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The heart requires high levels of mitochondria to sustain function, and mitochondrial stressors can be transmitted to the nucleus and reprogram metabolism. Here, the authors show that a mitochondrial ribosomal protein is important for heart development in mice by increasing nuclear Klf15 expression.

Steel slag is the main industrial solid waste generated from the steelmaking process. It can be returned to the steelmaking process for reuse due to its chemical composition and structural properties. For the structure of steel slag components, the combination of high temperature holding and slow cooling operation with magnetic separation can efficiently improve the recovery efficiency of valuable elements from the converter slag. In this study, chemical analysis, X-ray diffraction, and scanning electron microscopy were used to analyze the changes in phase composition and morphology during high-temperature holding and slow cooling. In addition, the reasonable magnetic separation process conditions suitable for converter slag were experimentally studied. The results showed that the RO phase in the slag significantly grew under the conditions of holding at 1500 °C for 90 min, cooling at 1 °C/min to 1100 °C, and holding for 90 min. The high temperature insulation allows the steel slag to be fully melted and uniformly mixed, and the slow cooling process applied to the slag provides enough time to grow for RO phase. The multi-stage wet weak magnetic separation method is suitable for steel slag, with a best magnetic separation intensity of 100 mT in the laboratory range and a single magnetic separation time of 1 min. The steel slag concentrate rate is 30.54% and the T.Fe content is 54.10%. It can replace part of the sintered ore to return to the iron making process. Moreover, the tailings can be used to produce high value-added materials such as subgrade and phosphate fertilizer. Therefore, the current technological route can transform the industrial solid waste into a useable resource and achieve efficient and low consumption recycling of steel slag.

The lipid metabolizing enzyme 12/15 lipoxygenase (12/15LOX) induces proinflammatory responses that may increase cardiovascular and renal complications after cardiac insult. To define the role of 12/15LOX, 8–12-week-old male C57BL/6J wild-type (WT; n = 49) and 12/15LOX−/− mice (n = 50) were subject to transverse aortic constriction (TAC) and monitored for 7, 28, and 56 days (d) post-TAC. Compared with WT, 12/15LOX−/− mice experienced less left ventricle (LV) dysfunction with limited LV hypertrophy and lung edema post-TAC. 12/15LOX deletion decreased TAC-induced proinflammatory mediators 12-HETE and prostaglandins with modulation in mir-7a-5p, mir 26a-5p, miR-21e-5p, and miR-107-3p during chronic remodeling period (after d28). At d7 post-TAC, 12/15LOX−/− mice showed increased cardiac gene expression of Arg-1 and the prostanoid receptors EP2 and EP4. The EP4 receptor expression was consistently elevated from d7 till d56 in 12/15LOX−/− mice post-TAC compared with WT controls. Post-TAC, wheat germ agglutinin staining revealed less cardiomyocyte hypertrophy at d28 and d56 in 12/15LOX−/− mice compared with WT. TAC-induced vascular remodeling was marked by disruption in the endothelium, evident by irregular CD31 staining and increased alpha-smooth muscle actin (α-SMA) in WT mice at d28 and d56. Compared to WT, 12/15LOX−/− mice exhibited a diminished expression of NGAL in the kidney, suggesting that 12/15LOX−/− reduced cardiorenal dysfunction post-TAC. In WT-TAC mice, structural analyses of the kidney revealed glomerular swelling during the maladaptive phase of heart failure, with decreases in the capsula glomeruli space and glomerular sclerosis compared to 12/15LOX−/− mice. Overall, vascular and kidney inflammation markers were higher in WT than in 12/15LOX−/− post-TAC. Thus, deletion of 12/15LOX limits LV hypertrophy associated with perivascular inflammation and cardiorenal remodeling after pressure overload. Deficiency of 12/15 LOX serves a dual role in delaying an early adaptive interstitial remodeling with long-term protective effects on cardiac hypertrophy and cardiac fibrosis and detrimental adverse vascular remodeling during later maladaptive remodeling after pressure overload.

Coral reef ecosystems are one of the most diverse and productive habitats on Earth. Microbes in the reef-overlying waters are key players in maintaining this ecosystem through regulating biogeochemical and ecological processes. However, the composition structure and assembly mechanism of microbial community in the reef-overlying waters remain largely unknown. In the present study, the bacterial communities from the overlying waters of atolls and fringing reefs as well as the surface waters of the adjacent open ocean of the Xisha Islands in the South China Sea were investigated using 16S rRNA high-throughput sequencing combined with a size-fractionation strategy. The results showed that environments of all sampling stations were similar, characterized by an almost complete lack of inorganic nutrients such as nitrogen and phosphorus. Proteobacteria, Cyanobacteria and Bacteroidetes were the dominant phyla, and Synechococcus was most abundant at the genus level in both large fraction (LF; 1.6–200 μm) and small fraction (SF; 0.2–1.6 μm) communities. Only a slight difference in community composition between LF and SF samples was observed. The bacterial communities among the three habitat types showed noticeable differences, and the bacterial composition among the atoll reefs was more varied than that among the fringing reefs. The similarity of bacterial communities significantly declined with the increasing geographic distance, and stochastic processes were more important than deterministic processes in bacterial community assembly. This study sheds lights on the bacterial biodiversity of coral reefs and the importance of stochastic process in structuring bacterial communities.

The efficient phagocytic clearance of dying cells and apoptotic cells is one of the processes that is essential for the maintenance of physiologic tissue function and homeostasis, which is termed “efferocytosis.” Under normal conditions, “find me” and “eat me” signals are released by apoptotic cells to stimulate the engulfment and efferocytosis of apoptotic cells. In contrast, abnormal efferocytosis is related to chronic and non-resolving inflammatory diseases such as atherosclerosis. In the initial steps of atherosclerotic lesion development, monocyte-derived macrophages display efficient efferocytosis that restricts plaque progression; however, this capacity is reduced in more advanced lesions. Macrophage reprogramming as a result of the accumulation of apoptotic cells and augmented inflammation accounts for this diminishment of efferocytosis. Furthermore, defective efferocytosis plays an important role in necrotic core formation, which triggers plaque rupture and acute thrombotic cardiovascular events. Recent publications have focused on the essential role of macrophage efferocytosis in cardiac pathophysiology and have pointed toward new therapeutic strategies to modulate macrophage efferocytosis for cardiac tissue repair. In this review, we discuss the molecular and cellular mechanisms that regulate efferocytosis in vascular cells, including macrophages and other phagocytic cells and detail how efferocytosis-related molecules contribute to the maintenance of vascular hemostasis and how defective efferocytosis leads to the formation and progression of atherosclerotic plaques.

Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR-Cas9) is an ancient prokaryotic defense system that precisely cuts foreign genomic DNA under the control of a small number of guide RNAs. The CRISPR-Cas9 system facilitates efficient double-stranded DNA cleavage that has been recently adopted for genome editing to create or correct inherited genetic mutations causing disease. Congenital heart disease (CHD) is generally caused by genetic mutations such as base substitutions, deletions, and insertions, which result in diverse developmental defects and remains a leading cause of birth defects. Pediatric CHD patients exhibit a spectrum of cardiac abnormalities such as septal defects, valvular defects, and abnormal chamber development. CHD onset occurs during the prenatal period and often results in early lethality during childhood. Because CRISPR-Cas9-based genome editing technology has gained considerable attention for its potential to prevent and treat diseases, we will review the CRISPR-Cas9 system as a genome editing tool and focus on its therapeutic application for CHD.

MicroRNAs (miRNAs) are important regulators in the process of cardiac hypertrophy and heart failure. Previous studies have shown that miR-199a is upregulated in pressure-overload cardiac hypertrophy and that inhibition of miR-199a attenuates cardiac hypertrophy in vitro. However, the therapeutic role of anti-miR-199a treatment in the cardiac hypertrophy in vivo model is less known. Here, we show an efficient and useful method to treat mouse cardiac hypertrophy and restore cardiac function through injection of adeno-associated virus (AAV)-mediated anti-miR-199a tough decoys (TuDs). RNA-seq transcriptome analysis indicated that genes related to cytoplasmic translation and mitochondrial respiratory chain complex assembly were upregulated in anti-miR-199a-treated recovered hearts. We further validated that PGC-1α is the direct target of miR-199a involved in the therapeutic effect and the regulation of the PGC-1α/ERRα axis and that the downstream pathway of mitochondrial fatty acid oxidation and oxidative phosphorylation constitute the underlying mechanism of the restored mitochondrial structure and function in our anti-miR-199a-treated mice. Our study highlights the important regulatory role of miR-199a in cardiac hypertrophy and the value of the AAV-mediated miRNA delivery system.

Cardiac fibrosis occurs in most cardiac diseases, which reduces cardiac muscle compliance, impairs both systolic and diastolic heart function and, ultimately, leads to heart failure. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of a variety of biological processes; however, little is known about the expression and function of lncRNAs in cardiac fibrosis. Using unbiased transcriptome profiling in a mouse model of myocardial infarction (MI), we identified a cardiac fibroblast-enriched lncRNA (AK048087) named cardiac fibroblast-associated transcript (Cfast), which is significantly elevated after MI. Silencing Cfast expression by small interfering RNAs (siRNAs) or lentiviral short hairpin RNAs (shRNAs) resulted in suppression of fibrosis-related gene expression and transdifferentiation of myofibroblasts into cardiac fibroblasts. Depletion of Cfast by lentiviral shRNAs in mouse hearts significantly attenuated cardiac fibrosis induced by MI or isoproterenol-infusion. Importantly, inhibition of Cfast ameliorated cardiac function following cardiac injury. RNA pull-down followed by mass spectrometry analyses identified COTL1 (coactosin-like 1) as one of the Cfast interacting proteins. Mechanistically, Cfast competitively inhibits the COTL1 interaction with TRAP1 (transforming growth factor-β receptor-associated protein 1), which enhances TGF-β signaling by augmenting SMAD2/SMAD4 complex formation. Therefore, our study identifies Cfast as a novel cardiac fibroblast-enriched lncRNA that regulates cardiac fibroblast activation in response to pathophysiological stress. Cfast could serve as a potential therapeutic target for the prevention of cardiac fibrosis and cardiac diseases.

Intercalated discs ensure mechanical and electrochemical coupling during contraction of the heart. Here, the authors show that loss of Xinβ results in cardiomyocyte proliferation defects and cardiomyopathy by influencing the Hippo-YAP signalling pathway, thus affecting cardiac development and function.

Endothelial cell (EC) dysfunction and inflammation contribute to plaque destabilization in atherosclerosis, increasing the risk of thrombotic events. Here, the authors show that epsin promotes EC inflammation via a mechanism involving IP3R1 degradation, and that deletion of epsin in the endothelium prevents EC dysfunctoin and atherosclerosis in mice.

Heart failure is characterized by the inability of the heart to pump effectively and generate proper blood circulation to meet the body’s needs; it is a devastating condition that affects more than 100 million people globally. In spite of this, little is known about the mechanisms regulating the transition from cardiac hypertrophy to heart failure. Previously, we identified a cardiomyocyte-enriched gene, CIP, which regulates cardiac homeostasis under pathological stimulation. Here, we show that the cardiac transcriptional factor GATA4 binds the promotor of CIP gene and regulates its expression. We further determined that both CIP mRNA and protein decrease in diseased human hearts. In a mouse model, induced cardiac-specific overexpression of CIP after the establishment of cardiac hypertrophy protects the heart by inhibiting disease progression toward heart failure. Transcriptome analyses revealed that the IGF, mTORC2 and TGFβ signaling pathways mediate the inhibitory function of CIP on pathologic cardiac remodeling. Our study demonstrates GATA4 as an upstream regulator of CIP gene expression in cardiomyocytes, as well as the clinical significance of CIP expression in human heart disease. More importantly, our investigation suggests CIP is a key regulator of the transition from cardiac hypertrophy to heart failure. The ability of CIP to intervene in the onset of heart failure suggests a novel therapeutic avenue of investigation for the prevention of heart disease progression.

The proteins present in the extracellular environment of cells, named the “exoproteome,” are critical for microbial survival, growth, and interaction with their surroundings. However, little is known about microbial exoproteomes in natural marine environments. Here, we used a metaproteomic approach to characterize the exoprotein profiles (10 kDa-0.2 μm) throughout a water column in the South China Sea. Viruses, together with Alpha- and Gammaproteobacteria were the predominant contributors. However, the exoprotein-producing microbial communities varied with depth: SAR11 in the shallow waters, Pseudomonadales and Nitrososphaeria in the mesopelagic layer, and Alteromonadales, Rhizobiales, and Betaproteobacteria in the bathypelagic layer. Besides viral and unknown proteins, diverse transporters contributed substantially to the exoproteomes and varied vertically in their microbial origins, but presented similar patterns in their predicted substrate identities throughout the water column. Other microbial metabolic processes subject to vertical zonation included proteolysis, the oxidation of ammonia, nitrite and carbon monoxide, C1 metabolism, and the degradation of sulfur-containing dissolved organic matter (DOM). Our metaexoproteomic study provides insights into the depth-variable trends in the in situ ecological traits of the marine microbial community hidden in the non-cellular world, including nutrient cycling, niche partitioning and DOM remineralization.

The miR-17-92 cluster has been shown to regulate cardiomyocyte proliferation in vitro and in genetic mutation and overexpression models. Here the authors show that the cluster member miR-19a/19b regulates cardiomyocyte proliferation in vivo, and that delivery of miR-19a/19b to the heart leads to both short-term and long-term protective responses to myocardial infarction.

