reliable assessment of individual coatings on DNA extraction. Moreover, studies on adsorption medium (monovalent vs. divalent ions) and extraction buffer composition were carried out. As a result, essential relationships between nanoparticle coatings and DNA adsorption efficiencies have been noticed. Fe3O4@PEI MNPs turned out to be the most efficient nano sorbents. The optimized composition of the extraction buffer (medium containing 0.1 mM EDTA) helped avoid problems with Fe3+ stripping, which improved the validity of the spectroscopic determination of DNA recovery.
The Role of CD28 and CD8+ T Cells in Keloid Development
Authors: Shan Mengjie , Liu Hao , Hao Yan , Song Kexin , Feng Cheng , Wang Youbin
Published: August 2022

Background: A keloid is a benign skin tumor that extends beyond the initial injury area, and its pathologic mechanism remains unclear. Method: High-throughput sequencing data were obtained from normal skin tissue of patients with keloids (Group N) and healthy controls (Group C). Important genes were mined by bioinformatics analysis and identified by RT–qPCR, Western blotting, immunohistochemistry and immunofluorescence assays. The CIBERSORT algorithm was used to convert gene expression information into immune cell information. Flow cytometry was used to verify the key immune cells. Fluorescence-activated cell sorting coculture and CCK8 experiments were used to explore the effect of CD8+ T cells on keloid-associated fibroblasts. Neural network models were used to construct associations among CD28, CD8+ T cells and the severity of keloids and to identify high-risk values. Result: The expression levels of costimulatory molecules (CD28, CD80, CD86 and CD40L) in the skin tissue of patients with keloids were higher than the levels in healthy people (p < 0.05). The number of CD8+ T cells was significantly higher in Group N than in Group C (p < 0.05). The fluorescence intensities of CD28 and CD8+ T cells in Group N were significantly higher than those in Group C (p = 0.0051). The number and viability of fibroblasts cocultured with CD8+ T cells were significantly reduced compared with those of the control (p < 0.05). The expression of CD28 and CD8+ T cells as the input layer may be predictors of the severity of keloids with mVSS as the output layer. The high-risk early warning indicator for CD28 is 10–34, and the high-risk predictive indicator for CD8+ T cells is 13–28. Conclusions: The abnormal expression of costimulatory molecules may lead to the abnormal activation of CD8+ T cells. CD8+ T cells may drive keloid-associated immunosuppression. The expression of CD28 and CD8+ T cells as an input layer may be a predictor of keloid severity. CD28 and CD8+ T cells play an important role in the development of keloids.
High-Intensity Focused Ultrasound Induces Adipogenesis via Control of Cilia in Adipose-Derived Stem Cells in Subcutaneous Adipose Tissue
Authors: Oh Seyeon , Kim Hyoung Moon , Batsukh Sosorburam , Sun Hye Jin , Kim Taehui , Kang Donghwan , Son Kuk Hui , Byun Kyunghee
Published: August 2022

During skin aging, the volume of subcutaneous adipose tissue (sWAT) and the adipogenesis potential of adipose-derived stem cells (ASCs) decrease. It is known that the shortening of cilia length by pro-inflammatory cytokines is related to the decreased adipogenic differentiation of ASCs via increase in Wnt5a/β-catenin. High-intensity focused ultrasound (HIFU) is known to upregulate heat shock proteins (HSP), which decrease levels of pro-inflammatory cytokines. In this study, we evaluated whether HIFU modulates the cilia of ASCs by upregulating HSP70 and decreasing inflammatory cytokines. HIFU was applied at 0.2 J to rat skin, which was harvested at 1, 3, 7, and 28 days. All results for HIFU-applied animals were compared with control animals that were not treated. HIFU increased expression of HSP70 and decreased expression of NF-κB, IL-6, and TNF-α in sWAT. HIFU decreased the expression of cilia disassembly-related factors (AurA and HDAC9) in ASCs. Furthermore, HIFU increased the expression of cilia assembly-related factors (KIF3A and IFT88), decreased that of WNT5A/β-catenin, and increased that of the adipogenesis markers PPARγ and CEBPα in sWAT. HIFU increased the number of adipocytes in the sWAT and the thickness of sWAT. In conclusion, HIFU could selectively increase sWAT levels by modulating the cilia of ASCs and be used for skin rejuvenation.
Extraction and Biological Evaluation of Matrix-Bound Nanovesicles (MBVs) from High-Hydrostatic Pressure-Decellularized Tissues
Authors: Kobayashi Mako , Ishida Naoki , Hashimoto Yoshihide , Negishi Jun , Saga Hideki , Sasaki Yoshihiro , Akiyoshi Kazunari , Kimura Tsuyoshi , Kishida Akio
Published: August 2022

