METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation.

The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (m7G) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of m7G-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of m7G-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA "translatome" to increase expression of growth-promoting proteins and represents a promising anti-cancer target.

A Factor-Free Hydrogel with ROS Scavenging and Responsive Degradation for Enhanced Diabetic Bone Healing.

In view of the increased levels of reactive oxygen species (ROS) that disturb the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), the repair of diabetic bone defects remains a great challenge. Herein, a factor-free hydrogel is reported with ROS scavenging and responsive degradation properties for enhanced diabetic bone healing. These hydrogels contain ROS-cleavable thioketal (TK) linkers and ultraviolet (UV)-responsive norbornene (NB) groups conjugated with 8-arm PEG macromers, which are formed via UV crosslinking-mediated gelation. Upon reacting with high levels of ROS in the bone defect microenvironment, ROS-cleavable TK linkers are destroyed, allowing the responsive degradation of hydrogels, which promotes the migration of BMSCs. Moreover, ROS levels are reduced through hydrogel-mediated ROS scavenging to reverse BMSC differentiation from adipogenic to osteogenic phenotype. As such, a favorable microenvironment is created after simultaneous ROS scavenging and hydrogel degradation, leading to the effective repair of bone defects in diabetic mouse models, even without the addition of growth factors. Thus, this study presents a responsive hydrogel platform that regulates ROS scavenging and stromal degradation in bone engineering.

Reinstatement of the fission yeast species Schizosaccharomyces versatilis Wickerham et Duprat, a sibling species of Schizosaccharomyces japonicus.

Schizosaccharomyces japonicus Yukawa et Maki (1931) and Schizosaccharomyces versatilis Wickerham et Duprat (1945) have been treated as varieties of S. japonicus or as conspecific, based on various approaches including mating trials and nDNA/nDNA optical reassociation studies. However, the type strains of S. japonicus and S. versatilis differ by five substitutions (99.15% identity) and one 1-bp indel in the sequences of the D1/D2 domain of the 26S rRNA gene, and 23 substitutions (96.3% identity) and 31-bp indels in the sequences of internal transcribed spacer (ITS) of rRNA, suggesting that they may not be conspecific. To reassess their taxonomic status, we conducted mating trials and whole-genome analyses. Mating trials using the type strains showed a strong but incomplete prezygotic sterility barrier, yielding interspecies mating products at two orders of magnitude lower efficiency than intraspecies matings. These mating products, which were exclusively allodiploid hybrids, were unable to undergo the haplontic life cycle of the parents. We generated chromosome-level gap-less genome assemblies for both type strains. Whole genome sequences yielded an average nucleotide identity (ANI) of 86.4%, indicating clear separation of S. japonicus and S. versatilis. Based on these findings, we propose the reinstatement of S. versatilis as a distinct species (holotype strain: CBS 103T and ex-types: NRRL Y-1026, NBRC 1607, ATCC 9987, PYCC 7100; Mycobank no.: 847838).

Inhibition of GBP5 activates autophagy to alleviate inflammatory response in LPS-induced lung injury in mice.

BACKGROUND: Pulmonary emphysema is a condition that causes damage to the lung tissue over time. GBP5, as part of the guanylate-binding protein family, is dysregulated in mouse pulmonary emphysema. However, the role of GBP5 in lung inflammation in ARDS remains unveiled. METHODS: To investigate whether GBP5 regulates lung inflammation and autophagy regulation, the study employed a mouse ARDS model and MLE-12 cell culture. Vector transfection was performed for the genetic manipulation of GBP5. Then, RT-qPCR, WB and IHC staining were conducted to assess its transcriptional and expression levels. Histological features of the lung tissue were observed through HE staining. Moreover, ELISA was conducted to evaluate the secretion of inflammatory cytokines, autophagy was assessed by immunofluorescent staining, and MPO activity was determined using a commercial kit. RESULTS: Our study revealed that GBP5 expression was altered in mouse ARDS and LPS-induced MLE-12 cell models. Moreover, the suppression of GBP5 reduced lung inflammation induced by LPS in mice. Conversely, overexpression of GBP5 diminished the inhibitory impact of LPS on ARDS during autophagy, leading to increased inflammation. In the cell line of MLE-12, GBP5 exacerbates LPS-induced inflammation by blocking autophagy. CONCLUSION: The study suggests that GBP5 facilitates lung inflammation and autophagy regulation. Thus, GBP5 could be a potential therapeutic approach for improving ARDS treatment outcomes, but further research is required to validate these findings.

mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.