Gambierdiscus is a dinoflagellate genus widely distributed throughout tropical and subtropical regions. Some members of this genus can produce a group of potent polycyclic polyether neurotoxins responsible for ciguatera fish poisoning (CFP), one of the most significant food-borne illnesses associated with fish consumption. Ciguatoxins and maitotoxins, the two major toxins produced by Gambierdiscus, act on voltage-gated channels and TRPA1 receptors, consequently leading to poisoning and even death in both humans and animals. Over the past few decades, the occurrence and geographic distribution of CFP have undergone a significant expansion due to intensive anthropogenic activities and global climate change, which results in more human illness, a greater public health impact, and larger economic losses. The global spread of CFP has led to Gambierdiscus and its toxins being considered an environmental and human health concern worldwide. In this review, we seek to provide an overview of recent advances in the field of Gambierdiscus and its associated toxins based on the existing literature combined with re-analyses of current data. The taxonomy, phylogenetics, geographic distribution, environmental regulation, toxin detection method, toxin biosynthesis, and pharmacology and toxicology of Gambierdiscus are summarized and discussed. We also highlight future perspectives on Gambierdiscus and its associated toxins.

Solubilized particulate organic matter (POM) rather than dissolved organic matter (DOM) has been speculated to be the major carbon and energy sources for heterotrophic prokaryotes in the ocean. However, the direct evidence is still lack. Here we characterized microbial transport proteins of POM collected from both euphotic (75 m, deep chlorophyll maximum DCM, and 100 m) and upper-twilight (200 m and 500 m) zones in three contrasting environments in the northwest Pacific Ocean using a metaproteomic approach. The proportion of transport proteins was relatively high at the bottom of the euphotic zone (200 m), indicating that this layer was the most active area of microbe-driven POM remineralization in the water column. In the upper-twilight zone, the predicted substrates of the identified transporters indicated that amino acids, carbohydrates, taurine, inorganic nutrients, urea, biopolymers, and cobalamin were essential substrates for the microbial community. SAR11, Rhodobacterales, Alteromonadales, and Enterobacteriales were the key contributors with the highest expression of transporters. Interestingly, both the taxonomy and function of the microbial communities varied among water layers and sites with different environments; however, the distribution of transporter types and their relevant organic substrates were similar among samples, suggesting that microbial communities took up similar compounds and were functionally redundant in organic matter utilization throughout the water column. The similar vertical distribution of transport proteins from the euphotic zone to the upper twilight zone among the contrasting environments indicated that solubilized POM rather than DOM was the preferable carbon and energy sources for the microbial communities.

Despite being the world’s third largest ocean, the Indian Ocean is one of the least studied and understood with respect to microbial diversity as well as biogeochemical and ecological functions. In this study, we investigated the microbial community and its metabolic potential for nitrogen (N) acquisition in the oligotrophic surface waters of the Indian Ocean using a metagenomic approach. Proteobacteria and Cyanobacteria dominated the microbial community with an average 37.85 and 23.56% of relative abundance, respectively, followed by Bacteroidetes (3.73%), Actinobacteria (1.69%), Firmicutes (0.76%), Verrucomicrobia (0.36%), and Planctomycetes (0.31%). Overall, only 24.3% of functional genes were common among all sampling stations indicating a high level of gene diversity. However, the presence of 82.6% common KEGG Orthology (KOs) in all samples showed high functional redundancy across the Indian Ocean. Temperature, phosphate, silicate and pH were important environmental factors regulating the microbial distribution in the Indian Ocean. The cyanobacterial genus Prochlorococcus was abundant with an average 17.4% of relative abundance in the surface waters, and while 54 Prochlorococcus genomes were detected, 53 were grouped mainly within HLII clade. In total, 179 of 234 Prochlorococcus sequences extracted from the global ocean dataset were clustered into HL clades and exhibited less divergence, but 55 sequences of LL clades presented more divergence exhibiting different branch length. The genes encoding enzymes related to ammonia metabolism, such as urease, glutamate dehydrogenase, ammonia transporter, and nitrilase presented higher abundances than the genes involved in inorganic N assimilation in both microbial community and metagenomic Prochlorococcus population. Furthermore, genes associated with dissimilatory nitrate reduction, denitrification, nitrogen fixation, nitrification and anammox were absent in metagenome Prochlorococcus population, i.e., nitrogenase and nitrate reductase. Notably, the de novo biosynthesis pathways of six different amino acids were incomplete in the metagenomic Prochlorococcus population and Prochlorococcus genomes, suggesting compensatory uptake of these amino acids from the environment. These results reveal the features of the taxonomic and functional structure of the Indian Ocean microbiome and their adaptive strategies to ambient N deficiency in the oligotrophic ocean.

Skeletal muscles are the largest tissues in our body and the physiological function of muscle is essential to every aspect of life. The regulation of development, homeostasis, and metabolism is critical for the proper functioning of skeletal muscle. Consequently, understanding the processes involved in the regulation of myogenesis is of great interest. Non-coding RNAs especially microRNAs (miRNAs) are important regulators of gene expression and function. MiRNAs are small (~22 nucleotides long) noncoding RNAs known to negatively regulate target gene expression post-transcriptionally and are abundantly expressed in skeletal muscle. Gain- and loss-of function studies have revealed important roles of this class of small molecules in muscle biology and disease. In this review, we summarize the latest research that explores the role of miRNAs in skeletal muscle development, gene expression, and function as well as in muscle disorders like sarcopenia and Duchenne muscular dystrophy (DMD). Continuing with the theme of the current review series, we also briefly discuss the role of miRNAs in cancer cachexia.