Decellularized tissues are widely used as promising materials in tissue engineering and regenerative medicine. Research on the microstructure and components of the extracellular matrix (ECM) was conducted to improve the current understanding of decellularized tissue functionality. The presence of matrix-bound nanovesicles (MBVs) embedded within the ECM was recently reported. Results of a previous experimental investigation revealed that decellularized tissues prepared using high hydrostatic pressure (HHP) exhibited good in vivo performance. In the current study, according to the hypothesis that MBVs are one of the functional components in HHP-decellularized tissue, we investigated the extraction of MBVs and the associated effects on vascular endothelial cells. Using nanoparticle tracking assay (NTA), transmission electron microscopy (TEM), and RNA analysis, nanosized (100–300 nm) and membranous particles containing small RNA were detected in MBVs derived from HHP-decellularized small intestinal submucosa (SIS), urinary bladder matrix (UBM), and liver. To evaluate the effect on the growth of vascular endothelial cells, which are important in the tissue regeneration process, isolated SIS-derived MBVs were exposed to vascular endothelial cells to induce cell proliferation. These results indicate that MBVs can be extracted from HHP-decellularized tissues and may play a significant role in tissue remodeling.
Differential Impact of Random GC Tetrad Binding and Chromatin Events on Transcriptional Inhibition by Olivomycin A
Authors: Isagulieva Alexandra K. , Kaluzhny Dmitry N. , Beniaminov Artemy D. , Soshnikova Nataliya V. , Shtil Alexander A.
Published: August 2022

Olivomycin A (OA), an antibiotic of the aureolic acid family, interferes with gene transcription upon forming complexes with GC-rich regions in the DNA minor groove. We demonstrate that the mechanism of transcriptional deregulation is not limited to OA interaction with GC-containing binding sites for transcription factors. Using electrophoretic mobility shift assays and DNAse I footprinting of cytomegalovirus (CMV) promoter fragments carrying OA-preferred GC tetrads (CMVwt), we showed OA binding specifically to GC islands. Replacement of G for A in these tetrads (CMVmut) abrogated OA binding. Furthermore, OA decreased RNA polymerase II (RNAPII) binding to the CMVwt promoter and inhibited the reporter gene expression. In line with the absence of OA binding sites in CMVmut DNA, the expression driven from this promoter was weakly sensitive to OA. In the endogenous genes OA decreased RNAPII on promoters and coding regions. In certain cases this phenomenon was concomitant with the increased histone 3 abundance. However, the sensitivity to OA did not correlate with GC patterns around transcription start sites, suggesting that certain GC stretches play unequal roles in OA-induced transcriptional perturbations. Thus, OA affects transcription via complex mechanisms in which GC tetranucleotide binding causes RNAPII/chromatin alterations differentially manifested in individual gene contexts.
Identification and Functional Analysis of Key Autophosphorylation Residues of Arabidopsis Senescence Associated Receptor-like Kinase
Authors: Guo Zhaoxia , Mei Yuanyuan , Wang Dan , Xiao Dong , Tang Xianglin , Gong Yaru , Xu Xinxin , Wang Ning Ning
Published: August 2022