N6-methyladenosine (m6A) modification of mRNA is emerging as an important regulator of gene expression that affects different developmental and biological processes, and altered m6A homeostasis is linked to cancer1-5. m6A modification is catalysed by METTL3 and enriched in the 3' untranslated region of a large subset of mRNAs at sites close to the stop codon5. METTL3 can promote translation but the mechanism and relevance of this process remain unknown1. Here we show that METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop codon, supporting a mechanism of mRNA looping for ribosome recycling and translational control. Electron microscopy reveals the topology of individual polyribosomes with single METTL3 foci in close proximity to 5' cap-binding proteins. We identify a direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit h (eIF3h). METTL3 promotes translation of a large subset of oncogenic mRNAs-including bromodomain-containing protein 4-that is also m6A-modified in human primary lung tumours. The METTL3-eIF3h interaction is required for enhanced translation, formation of densely packed polyribosomes and oncogenic transformation. METTL3 depletion inhibits tumorigenicity and sensitizes lung cancer cells to BRD4 inhibition. These findings uncover a mechanism of translation control that is based on mRNA looping and identify METTL3-eIF3h as a potential therapeutic target for patients with cancer.

Primary care providers' preferences for pay-for-performance programs: a discrete choice experiment study in Shandong China.

BACKGROUND: Pay-for-performance (P4P) schemes are commonly used to incentivize primary healthcare (PHC) providers to improve the quality of care they deliver. However, the effectiveness of P4P schemes can vary depending on their design. In this study, we aimed to investigate the preferences of PHC providers for participating in P4P programs in a city in Shandong province, China. METHOD: We conducted a discrete choice experiment (DCE) with 882 PHC providers, using six attributes: type of incentive, whom to incentivize, frequency of incentive, size of incentive, the domain of performance measurement, and release of performance results. Mixed logit models and latent class models were used for the statistical analyses. RESULTS: Our results showed that PHC providers had a strong negative preference for fines compared to bonuses (- 1.91; 95%CI - 2.13 to - 1.69) and for annual incentive payments compared to monthly (- 1.37; 95%CI - 1.59 to - 1.14). Providers also showed negative preferences for incentive size of 60% of monthly income, group incentives, and non-release of performance results. On the other hand, an incentive size of 20% of monthly income and including quality of care in performance measures were preferred. We identified four distinct classes of providers with different preferences for P4P schemes. Class 2 and Class 3 valued most of the attributes differently, while Class 1 and Class 4 had a relatively small influence from most attributes. CONCLUSION: P4P schemes that offer bonuses rather than fines, monthly rather than annual payments, incentive size of 20% of monthly income, paid to individuals, including quality of care in performance measures, and release of performance results are likely to be more effective in improving PHC performance. Our findings also highlight the importance of considering preference heterogeneity when designing P4P schemes.

Comparative analysis of the organelle genomes of three Rhodiola species provide insights into their structural dynamics and sequence divergences.