Transfer RNAs (tRNAs) are abundantly expressed, small non-coding RNAs that have long been recognized as essential components of the protein translation machinery. The tRNA-derived small RNAs (tsRNAs), including tRNA halves (tiRNAs), and tRNA fragments (tRFs), were unexpectedly discovered and have been implicated in a variety of important biological functions such as cell proliferation, cell differentiation, and apoptosis. Mechanistically, tsRNAs regulate mRNA destabilization and translation, as well as retro-element reverse transcriptional and post-transcriptional processes. Emerging evidence has shown that tsRNAs are expressed in the heart, and their expression can be induced by pathological stress, such as hypertrophy. Interestingly, cardiac pathophysiological conditions, such as oxidative stress, aging, and metabolic disorders can be viewed as inducers of tsRNA biogenesis, which further highlights the potential involvement of tsRNAs in these conditions. There is increasing enthusiasm for investigating the molecular and biological functions of tsRNAs in the heart and their role in cardiovascular disease. It is anticipated that this new class of small non-coding RNAs will offer new perspectives in understanding disease mechanisms and may provide new therapeutic targets to treat cardiovascular disease.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine associated with skeletal muscle wasting in cancer cachexia. The control of gene expression by microRNAs (miRNAs) in muscle wasting involves the regulation of thousands of target transcripts. However, the miRNA-target networks associated with IL6-induced muscle atrophy remain to be characterized. Here, we show that IL-6 promotes the atrophy of C2C12 myotubes and changes the expression of 20 miRNAs (5 up-regulated and 15 down-regulated). Gene Ontology analysis of predicted miRNAs targets revealed post-transcriptional regulation of genes involved in cell differentiation, apoptosis, migration, and catabolic processes. Next, we performed a meta-analysis of miRNA-published data that identified miR-497-5p, a down-regulated miRNAs induced by IL-6, also down-regulated in other muscle-wasting conditions. We used miR-497-5p mimics and inhibitors to explore the function of miR-497-5p in C2C12 myoblasts and myotubes. We found that miR-497-5p can regulate the expression of the cell cycle genes CcnD2 and CcnE1 without affecting the rate of myoblast cellular proliferation. Notably, miR-497-5p mimics induced myotube atrophy and reduced Insr expression. Treatment with miR-497-5p inhibitors did not change the diameter of the myotubes but increased the expression of its target genes Insr and Igf1r. These genes are known to regulate skeletal muscle regeneration and hypertrophy via insulin-like growth factor pathway and were up-regulated in cachectic muscle samples. Our miRNA-regulated network analysis revealed a potential role for miR-497-5p during IL6-induced muscle cell atrophy and suggests that miR-497-5p is likely involved in a compensatory mechanism of muscle atrophy in response to IL-6.

Synechococcus is one of the most important contributors to global primary productivity, and ocean warming is predicted to increase abundance and distribution of Synechococcus in the ocean. Here, we investigated molecular response of an oceanic Synechococcus strain WH8102 grown in two nitrogen sources (nitrate and urea) under present (25°C) and predicted future (28°C) temperature conditions using an isobaric tag (IBT)-based quantitative proteomic approach. Rising temperature decreased growth rate, contents of chlorophyll a, protein and sugar in the nitrate-grown cells, but only decreased protein content and significantly increased zeaxanthin content of the urea-grown cells. Expressions of CsoS2 protein involved in carboxysome formation and ribosomal subunits in both nitrate- and urea-grown cells were significantly decreased in rising temperature, whereas carbohydrate selective porin and sucrose-phosphate synthase (SPS) were remarkably up-regulated, and carbohydrate degradation associated proteins, i.e., glycogen phosphorylase kinase, fructokinase and glucose-6-phosphate dehydrogenase, were down-regulated in the urea-grown cells. Rising temperature also increased expressions of three redox-sensitive enzymes (peroxiredoxin, thioredoxin, and CP12) in both nitrate- and urea-grown cells. Our results indicated that rising temperature did not enhance cell growth of Synechococcus; on the contrary, it impaired cell functions, and this might influence cell abundance and distribution of Synechococcus in a future ocean.

In an effort to identify human endothelial cell (EC)-enriched lncRNAs,~500 lncRNAs were shown to be highly restricted in primary human ECs. Among them, lncEGFL7OS, located in the opposite strand of the EGFL7/miR-126 gene, is regulated by ETS factors through a bidirectional promoter in ECs. It is enriched in highly vascularized human tissues, and upregulated in the hearts of dilated cardiomyopathy patients. LncEGFL7OS silencing impairs angiogenesis as shown by EC/fibroblast co-culture, in vitro/in vivo and ex vivo human choroid sprouting angiogenesis assays, while lncEGFL7OS overexpression has the opposite function. Mechanistically, lncEGFL7OS is required for MAPK and AKT pathway activation by regulating EGFL7/miR-126 expression. MAX protein was identified as a lncEGFL7OS-interacting protein that functions to regulate histone acetylation in the EGFL7/miR-126 promoter/enhancer. CRISPR-mediated targeting of EGLF7/miR-126/lncEGFL7OS locus inhibits angiogenesis, inciting therapeutic potential of targeting this locus. Our study establishes lncEGFL7OS as a human/primate-specific EC-restricted lncRNA critical for human angiogenesis.

Macronutrients such as nitrogen (N), phosphorus (P), and silicon (Si) are essential for the productivity and distribution of diatoms in the ocean. Responses of diatoms to a particular macronutrient deficiency have been investigated, however, we know little about their common or specific responses to different macronutrients. Here, we investigated the physiology and quantitative proteomics of a diatom Thalassiosira pseudonana grown in nutrient-replete, N-, P-, and Si-deficient conditions. Cell growth was ceased in all macronutrient deficient conditions while cell volume and cellular C content under P- and Si-deficiencies increased. Contents of chlorophyll a, protein and cellular N decreased in both N- and P-deficient cells but chlorophyll a and cellular N increased in the Si-deficient cells. Cellular P content increased under N- and Si-deficiencies. Proteins involved in carbon fixation and photorespiration were down-regulated under all macronutrient deficiencies while neutral lipid synthesis and carbohydrate accumulation were enhanced. Photosynthesis, chlorophyll biosynthesis, and protein biosynthesis were down-regulated in both N- and P-deficient cells, while Si transporters, light-harvesting complex proteins, chloroplastic ATP synthase, plastid transcription and protein synthesis were up-regulated in the Si-deficient cells. Our results provided insights into the common and specific responses of T. pseudonana to different macronutrient deficiencies and identified specific proteins potentially indicating a particular macronutrient deficiency.

Paralytic shellfish toxins (PSTs) are a group of potent neurotoxic alkaloids mainly produced by marine dinoflagellates and their biosynthesis is associated with the cell cycle. Study shows that colchicine can cease cell division and inhibit PST production of dinoflagellates. However, the molecular mechanism behind this linkage is unknown. Here, we applied the iTRAQ-based proteomic approach to investigate protein expression profiles of a toxigenic dinoflagellate Alexandrium catenella (ACHK-T) and its non-toxigenic mutant (ACHK-NT) when treated with colchicine. The results showed that the cell cycles of both strains were arrested at the G1 phase by colchicine, and the toxin biosynthesis of ACHK-T was inhibited. Among 6,988 proteins identified, 113 and 253 proteins were differentially expressed in the colchicine-treated ACHK-T and ACHK-NT, respectively, compared with their non-colchicine treatments. Proteins involved in reactive oxygen species scavenging and protein degradation were upregulated in both strains while proteins participating in photosynthetic pigment biosynthesis and nitrogen metabolism presented different expressions. Nitrate reductase and glutamine synthetase were altered insignificantly in the colchicine-treated ACHK-T while both of them were remarkably downregulated in the colchicine-treated ACHK-NT, suggesting a feedback regulation between PST production and nitrogen metabolism in ACHK-T. Nitrogen originally for PST biosynthesis might be reallocated to photosynthetic pigment biosynthesis in the colchicine-treated ACHK-T. A total of 55 homologs of 7 toxin-related proteins were obtained; however, they altered insignificantly in both colchicine-treated strains, suggesting that toxin biosynthesis might be post-translationally regulated. Our study provided new insights into toxin biosynthesis in marine dinoflagellates.