Reversible protein phosphorylation mediated by protein kinases and phosphatases plays important roles in the regulation of leaf senescence. We previously reported that the senescence-associated leucine-rich repeat receptor-like kinase AtSARK autophosphorylates on both serine/threonine and tyrosine residues and functions as a positive regulator of Arabidopsis leaf senescence; the senescence-suppressed protein phosphatase SSPP interacts with and dephosphorylates the cytoplasmic domain of AtSARK, thereby negatively regulating leaf senescence. Here, 27 autophosphorylation residues of AtSARK were revealed by mass spectrometry analysis, and six of them, including two Ser, two Thr, and two Tyr residues, were further found to be important for the biological functions of AtSARK. All site-directed mutations of these six residues that resulted in decreased autophosphorylation level of AtSARK could significantly inhibit AtSARK-induced leaf senescence. In addition, mutations mimicking the dephosphorylation form of Ser384 (S384A) or the phosphorylation form of Tyr413 (Y413E) substantially reduced the interaction between AtSARK and SSPP. All results suggest that autophosphorylation of AtSARK is essential for its functions in promoting leaf senescence. The possible roles of S384 and Y413 residues in fine-tuning the interaction between AtSARK and SSPP are discussed herein.
Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold—A Short Review of Most Recent Studies 2013–2022
Authors: Kozyra Paweł , Pitucha Monika
Published: August 2022

The terminal phenoxy group is a moiety of many drugs in use today. Numerous literature reports indicated its crucial importance for biological activity; thus, it is a privileged scaffold in medicinal chemistry. This review focuses on the latest achievements in the field of novel potential agents bearing a terminal phenoxy group in 2013–2022. The article provided information on neurological, anticancer, potential lymphoma agent, anti-HIV, antimicrobial, antiparasitic, analgesic, anti-diabetic as well as larvicidal, cholesterol esterase inhibitors, and antithrombotic or agonistic activities towards the adrenergic receptor. Additionally, for selected agents, the Structure–Activity–Relationship (SAR) is also discussed. Thus, this study may help the readers to better understand the nature of the phenoxy group, which will translate into rational drug design and the development of a more efficient drug. To the best of our knowledge, this is the first review devoted to an in-depth analysis of the various activities of compounds bearing terminal phenoxy moiety.
Comprehensive Collection and Prediction of ABC Transmembrane Protein Structures in the AI Era of Structural Biology
Authors: Tordai Hedvig , Suhajda Erzsebet , Sillitoe Ian , Nair Sreenath , Varadi Mihaly , Hegedus Tamas
Published: August 2022

The number of unique transmembrane (TM) protein structures doubled in the last four years, which can be attributed to the revolution of cryo-electron microscopy. In addition, AlphaFold2 (AF2) also provided a large number of predicted structures with high quality. However, if a specific protein family is the subject of a study, collecting the structures of the family members is highly challenging in spite of existing general and protein domain-specific databases. Here, we demonstrate this and assess the applicability and usability of automatic collection and presentation of protein structures via the ABC protein superfamily. Our pipeline identifies and classifies transmembrane ABC protein structures using the PFAM search and also aims to determine their conformational states based on special geometric measures, conftors. Since the AlphaFold database contains structure predictions only for single polypeptide chains, we performed AF2-Multimer predictions for human ABC half transporters functioning as dimers. Our AF2 predictions warn of possibly ambiguous interpretation of some biochemical data regarding interaction partners and call for further experiments and experimental structure determination. We made our predicted ABC protein structures available through a web application, and we joined the 3D-Beacons Network to reach the broader scientific community through platforms such as PDBe-KB.
Rationale and Clinical Research Progress on PD-1/PD-L1-Based Immunotherapy for Metastatic Triple-Negative Breast Cancer
Authors: Ren Yifan , Song Jialong , Li Xinyi , Luo Na
Published: August 2022