BACKGROUND: Plant organelle genomes are a valuable resource for evolutionary biology research, yet their genome architectures, evolutionary patterns and environmental adaptations are poorly understood in many lineages. Rhodiola species is a type of flora mainly distributed in highland habitats, with high medicinal value. Here, we assembled the organelle genomes of three Rhodiola species (R. wallichiana, R. crenulata and R. sacra) collected from the Qinghai-Tibet plateau (QTP), and compared their genome structure, gene content, structural rearrangements, sequence transfer and sequence evolution rates. RESULTS: The results demonstrated the contrasting evolutionary pattern between plastomes and mitogenomes in three Rhodiola species, with the former possessing more conserved genome structure but faster evolutionary rates of sequence, while the latter exhibiting structural diversity but slower rates of sequence evolution. Some lineage-specific features were observed in Rhodiola mitogenomes, including chromosome fission, gene loss and structural rearrangement. Repeat element analysis shows that the repeats occurring between the two chromosomes may mediate the formation of multichromosomal structure in the mitogenomes of Rhodiola, and this multichromosomal structure may have recently formed. The identification of homologous sequences between plastomes and mitogenomes reveals several unidirectional protein-coding gene transfer events from chloroplasts to mitochondria. Moreover, we found that their organelle genomes contained multiple fragments of nuclear transposable elements (TEs) and exhibited different preferences for TEs insertion type. Genome-wide scans of positive selection identified one gene matR from the mitogenome. Since the matR is crucial for plant growth and development, as well as for respiration and stress responses, our findings suggest that matR may participate in the adaptive response of Rhodiola species to environmental stress of QTP. CONCLUSION: The study analyzed the organelle genomes of three Rhodiola species and demonstrated the contrasting evolutionary pattern between plastomes and mitogenomes. Signals of positive selection were detected in the matR gene of Rhodiola mitogenomes, suggesting the potential role of this gene in Rhodiola adaptation to QTP. Together, the study is expected to enrich the genomic resources and provide valuable insights into the structural dynamics and sequence divergences of Rhodiola species.

In silico model for miRNA-mediated regulatory network in cancer.

Deregulation of gene expression is associated with the pathogenesis of numerous human diseases including cancer. Current data analyses on gene expression are mostly focused on differential gene/transcript expression in big data-driven studies. However, a poor connection to the proteome changes is a widespread problem in current data analyses. This is partly due to the complexity of gene regulatory pathways at the post-transcriptional level. In this study, we overcome these limitations and introduce a graph-based learning model, PTNet, which simulates the microRNAs (miRNAs) that regulate gene expression post-transcriptionally in silico. Our model does not require large-scale proteomics studies to measure the protein expression and can successfully predict the protein levels by considering the miRNA-mRNA interaction network, the mRNA expression, and the miRNA expression. Large-scale experiments on simulations and real cancer high-throughput datasets using PTNet validated that (i) the miRNA-mediated interaction network affects the abundance of corresponding proteins and (ii) the predicted protein expression has a higher correlation with the proteomics data (ground-truth) than the mRNA expression data. The classification performance also shows that the predicted protein expression has an improved prediction power on cancer outcomes compared to the prediction done by the mRNA expression data only or considering both mRNA and miRNA. Availability: PTNet toolbox is available at http://github.com/CompbioLabUCF/PTNet.

qGL3/OsPPKL1 induces phosphorylation of 14-3-3 protein OsGF14b to inhibit OsBZR1 function in brassinosteroid signaling.

Brassinosteroids (BRs) play essential roles in regulating plant growth and development, however, gaps still remain in our understanding of the BR signaling network. We previously cloned a grain length quantitative trait locus qGL3, encoding a rice (Oryza sativa L.) protein phosphatase with Kelch-like repeat domain (OsPPKL1), that negatively regulates grain length and BR signaling. To further explore the BR signaling network, we performed phosphoproteomic analysis to screen qGL3-regulated downstream components. We selected a 14-3-3 protein OsGF14b from the phosphoproteomic data for further analysis. qGL3 promoted the phosphorylation of OsGF14b and induced the interaction intensity between OsGF14b and OsBZR1. In addition, phosphorylation of OsGF14b played an important role in regulating nucleocytoplasmic shuttling of OsBZR1. The serine acids (Ser258Ser259) residues of OsGF14b play an essential role in BR-mediated responses and plant development. Genetic and molecular analyses indicated that OsGF14b functions as a negative regulator in BR signaling and represses the transcriptional activation activity of OsBZR1. Collectively, these results demonstrate that qGL3 induces the phosphorylation of OsGF14b, which modulates nucleocytoplasmic shuttling and transcriptional activation activity of OsBZR1, to eventually negatively regulate BR signaling and grain length in rice.