Nitrogen (N) is a primary limiting nutrient for bacterial growth and productivity in the ocean. To better understand bacterial community and their N utilization strategy in different N regimes of the ocean, we examined bacterial diversity, diazotrophic diversity, and N utilization gene expressions in the northwestern Pacific Ocean (NWPO) using a combination of high-throughput sequencing and real-time qPCR methods. 521 and 204 different operational taxonomic units (OTUs) were identified in the 16s rRNA and nifH libraries from nine surface samples. Of the 16s rRNA gene OTUs, 11.9% were observed in all samples while 3.5 and 15.9% were detected only in N-sufficient and N-deficient samples. Proteobacteria, Cyanobacteria and Bacteroidetes dominated the bacterial community. Prochlorococcus and Pseudoalteromonas were the most abundant at the genus level in N-deficient regimes, while SAR86, Synechococcus and SAR92 were predominant in the Kuroshio-Oyashio confluence region. The distribution of the nifH gene presented great divergence among sampling stations: Cyanobacterium_UCYN-A dominated the N-deficient stations, while clusters related to the Alpha-, Beta-, and Gamma-Proteobacteria were abundant in other stations. Temperature was the main factor that determined bacterial community structure and diversity while concentration of NOX-N was significantly correlated with structure and distribution of N2-fixing microorganisms. Expression of the ammonium transporter was much higher than that of urea transporter subunit A (urtA) and ferredoxin-nitrate reductase, while urtA had an increased expression in N-deficient surface water. The predicted ammonium transporter and ammonium assimilation enzymes were most abundant in surface samples while urease and nitrogenase were more abundant in the N-deficient regions. These findings underscore the fact that marine bacteria have evolved diverse N utilization strategies to adapt to different N habitats, and that urea metabolism is of vital ecological importance in N-deficient regimes.

In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PRC2 writing of H3K27me3 is mechanistically required for gene silencing. Here, we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (embryonic ectoderm development) inactivation in the postnatal heart (EedCKO) caused lethal dilated cardiomyopathy. Surprisingly, gene upregulation in EedCKO was not coupled with loss of H3K27me3. Rather, the activating histone mark H3K27ac increased. EED interacted with histone deacetylases (HDACs) and enhanced their catalytic activity. HDAC overexpression normalized EedCKO heart function and expression of derepressed genes. Our results uncovered a non-canonical, H3K27me3-independent EED repressive mechanism that is essential for normal heart function. Our results further illustrate that organ dysfunction due to epigenetic dysregulation can be corrected by epigenetic rewiring.

The dinoflagellates and cyanobacteria are two major kingdoms of life producing paralytic shellfish toxins (PSTs), a large group of neurotoxic alkaloids causing paralytic shellfish poisonings around the world. In contrast to the well elucidated PST biosynthetic genes in cyanobacteria, little is known about the dinoflagellates. This study compared transcriptome profiles of a toxin-producing dinoflagellate, Alexandrium catenella (ACHK-T), and its non-toxic mutant form (ACHK-NT) using RNA-seq. All clean reads were assembled de novo into a total of 113,674 unigenes, and 66,812 unigenes were annotated in the known databases. Out of them, 35 genes were found to express differentially between the two strains. The up-regulated genes in ACHK-NT were involved in photosynthesis, carbon fixation and amino acid metabolism processes, indicating that more carbon and energy were utilized for cell growth. Among the down-regulated genes, expression of a unigene assigned to the long isoform of sxtA, the initiator of toxin biosynthesis in cyanobacteria, was significantly depressed, suggesting that this long transcript of sxtA might be directly involved in toxin biosynthesis and its depression resulted in the loss of the ability to synthesize PSTs in ACHK-NT. In addition, 101 putative homologs of 12 cyanobacterial sxt genes were identified, and the sxtO and sxtZ genes were identified in dinoflagellates for the first time. The findings of this study should shed light on the biosynthesis of PSTs in the dinoflagellates.

It has been recognized for decades that proteins, which are encoded by our genome and produced via transcription and translation steps, are building blocks that play vital roles in almost all biological processes. Mutations identified in many protein-coding genes are linked to various human diseases. However, this “protein-centered” dogma has been challenged in recent years with the discovery that the majority of our genome is “non-coding” yet transcribed. Non-coding RNA has become the focus of “next generation” biology. Here, we review the emerging field of non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), and their role in cardiovascular function and disease.

Alexandrium is a neurotoxin-producing dinoflagellate genus resulting in paralytic shellfish poisonings around the world. However, little is known about the toxin biosynthesis mechanism in Alexandrium. This study compared protein profiles of A. catenella collected at different toxin biosynthesis stages (non-toxin synthesis, initial toxin synthesis and toxin synthesizing) coupled with the cell cycle, and identified differentially expressed proteins using 2-DE and MALDI-TOF-TOF mass spectrometry. The results showed that toxin biosynthesis of A. catenella occurred within a defined time frame in the G1 phase of the cell cycle. Proteomic analysis indicated that 102 protein spots altered significantly in abundance (P < 0.05), and 53 proteins were identified using database searching. These proteins were involved in a variety of biological processes, i.e., protein modification and biosynthesis, metabolism, cell division, oxidative stress, transport, signal transduction, and translation. Among them, nine proteins with known functions in paralytic shellfish toxin-producing cyanobacteria, i.e., methionine S-adenosyltransferase, chloroplast ferredoxin-NADP+ reductase, S-adenosylhomocysteinase, adenosylhomocysteinase, ornithine carbamoyltransferase, inorganic pyrophosphatase, sulfotransferase (similar to), alcohol dehydrogenase and arginine deiminase, varied significantly at different toxin biosynthesis stages and formed an interaction network, indicating that they might be involved in toxin biosynthesis in A. catenella. This study is the first step in the dissection of the behavior of the A. catenella proteome during different toxin biosynthesis stages and provides new insights into toxin biosynthesis in dinoflagellates.

Phosphorus (P) is a limiting macronutrient for diatom growth and productivity in the ocean. Much effort has been devoted to the physiological response of marine diatoms to ambient P change, however, the whole-genome molecular mechanisms are poorly understood. Here, we utilized RNA-Seq to compare the global gene expression patterns of a marine diatom Skeletonema costatum grown in inorganic P-replete, P-deficient, and inorganic- and organic-P resupplied conditions. In total 34,942 unique genes were assembled and 20.8% of them altered significantly in abundance under different P conditions. Genes encoding key enzymes/proteins involved in P utilization, nucleotide metabolism, photosynthesis, glycolysis and cell cycle regulation were significantly up-regulated in P-deficient cells. Genes participating in circadian rhythm regulation, such as circadian clock associated 1, were also up-regulated in P-deficient cells. The response of S. costatum to ambient P deficiency shows several similarities to the well-described responses of other marine diatom species, but also has its unique features. S. costatum has evolved the ability to re-program its circadian clock and intracellular biological processes in response to ambient P deficiency. This study provides new insights into the adaptive mechanisms to ambient P deficiency in marine diatoms.