Metastatic triple-negative breast cancer (mTNBC), a highly aggressive and malignant tumor, currently lacks an effective treatment. There has been some progress in the treatment of mTNBC with programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) immunotherapy in recent years. The combination of PD-1/PD-L1 inhibitors with other therapies is a noteworthy treatment strategy. Immunotherapy in combination with chemotherapy or small-molecule inhibitors still faces many challenges. Additionally, there are some new immunotherapy targets in development. We aimed to further evaluate the effectiveness and usefulness of immunotherapy for treating mTNBC and to propose new immunotherapy strategies. This review explains the rationale and results of existing clinical trials evaluating PD-1/PD-L1 inhibitors alone or in combination for the treatment of mTNBC. For patients with aggressive tumors and poor health, PD-1/PD-L1 inhibitors, either alone or in combination with other modalities, have proven to be effective. However, more research is needed to explore more effective immunotherapy regimens that will lead to new breakthroughs in the treatment of mTNBC.
Analysis of the Chemical Composition and Morphological Characterization of Tissue Osseointegrated to a Dental Implant after 5 Years of Function
Authors: Apablaza Josefa Alarcón , Días Fernando José , Sánchez Karina Godoy , Navarro Pablo , Venegas Camila , Fuentes Ramón
Published: August 2022

Osseointegration implies the coexistence of a biocompatible implant subjected to masticatory loads and living bone tissue adhered to its surface; this interaction is a critical process for the success of implants. The objective of this work is to analyze the osseoformation and osseointegration of a dental implant in operation for 5 years microscopically through morphological analysis of the surface and chemical composition through a variable pressure scanning electron microscope (VP-SEM) and energy dispersive X-ray spectrometry (EDX). The chemical composition and general characteristics of the structural morphology of random areas of the surfaces of an osseointegrated dental implant from an ex vivo sample were analyzed. On the surface of the implant free of bone tissue, titanium (TI) was mainly identified in the area of the implant threads and carbon (C) in the depth of the implant threads. Phosphorus (P), calcium (Ca), oxygen (O), carbon (C), with dense and homogeneous distribution, and, to a lesser extent, sodium (Na) were detected on the bone surface around the contour of the implant. Regarding the morphological characteristics of the implant surface, a rough structure with some irregularities and detachments of the implant lodged in the bone tissue was observed. Microscopic analysis showed calcified bone tissue distributed in an orderly manner on the coronal and medial surface and sinuous and irregular in the apical area, with the presence of red blood cells. The composition of the implant allows a dynamic process of bone remodeling and regeneration subject to the biological and mechanical needs of the operation. Dental implants are shown to have exceptional and long-lasting biocompatibility that enables the formation of mature peri-implant bone tissue.
A Systematic Review of the Effects of High-Fat Diet Exposure on Oocyte and Follicular Quality: A Molecular Point of View
Authors: Gonnella Francesca , Konstantinidou Fani , Di Berardino Chiara , Capacchietti Giulia , Peserico Alessia , Russo Valentina , Barboni Barbara , Stuppia Liborio , Gatta Valentina
Published: August 2022

Worldwide, infertility affects between 10 and 15% of reproductive-aged couples. Female infertility represents an increasing health issue, principally in developing countries, as the current inclinations of delaying pregnancy beyond 35 years of age significantly decrease fertility rates. Female infertility, commonly imputable to ovulation disorders, can be influenced by several factors, including congenital malformations, hormonal dysfunction, and individual lifestyle choices, such as smoking cigarettes, stress, drug use and physical activity. Moreover, diet-related elements play an important role in the regulation of ovulation. Modern types of diet that encourage a high fat intake exert a particularly negative effect on ovulation, affecting the safety of gametes and the implantation of a healthy embryo. Identifying and understanding the cellular and molecular mechanisms responsible for diet-associated infertility might help clarify the confounding multifaceted elements of infertility and uncover novel, potentially curative treatments. In this view, this systematic revision of literature will summarize the current body of knowledge of the potential effect of high-fat diet (HFD) exposure on oocyte and follicular quality and consequent female reproductive function, with particular reference to molecular mechanisms and pathways. Inflammation, oxidative stress, gene expression and epigenetics represent the main mechanisms associated with mammal folliculogenesis and oogenesis.
Prevalence of Plasmid-Mediated Quinolone Resistance (PMQRs) Determinants and Whole Genome Sequence Screening of PMQR-Producing E. coli Isolated from Men Undergoing a Transrectal Prostate Biopsy
Authors: Piekarska Katarzyna , Zacharczuk Katarzyna , Wołkowicz Tomasz , Gierczyński Rafał
Published: August 2022