Population transcriptomics uncover the relative roles of positive selection and differential expression in Batrachium bungei adaptation to the Qinghai-Tibetan plateau.

KEY MESSAGE: Positive selection genes are related to metabolism, while differentially expressed genes are related to photosynthesis, suggesting that genetic adaptation and expression regulation may play independent roles in different gene classes. Genome-wide investigation of the molecular mechanisms for high-altitude adaptation is an intriguing topic in evolutionary biology. The Qinghai-Tibet Plateau (QTP) with its extremely variable environments is an ideal site for studying high-altitude adaptation. Here, we used transcriptome data of 100 individuals from 20 populations collected from various altitudes on the QTP to investigate the adaptive mechanisms of the aquatic plant Batrachium bungei at both the genetic and transcriptional level. To explore genes and biological pathways that may contribute to QTP adaptation, we employed a two-step approach, in which we identified positively selected genes and differentially expressed genes using the landscape genomic and differential expression approaches. The positive selection analysis showed that genes involved in metabolic regulation played a crucial role in B. bungei adaptation to the extreme environments of the QTP, especially intense ultraviolet radiation. Altitude-based differential expression analysis suggested that B. bungei could increase the rate of energy dissipation or reduce the efficiency of light energy absorption by down regulating the expression of photosynthesis-related genes to adapt to the strong ultraviolet radiation. Weighted gene co-expression network analysis identified ribosomal genes as hubs of altitude adaptation in B. bungei. Only a small part of genes (about 10%) overlapped between positively selected genes and differentially expressed genes in B. bungei, suggesting that genetic adaptation and gene expression regulation might play relatively independent roles in different categories of functional genes. Taken together, this study enriches our understanding of the high-altitude adaptation mechanism of B. bungei on the QTP.

Cell unit-inspired natural nano-based biomaterials as versatile building blocks for bone/cartilage regeneration.

The regeneration of weight-bearing bone defects and critical-sized cartilage defects remains a significant challenge. A wide range of nano-biomaterials are available for the treatment of bone/cartilage defects. However, their poor compatibility and biodegradability pose challenges to the practical applications of these nano-based biomaterials. Natural biomaterials inspired by the cell units (e.g., nucleic acids and proteins), have gained increasing attention in recent decades due to their versatile functionality, compatibility, biodegradability, and great potential for modification, combination, and hybridization. In the field of bone/cartilage regeneration, natural nano-based biomaterials have presented an unparalleled role in providing optimal cues and microenvironments for cell growth and differentiation. In this review, we systematically summarize the versatile building blocks inspired by the cell unit used as natural nano-based biomaterials in bone/cartilage regeneration, including nucleic acids, proteins, carbohydrates, lipids, and membranes. In addition, the opportunities and challenges of natural nano-based biomaterials for the future use of bone/cartilage regeneration are discussed.

Interleukin-21 knockout reduces bone loss in ovariectomized mice by inhibiting osteoclastogenesis.

Estrogen deficiency accelerates osteoporosis in elderly women. However, the role of IL-21 in postmenopausal osteoporosis remains unclear. Female wild-type (WT) C57BL/6 and IL-21 knockout (KO) mice were used for ovariectomy (OVX). Here, IL-21 levels were significantly increased in the serum and bone tissues of WT-OVX mice. The trabecular bone space of the femur was significantly increased, and the bone mass was reduced in OVX mice, accompanied by a significant decrease in the maximum load, energy absorption, and elastic modulus indices. In contrast, IL-21 knockout effectively alleviated the effects of OVX on bone mass. Serum TRACP-5b and receptor activator of nuclear factor kappa B ligand (RANKL) levels and osteoclastogenesis were significantly higher in OVX mice than in sham mice, while serum TRACP-5b and RANKL levels and osteoclastogenesis were significantly decreased in IL-21 KO + OVX mice compared to WT + OVX mice. IL-21 knockdown reduces TRACP-5b, RANKL, and osteoclastogenesis, effectively preventing bone resorption and alleviating the progression of OVX-induced osteoporosis.