Global inactivation of Trbp, a regulator of miRNA pathways, resulted in developmental defects and postnatal lethality in mice. Recently, we showed that cardiac-specific deletion of Trbp caused heart failure. However, its functional role(s) in skeletal muscle has not been characterized. Using a conditional knockout model, we generated mice lacking Trbp in the skeletal muscle. Unexpectedly, skeletal muscle specific Trbp mutant mice appear to be phenotypically normal under normal physiological conditions. However, these mice exhibited impaired muscle regeneration and increased fibrosis in response to cardiotoxin-induced muscle injury, suggesting that Trbp is required for muscle repair. Using cultured myoblast cells we further showed that inhibition of Trbp repressed myoblast differentiation in vitro. The impaired myogenesis is associated with reduced expression of muscle-specific miRNAs, miR-1a and miR-133a. Together, our study demonstrated that Trbp participates in the regulation of muscle differentiation and regeneration.

Paralytic shellfish toxins (PSTs) are a group of potent neurotoxic alkaloids that are produced mainly by marine dinoflagellates. PST biosynthesis in dinoflagellates is a discontinuous process that is coupled to the cell cycle. However, little is known about the molecular mechanism underlying this association. Here, we compared global protein expression profiles of a toxigenic dinoflagellate, Alexandrium catenella, collected at four different stages of toxin biosynthesis during the cell cycle, using an isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomic approach. The results showed that toxin biosynthesis occurred mainly in the G1 phase, especially the late G1 phase. In total, 7232 proteins were confidently identified, and 210 proteins exhibited differential expression among the four stages. Proteins involved in protein translation and photosynthetic pigment biosynthesis were significantly upregulated during toxin biosynthesis, indicating close associations among the three processes. Nine toxin-related proteins were detected, and two core toxin biosynthesis proteins, namely, sxtA and sxtI, were identified for the first time in dinoflagellates. Among these proteins, sxtI and ompR were significantly downregulated when toxin biosynthesis stopped, indicating that they played important roles in the regulation of PST biosynthesis. Our study provides new insights into toxin biosynthesis in marine dinoflagellates: nitrogen balance among different biological processes regulates toxin biosynthesis, and that glutamate might play a key modulatory role.

Dinoflagellates are not only important marine primary producers and grazers, but also the major causative agents of harmful algal blooms. It has been reported that many dinoflagellate species can produce various natural toxins. These toxins can be extremely toxic and many of them are effective at far lower dosages than conventional chemical agents. Consumption of seafood contaminated by algal toxins results in various seafood poisoning syndromes: paralytic shellfish poisoning (PSP), neurotoxic shellfish poisoning (NSP), amnesic shellfish poisoning (ASP), diarrheic shellfish poisoning (DSP), ciguatera fish poisoning (CFP) and azaspiracid shellfish poisoning (ASP). Most of these poisonings are caused by neurotoxins which present themselves with highly specific effects on the nervous system of animals, including humans, by interfering with nerve impulse transmission. Neurotoxins are a varied group of compounds, both chemically and pharmacologically. They vary in both chemical structure and mechanism of action, and produce very distinct biological effects, which provides a potential application of these toxins in pharmacology and toxicology. This review summarizes the origin, structure and clinical symptoms of PSP, NSP, CFP, AZP, yessotoxin and palytoxin produced by marine dinoflagellates, as well as their molecular mechanisms of action on voltage-gated ion channels.

GATA4 and GATA6 are central cardiac transcriptional regulators. The postnatal, stage-specific function of the cardiac transcription factors GATA4 and GATA6 have not been evaluated. In part, this is because current Cre-loxP approaches to cardiac gene inactivation require time consuming and costly breeding of Cre-expressing and "floxed" mouse lines, often with limited control of the extent or timing of gene inactivation. We investigated the stage-specific functions of GATA4 and GATA6 in the postnatal heart by using adeno-associated virus serotype 9 to control the timing and extent of gene inactivation by Cre. Systemic delivery of recombinant, adeno-associated virus 9 (AAV9) expressing Cre from the cardiac specific Tnnt2 promoter was well tolerated and selectively and efficiently recombined floxed target genes in cardiomyocytes. AAV9:Tnnt2-Cre efficiently inactivated Gata4 and Gata6. Neonatal Gata4/6 inactivation caused severe, rapidly lethal systolic heart failure. In contrast, Gata4/6 inactivation in adult heart caused only mild systolic dysfunction but severe diastolic dysfunction. Reducing the dose of AAV9:Tnnt2-Cre generated mosaics in which scattered cardiomyocytes lacked Gata4/6. This mosaic knockout revealed that Gata4/6 are required cell autonomously for physiological cardiomyocyte growth. Our results define novel roles of GATA4 and GATA6 in the neonatal and adult heart. Furthermore, our data demonstrate that evaluation of gene function hinges on controlling the timing and extent of gene inactivation. AAV9:Tnnt2-Cre is a powerful tool for controlling these parameters.

Paralytic shellfish toxins (PSTs), a group of neurotoxic alkaloids, are the most potent biotoxins for aquatic ecosystems and human health. Marine dinoflagellates and freshwater cyanobacteria are two producers of PSTs. The biosynthesis mechanism of PSTs has been well elucidated in cyanobacteria; however, it remains ambiguous in dinoflagellates. Here, we compared the transcriptome profiles of a toxin-producing dinoflagellate Alexandrium catenella (ACHK-T) at different toxin biosynthesis stages within the cell cycle using RNA-seq. The intracellular toxin content increased gradually in the middle G1 phase and rapidly in the late G1 phase, and then remained relatively stable in other phases. Samples from four toxin biosynthesis stages were selected for sequencing, and finally yielded 110,370 unigenes, of which 66,141 were successfully annotated in the known databases. An analysis of differentially expressed genes revealed that 2866 genes altered significantly and 297 were co-expressed throughout the four stages. These genes participated mainly in protein metabolism, carbohydrate metabolism, and the oxidation-reduction process. A total of 138 homologues of toxin genes were identified, but they altered insignificantly among different stages, indicating that toxin biosynthesis might be regulated translationally or post-translationally. Our results will serve as an important transcriptomic resource to characterize key molecular processes underlying dinoflagellate toxin biosynthesis.