Fluoroquinolones (FQs) are recommended as prophylaxis for men undergoing transrectal prostate biopsy (TRUS-Bx). Recent studies suggest a significant share of FQ-resistant rectal flora in post-TRUST-Bx infections. Methods: 435 Enterobacterales isolates from 621 patients attending 12 urological departments in Poland were screened by PCR for PMQR genes. PMQR-positive isolates were tested for quinolone susceptibility and investigated by whole genome sequencing (WGS) methods. Results: In total, 32 (7.35%) E. coli strains with ciprofloxacin MIC in the range 0.125–32 mg/L harbored at least one PMQR gene. qnrS and qnrB were the most frequent genes detected in 16 and 12 isolates, respectively. WGS was performed for 28 of 32 PMQR-producing strains. A variety of serotypes and sequence types (STs) of E. coli was noticed. All strains carried at least one virulence gene. AMR genes that encoded resistance against different classes of antibiotics were identified. Additionally, five of 13 ciprofloxacin-susceptible E. coli had alterations in codon 83 of the GyrA subunits. Conclusion: This study provides information on the common presence of PMQRs among E. coli, which may explain the cause for development of post-TRUS-Bx infections. High numbers of virulence and antimicrobial resistance genes detected show a potential for analysed strains to develop infections.
Effects of the Rhizosphere Fungus Cunninghamella bertholletiae on the Solanum lycopersicum Response to Diverse Abiotic Stresses
Authors: Kazerooni Elham Ahmed , Maharachchikumbura Sajeewa S. N. , Al-Sadi Abdullah Mohammed , Rashid Umer , Kim Il-Doo , Kang Sang-Mo , Lee In-Jung
Published: August 2022

This study examined the efficiency of fungal strain (Cunninghamella bertholletiae) isolated from the rhizosphere of Solanum lycopersicum to reduce symptoms of salinity, drought and heavy metal stresses in tomato plants. In vitro evaluation of C. bertholletiae demonstrated its ability to produce indole-3-Acetic Acid (IAA), ammonia and tolerate varied abiotic stresses on solid media. Tomato plants at 33 days’ old, inoculated with or without C. bertholletiae, were treated with 1.5% sodium chloride, 25% polyethylene glycol, 3 mM cadmium and 3 mM lead for 10 days, and the impact of C. bertholletiae on plant performance was investigated. Inoculation with C. bertholletiae enhanced plant biomass and growth attributes in stressed plants. In addition, C. bertholletiae modulated the physiochemical apparatus of stressed plants by raising chlorophyll, carotenoid, glucose, fructose, and sucrose contents, and reducing hydrogen peroxide, protein, lipid metabolism, amino acid, antioxidant activities, and abscisic acid. Gene expression analysis showed enhanced expression of SlCDF3 and SlICS genes and reduced expression of SlACCase, SlAOS, SlGRAS6, SlRBOHD, SlRING1, SlTAF1, and SlZH13 genes following C. bertholletiae application. In conclusion, our study supports the potential of C. bertholletiae as a biofertilizer to reduce plant damage, improve crop endurance and remediation under stress conditions.
Type 2 Diabetes Induces a Pro-Oxidative Environment in Rat Epididymis by Disrupting SIRT1/PGC-1α/SIRT3 Pathway
Authors: Diniz Antónia , Alves Marco G. , Candeias Emanuel , Duarte Ana I. , Moreira Paula I. , Silva Branca M. , Oliveira Pedro F. , Rato Luís
Published: August 2022