Serum concentrations of neonicotinoids and their characteristic metabolites in elderly population from South China: Association with osteoporosis.

Neonicotinoids (NEOs) are extensively applied in global agricultural production for pest control but have adverse effects on human health. In this study, the concentrations of six NEOs and three characteristic metabolites were investigated by collecting 200 serum samples from an elderly population in China. Results showed that the NEOs and their metabolites were widely detected (89%-98 %) in the serum samples from the osteoporosis (OP) (n = 120) and non-OP (n = 80) population, and their median concentrations ranged from 0.04 ng/mL to 5.99 ng/mL and 0.01 ng/mL to 2.02 ng/mL, respectively. N-desmethyl-acetamiprid (ACE-dm) was the most abundant NEOs in the serum samples. Gender-related differences were found in concentrations of most NEOs and their metabolites in serum, with males having higher target analytes than females. Significantly (p < 0.05) positive correlations were observed among most NEO concentrations, suggesting that exposure source of these substances is common or related. However, associations between the concentrations of characteristic metabolites and their corresponding NEOs were insignificant, probably because the exogenous intake are the primary sources of metabolites of NEOs instead of the internal biotransformation. The associations between NEO concentrations (i.e., ACE-dm, dinotefuran, and olefin-imidacloprid) and OP (OR = 2.33-6.92, 95 % CI = 0.37-16.9, p-trend < 0.05) indicate that NEO exposure is correlated with increased odds of prevalent OP. This study is the first to document the profiles of NEOs and their metabolites in serum samples collected from an elderly population in South China and examine the relationships between NEO exposure and OP.

A Docking Mechanism Based on a Stewart Platform and Its Tracking Control Based on Information Fusion Algorithm.

Aiming at the problem of unmanned reconfiguration and docking of ground vehicles under complex working conditions, we designed a piece of docking equipment composed of an active mechanism based on a six-degree-of-freedom platform and a locking mechanism with multi-sensors. Through the proposed control method based on laser and image sensor information fusion calculation, the six-dimensional posture information of the mechanism during the docking process is captured in real time so as to achieve high-precision docking. Finally, the effectiveness of the method and the feasibility of the 6-DOF platform are verified by the established model. The results show that the mechanism can meet the requirements of smooth docking of ground unmanned vehicles.

Recruitment of γδ T cells to the lesion via the CCL2/CCR2 signaling after spinal cord injury.

BACKGROUND: Immune cell infiltration and neuroinflammation are heavily associated with spinal cord injury (SCI). C-C motif chemokine ligand 2/C-C chemokine receptor type 2 (CCL2/CCR2) axis has been identified as a critical role player during the invasion of immune cells to lesions in many diseases. γδ T cells, a subgroup of T cells, manage the course of inflammation response in various diseases; however, it remains unknown whether γδ T cells are recruited to injury site through CCL2/CCR2 signaling and exert the regulation effect on neuroinflammation after SCI. METHODS: Basso Mouse Scale (BMS), regularity index, cadence, max contact area, and motor-evoked potential testing (MEP) were measured to determine the neurological function recovery after spinal cord injury. Nissl staining was performed to identify the number of surviving motor neurons at lesion epicenter. Immunofluorescence, Western blot, enzyme-linked immunosorbent assays (ELISA), and quantitative real-time polymerase chain reaction (QRT-PCR) also were employed to evaluate the expression of associated proteins and genes. RESULTS: In this study, we demonstrated that TCRδ-/- mice present improved neurological recovery after SCI. γδ T cell recruitment to the SCI site was significantly reduced and motor functional improvement enhanced in CCL2-/- and CCR2-/- mouse strains. Furthermore, reconstitution of TCRδ-/- mice with γδ T cells extracted from CCR2-/- mice also showed similar results to CCL2 and CCR2 deficient mice. CONCLUSIONS: In conclusion, γδ T cell recruitment to SCI site promotes inflammatory response and exacerbates neurological impairment. CCL2/CCR2 signaling is a vital recruitment mechanism of γδ T cells to the SCI site, and it may be taken as a novel therapeutic target for future SCI.