Dinoflagellates are the major causative agents of harmful algal blooms in the coastal zone, which has resulted in adverse effects on the marine ecosystem and public health, and has become a global concern. Knowledge of cell cycle regulation in proliferating cells is essential for understanding bloom dynamics, and so this study compared the protein profiles of Prorocentrum donghaiense at different cell cycle phases and identified differentially expressed proteins using 2-D fluorescence difference gel electrophoresis combined with MALDI-TOF-TOF mass spectrometry. The results showed that the synchronized cells of P. donghaiense completed a cell cycle within 24 hours and cell division was phased with the diurnal cycle. Comparison of the protein profiles at four cell cycle phases (G1, S, early and late G2/M) showed that 53 protein spots altered significantly in abundance. Among them, 41 were identified to be involved in a variety of biological processes, e.g. cell cycle and division, RNA metabolism, protein and amino acid metabolism, energy and carbon metabolism, oxidation-reduction processes, and ABC transport. The periodic expression of these proteins was critical to maintain the proper order and function of the cell cycle. This study, to our knowledge, for the first time revealed the major biological processes occurring at different cell cycle phases which provided new insights into the mechanisms regulating the cell cycle and growth of dinoflagellates.

Myocardial differentiation is associated with the activation and expression of an array of cardiac specific genes. However, the transcriptional networks that control cardiac gene expression are not completely understood. Myocardin is a cardiac and smooth muscle-specific expressed transcriptional coactivator of Serum Response Factor (SRF) and is able to potently activate cardiac and smooth muscle gene expression during development. We hypothesize that myocardin discriminates between cardiac and smooth muscle specific genes by associating with distinct co-factors. Here, we show that myocardin directly interacts with Tbx5, a member of the T-box family of transcription factors involved in the Holt-Oram syndrome. Tbx5 synergizes with myocardin to activate expression of the cardiac specific genes atrial natriuretic factor (ANF) and alpha myosin heavy chain (α-MHC), but not that of smooth muscle specific genes SM22 or smooth muscle myosin heavy chain (SM-MHC). We found that this synergistic activation of shared target genes is dependent on the binding sites for Tbx5, T-box factor-Binding Elements (TBEs). Myocardin and Tbx5 physically interact and their interaction domains were mapped to the basic domain and the coil domain of myocardin and Tbx5, respectively. Our analysis demonstrates that the Tbx5G80R mutation, which leads to the Holt-Oram syndrome in humans, failed to synergize with myocardin to activate cardiac gene expression. These data uncover a key role for Tbx5 and myocardin in establishing the transcriptional foundation for cardiac gene activation and suggest that the interaction of myocardin and Tbx5 maybe involved in cardiac development and diseases.

Cardiovascular diseases are the main cause of death worldwide. Recent studies have revealed the influence of histone-modifying enzymes in cardiac remodeling and heart dysfunction. The Set7 methyltransferase regulates the expression of several genes through the methylation of histones and modulates the activity of non-histone proteins. However, the role of Set7 in cardiac remodeling and heart dysfunction remains unknown. To address this question, wild-type (WT) and Set7 knockout (KO) male mice were injected with isoproterenol or saline. WT mice injected with isoproterenol displayed a decrease in Set7 activity in the heart. In addition, WT and Set7 KO mice injected with isoproterenol exhibited cardiac hypertrophy. Interestingly, Set7 deletion exacerbated cardiac hypertrophy in response to isoproterenol but attenuated myocardial fibrosis. Echocardiograms revealed that WT mice injected with isoproterenol had lowered ejection fractions and fractional shortening, and increased E′-wave deceleration time and E/A ratio compared with their controls. Conversely, Set7 KO mice did not show alteration in these parameters in response to isoproterenol. However, prolonged exposure to isoproterenol induced cardiac dysfunction both in WT and Set7 KO mice. Both isoproterenol and Set7 deletion changed the transcriptional profile of the heart. Moreover, Set7 deletion increased the expression of Pgc1α and mitochondrial DNA content in the heart, and reduced the expression of cellular senescence and inflammation markers in response to isoproterenol. Taken together, our data suggest that Set7 deletion attenuates isoproterenol-induced myocardial fibrosis and delays heart dysfunction, suggesting that Set7 plays an important role in cardiac remodeling and dysfunction in response to stress. [ABSTRACT FROM AUTHOR]

Background/Aims: An obesogenic diet (high fat and sugar, low fiber) is associated with an increased risk for metabolic and cardiovascular disorders. Previous studies have demonstrated that epigenetic changes can modify gene transcription and protein function, playing a key role in the development of several diseases. The methyltransferase Set7 methylates histone and non-histone proteins, influencing diverse biological and pathological processes. However, the functional role of Set7 in obesity-associated metabolic and cardiovascular complications is unknown. Methods: Wild type and Set7 knockout female mice were fed a normal diet or an obesogenic diet for 12 weeks. Body weight gain and glucose tolerance were measured. The 3T3-L1 cells were used to determine the role of Set7 in white adipogenic differentiation. Cardiac morphology and function were evaluated by histology and echocardiography. An ex vivo Langendorff perfusion system was used to model cardiac ischemia/reperfusion (I/R). Results: Here, we report that Set7 protein levels were enhanced in the heart and perigonadal adipose tissue (PAT) of female mice fed an obesogenic diet. Significantly, loss of Set7 prevented obesogenic diet-induced glucose intolerance in female mice although it did not affect the obesogenic diet-induced increase in body weight gain and adiposity in these animals, nor did Set7 inhibition change white adipogenic differentiation in vitro. In addition, loss of Set7 prevented the compromised cardiac functional recovery following ischemia and reperfusion (I/R) injury in obesogenic diet-fed female mice; however, deletion of Set7 did not influence obesogenic diet-induced cardiac hypertrophy nor the hemodynamic and echocardiographic parameters. Conclusion: These data indicate that Set7 plays a key role in obesogenic dietinduced glucose intolerance and compromised myocardial functional recovery after I/R in obese female mice. [ABSTRACT FROM AUTHOR]

Background/Aims: Obesity is a risk factor associated with cardiometabolic complications. Recently, we reported that miRNA-22 deletion attenuated high-fat diet-induced adiposity and prevented dyslipidemia without affecting cardiac hypertrophy in male mice. In this study, we examined the impact of miRNA-22 in obesogenic diet-induced cardiovascular and metabolic disorders in females. Methods: Wild type (WT) and miRNA-22 knockout (miRNA-22 KO) females were fed a control or an obesogenic diet. Body weight gain, adiposity, glucose tolerance, insulin tolerance, and plasma levels of total cholesterol and triglycerides were measured. Cardiac and white adipose tissue remodeling was assessed by histological analyses. Echocardiography was used to evaluate cardiac function and morphology. RNA-sequencing analysis was employed to characterize mRNA expression profiles in female hearts. Results: Loss of miRNA-22 attenuated body weight gain, adiposity, and prevented obesogenic diet-induced insulin resistance and dyslipidemia in females. WT obese females developed cardiac hypertrophy. Interestingly, miRNA-22 KO females displayed cardiac hypertrophy without left ventricular dysfunction and myocardial fibrosis. Both miRNA-22 deletion and obesogenic diet changed mRNA expression profiles in female hearts. Enrichment analysis revealed that genes associated with regulation of the force of heart contraction, protein folding and fatty acid oxidation were enriched in hearts of WT obese females. In addition, genes related to thyroid hormone responses, heart growth and PI3K signaling were enriched in hearts of miRNA-22 KO females. Interestingly, miRNA-22 KO obese females exhibited reduced mRNA levels of Yap1, Egfr and Tgfbr1 compared to their respective controls. Conclusion: This study reveals that miRNA-22 deletion induces cardiac hypertrophy in females without affecting myocardial function. In addition, our findings suggest miRNA-22 as a potential therapeutic target to treat obesity-related metabolic disorders in females. [ABSTRACT FROM AUTHOR]