Diabetes mellitus type 2 (T2DM) has been associated with alterations in the male reproductive tract, especially in the epididymis. Although it is known that T2DM alters epididymal physiology, disturbing mitochondrial function and favoring oxidative stress, the mechanisms remain unknown. Sirtuin 1 (SIRT1), peroxisome proliferators-activated receptor γ coactivator 1α (PGC-1α), and sirtuin 3 (SIRT3) are key regulators of mitochondrial function and inducers of antioxidant defenses. In this study, we hypothesized that the epididymal SIRT1/PGC-1α/SIRT3 axis mediates T2DM-induced epididymis dysfunction by controlling the oxidative profile. Using 7 Goto-Kakizaki (GK) rats (a non-obese model that spontaneously develops T2DM early in life), and 7 age-matched Wistar control rats, we evaluated the protein levels of SIRT1, PGC-1α, and SIRT3, as well as the expression of mitochondrial respiratory complexes. The activities of epididymal glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT) were determined, as well as the epididymal antioxidant capacity. We also evaluated protein nitration, carbonylation, and lipid peroxidation in the epididymis. The T2DM rats presented with hyperglycemia and glucose intolerance. Epididymal levels of SIRT1, PGC-1α, and SIRT3 were decreased, as well as the expression of the mitochondrial complexes II, III, and V, in the T2DM rats. We found a significant decrease in the activities of SOD, CAT, and GPx, consistent with the lower antioxidant capacity and higher protein nitration and lipid peroxidation detected in the epididymis of the T2DM rats. In sum, T2DM disrupted the epididymal SIRT1/PGC-1α/SIRT3 pathway, which is associated with a compromised mitochondrial function. This resulted in a decline of the antioxidant defenses and an increased oxidative damage in that tissue, which may be responsible for the impaired male reproductive function observed in diabetic men.
Tomato Root Colonization by Exogenously Inoculated Arbuscular Mycorrhizal Fungi Induces Resistance against Root-Knot Nematodes in a Dose-Dependent Manner
Authors: Molinari Sergio , Akbarimotlagh Masoud , Leonetti Paola
Published: August 2022

Arbuscular mycorrhizal fungi (AMF) are generally recognized to induce plant growth and prime plants against soil-borne parasites, such as plant parasitic nematodes. However, the effectiveness of commercial formulates containing AMF has been questioned. Increasing amounts per plant of one commercial AMF-containing formulate, reported in the text as Myco, were used to detect the effects on growth of tomato plants and the resistance induced against root-knot nematodes (RKNs) The doses used per plant (0.5, 1.0, 2.0 g, reported as Myco1, Myco2, Myco3, respectively) were soil-drenched to growing potted plants; the effects of such treatments were analyzed both in plants not inoculated or inoculated by Meloidogyne incognita juveniles. Consistent increases in plant weight were apparent as soon as 7 days only after Myco2 treatments. Moreover, only treatments with Myco2 induced a consistent repression of the nematode infection observed in untreated plants. Conversely, treatments with Myco1 and Myco3 did not produce such an early growth improvement; some plant weight increase was observable only at 28 dpt. Accordingly, such Myco doses did not restrict the level of infestation observed in untreated plants. Control of infection was dependent on the dose of Myco provided to plants five days before nematode inoculation. About one month after all Myco treatments, several areas of roots were found to be colonized by AMF, although in Myco2-treated plants, three genes involved in the AMF colonization process (SlCCaMK, SlLYK9, and SlLYK13) were found to be over-expressed already at 7 dpt; over-expression was generally less consistent at 14 and 21 dpt. The expressions of two key genes of plant defense, the hypersensitive cell death inducer PR4b gene and the glutathione peroxidase-encoding GPX gene, were monitored in roots of Myco2-treated plants 3 and 7 days after nematode inoculation. PR4b was over-expressed and GPX was silenced in treated plants with respect to untreated plants. The repressive effect of Myco2 treatment against RKN infection was completely abolished when Myco2 suspensions were autoclaved to sterilization or treated with the potent anti-fungal agent amphotericin B, thus indicating that the biological control agents contained in the commercial formulate were living fungi.