Drug-Coated Balloon-Only Angioplasty Outcomes in Diabetic and Nondiabetic Patients with De Novo Small Coronary Vessels Disease.

BACKGROUND: The revascularization of small vessels using drug-eluting stents remains challenging. The use of the drug-coated balloon is an attractive therapeutic strategy in de novo lesions in small coronary vessels, particularly in the diabetic group. This study aimed to assess the outcomes of DCB-only angioplasty in small vessel disease. METHODS: A total of 1198 patients with small vessel disease treated with DCB-only strategy were followed. Patients were divided into the diabetic and nondiabetic groups. Clinical and angiographical follow-up were organized at 12 months. The primary endpoints were target lesion failure and secondary major adverse cardiac events. RESULTS: There was a significantly higher rate of target lesion failure among diabetic patients compared to nondiabetic [17 (3.9%) vs. 11 (1.4%), P=0.006], taken separately, the rate of target lesion revascularization significantly differed between groups with a higher rate observed in the diabetic group [9 (2%) vs. 4 (0.5%), P=0.014]. Diabetes mellitus remained an independent predictor for TLF (HR: 2.712, CI: 1.254-5.864, P=0.011) and target lesion revascularization (HR: 3.698, CI: 1.112-12.298, P=0.033) after adjustment. However, no significant differences were observed between groups regarding the target vessel myocardial infarction (0.6% vs. 0.1%, P=0.110) and MACE [19 (4.4%) vs. 21 (2.7%), P=0.120]. CONCLUSION: Drug-coated balloon-only treatment achieved lower incidence rates of TLF and MACE. Diabetes is an independent predictor for target lesion failure and target lesion revascularization at one year following DCB treatment in small coronary vessels. We observed no significant differences between groups regarding MACE in one year.

Superior emotional regulating effects of creative cognitive reappraisal.

Although the effects of cognitive reappraisal in regulating negative emotion are generally well documented, its regulatory effects are usually not very strong because the ordinary reappraisals employed in previous studies were insufficient to overcome the mental set or response bias toward negative situations. In this study, we developed a new strategy employing creative reappraisals that provides an insightful reinterpretation of the negative stimulus. We believe this approach, through adopting a guided (creative) reappraisal rather than self-generation strategy, will greatly improve the emotion regulation effect of reappraisal through activating the neural networks representing the process of deep and structural mental representational change accompanied by the feeling of positive emotion and mental reward. The behavioral results suggested that 1) regarding the transient regulatory effect, creative reappraisal resulted in a positive rating for standardized negative pictures; 2) creative reappraisal had a long-lasting effect in reducing negative affect. In parallel with these behavioral results, the imaging data indicated that 1) creative reappraisal was specifically associated with greater engagement of the amygdala and hippocampus as well as regions in the ventral striatum, and 2) the engagement of the amygdala predicted the transient regulatory effect of creative reappraisal, while the involvement of the hippocampus and the ventral striatum predicted long-term regulatory effects. These findings suggest that the superior regulatory effect of creative reappraisal could be mediated by amygdala-based salient emotional arousal, hippocampus-based new association formation, and striatum-based mental rewarding to lead to a novel and positive experience that could be kept in long-term memory. This research indicates the key role of creative insight in reappraisal and presents a novel and highly efficient reappraisal strategy.

Hippocampus and amygdala: An insight-related network involved in metaphorical solution to mental distress problem.

This study was designed to determine whether metaphorical solutions to mental distress problems result in an insightful mental experience and activate the hippocampus and amygdala: areas associated with insight. We recruited 22 healthy university students. Trials presented 75 micro-counseling scenarios while event-related functional magnetic resonance imaging (fMRI) was applied to detect neural responses. Each scenario included a mental distress problem and one of the following solution types: metaphorical, literal, or problem-restatement. The results revealed that, compared with literal solutions or problem-restatement solutions, metaphorical solutions activated two neural networks: one associated with basic metaphorical language processing (i.e., the left inferior frontal gyrus and middle and superior temporal gyri), and a specific network associated with insightful problem solving (i.e., the bilateral hippocampus, amygdala, and fusiform gyrus). Our findings indicate that the use of metaphorical solutions to mental distress problems reliably produces salient neural activities for insight.

MiR-128/SOX7 alleviates myocardial ischemia injury by regulating IL-33/sST2 in acute myocardial infarction.

Acute myocardial infarction (AMI) induced by ischemia hypoxia severely threatens human life. Cell apoptosis of neurocytes was identified to mediate the pathogenesis, while the potential mechanism was still unclear. Sprague Dawley (SD) rats were used to establish the AMI rat model. Real-time polymerase chain reaction (PCR) and Western blot were performed to detect gene expression in mRNA and protein levels, respectively. A TUNEL assay was carried out to determine cell apoptosis. The relationship between SRY-related HMG-box (SOX7) and miR-128 was verified using luciferase reporter assay. The expression of SOX7 was decreased, while miR-128 was increased in AMI rats and ischemia hypoxia (IH) induced H9c2 cells. Hypoxia induction significantly promoted the expression of interleukin (IL)-33 and soluble ST2 (sST2), and also promoted cell apoptosis. MiR-128 targets SOX7 to regulate its expression. Down-regulated miR-128 reversed the effects of IH on expression of SOX7, sST2 and cell apoptosis, while down-regulated sST2 abolished the effects of miR-128 inhibitor. In addition, overexpressed IL-33 abolished the effects of miR-128 inhibitor that induced by IH on the expression of SOX7 and cell apoptosis. In vivo experiments validated the expression of miR-128 on cell apoptosis. The present study indicated that miR-128 modulated cell apoptosis by targeting SOX7, which was mediated by IL-33/sST2 signaling pathway.

Activated Circulating Myeloid-Derived Suppressor Cells in Patients with Dilated Cardiomyopathy.

BACKGROUND/AIMS: Myeloid-derived suppressor cells (MDSCs) are increased in inflammatory and autoimmune disorders. This study aims to evaluate the significance of MDSCs in dilated cardiomyopathy (DCM) patients. METHODS: In total, 42 newly hospitalized DCM patients and 39 healthy controls were enrolled in the study. The frequencies of circulating CD14+HLA-DR-/low MDSCs were determined by flow cytometry. Then, the functional properties of MDSCs in suppressing T cell proliferation and interferon-gamma (IFN-x03B3;) production were measured in a co-culture model. Then, mRNA expression levels of various important molecules in peripheral blood mononuclear cells were measured by real time polymerase chain reaction. Furthermore, correlation analyses between MDSC frequencies and cardiac function parameters were also performed. RESULTS: The frequencies of circulating CD14+HLA-DR-/low MDSCs were significantly elevated in DCM patients compared with healthy controls. It showed that MDSCs from DCM patients more effectively suppressed T cell proliferation and IFN-x03B3; production compared with those from healthy controls, which was partially mediated by arginase-1 (Arg-1). In addition, the correlation analysis suggested that MDSC frequencies were negatively correlated with left ventricular ejection fraction (LVEF), while positively with N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with DCM. CONCLUSIONS: Circulating activated MDSCs might play significant immunomodulatory roles in the pathogenesis of DCM.