Background/Aims: Obesity is a risk factor associated with cardiometabolic complications. Recently, we reported that miRNA-22 deletion attenuated high-fat diet-induced adiposity and prevented dyslipidemia without affecting cardiac hypertrophy in male mice. In this study, we examined the impact of miRNA-22 in obesogenic diet-induced cardiovascular and metabolic disorders in females. Methods: Wild type (WT) and miRNA-22 knockout (miRNA-22 KO) females were fed a control or an obesogenic diet. Body weight gain, adiposity, glucose tolerance, insulin tolerance, and plasma levels of total cholesterol and triglycerides were measured. Cardiac and white adipose tissue remodeling was assessed by histological analyses. Echocardiography was used to evaluate cardiac function and morphology. RNA-sequencing analysis was employed to characterize mRNA expression profiles in female hearts. Results: Loss of miRNA-22 attenuated body weight gain, adiposity, and prevented obesogenic diet-induced insulin resistance and dyslipidemia in females. WT obese females developed cardiac hypertrophy. Interestingly, miRNA-22 KO females displayed cardiac hypertrophy without left ventricular dysfunction and myocardial fibrosis. Both miRNA-22 deletion and obesogenic diet changed mRNA expression profiles in female hearts. Enrichment analysis revealed that genes associated with regulation of the force of heart contraction, protein folding and fatty acid oxidation were enriched in hearts of WT obese females. In addition, genes related to thyroid hormone responses, heart growth and PI3K signaling were enriched in hearts of miRNA-22 KO females. Interestingly, miRNA-22 KO obese females exhibited reduced mRNA levels of Yap1, Egfr and Tgfbr1 compared to their respective controls. Conclusion: This study reveals that miRNA-22 deletion induces cardiac hypertrophy in females without affecting myocardial function. In addition, our findings suggest miRNA-22 as a potential therapeutic target to treat obesity-related metabolic disorders in females. [ABSTRACT FROM AUTHOR]

The appropriate arrangement of myonuclei within skeletal muscle myofibers is of critical importance for normal muscle function, and improper myonuclear localization has been linked to a variety of skeletal muscle diseases, such as centronuclear myopathy and muscular dystrophies. However, the molecules that govern myonuclear positioning remain elusive. Here, we report that skeletal muscle-specific CIP (sk-CIP) is a regulator of nuclear positioning. Genetic deletion of sk-CIP in mice results in misalignment of myonuclei along the myofibers and at specialized structures such as neuromuscular junctions (NMJs) and myotendinous junctions (MTJs) in vivo, impairing myonuclear positioning after muscle regeneration, leading to severe muscle dystrophy in mdx mice, a mouse model of Duchenne muscular dystrophy. sk-CIP is localized to the centrosome in myoblasts and relocates to the outer nuclear envelope in myotubes upon differentiation. Mechanistically, we found that sk-CIP interacts with the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and the centriole Microtubule Organizing Center (MTOC) proteins to coordinately modulate myonuclear positioning and alignment. These findings indicate that sk-CIP may function as a muscle-specific anchoring protein to regulate nuclear position in multinucleated muscle cells. [ABSTRACT FROM AUTHOR]

The diversity and abundance of bacteria and diazotrophs in the euphotic and aphotic layers of the South China Sea (SCS) basin were investigated based on high-throughput sequencing of the 16S rRNA and nifH genes. Bacterial communities in the aphotic layers significantly differed from those at the euphotic layers, and were characterized by geographical specificities. Prochlorococcus and Alphaproteobacteria were abundant in the surface layer, whereas Gammaproteobacteria was more common in the aphotic layers. Moraxellaceae was the most abundant group in the aphotic layer in the northern basin of the SCS (nSCS), while SAR324, SAR202 and SAR406 occurred mainly in the southern basin of the SCS (sSCS). Diazotrophic Alphaproteobacteria was the predominant group in the SCS basin, whereas Marine Group II Euryarchaeota emerged in the euphotic bottom of both nSCS and sSCS. Abundances of genes encoding amino acid transporters and ammonium assimilating enzymes were relatively high in the SCS surface and the entire water column of the sSCS, while expression levels of urea and ammonium transporter-encoding genes were the highest at the surface of the SEATS site. Iron deficiency-induced gene IdiA and urease were highly expressed at the A2 site. Our results indicated that bacterial communities in the SCS were depth-stratified and exhibited geographic divergency in the aphotic layers between nSCS and sSCS. Amino acids and ammonium were the major nitrogen sources for bacteria while urea, ammonia and nitrite played important roles in regulating cell growth of Prochlorococcus in different regions of the SCS. [ABSTRACT FROM AUTHOR]

There is overwhelming evidence that regular exercise training is protective against cardiovascular disease (CVD), the main cause of death worldwide. Despite the benefits of exercise, the intricacies of their underlying molecular mechanisms remain largely unknown. Non-coding RNAs (ncRNAs) have been recognized as a major regulatory network governing gene expression in several physiological processes and appeared as pivotal modulators in a myriad of cardiovascular processes under physiological and pathological conditions. However, little is known about ncRNA expression and role in response to exercise. Revealing the molecular components and mechanisms of the link between exercise and health outcomes will catalyse discoveries of new biomarkers and therapeutic targets. Here we review the current understanding of the ncRNA role in exercise-induced adaptations focused on the cardiovascular system and address their potential role in clinical applications for CVD. Finally, considerations and perspectives for future studies will be proposed. [ABSTRACT FROM AUTHOR]

Obesity is associated with development of diverse diseases, including cardiovascular diseases and dyslipidemia. MiRNA-22 (miR-22) is a critical regulator of cardiac function and targets genes involved in metabolic processes. Previously, we generated miR-22 null mice and we showed that loss of miR-22 blunted cardiac hypertrophy induced by mechanohormornal stress. In the present study, we examined the role of miR-22 in the cardiac and metabolic alterations promoted by high-fat (HF) diet. We found that loss of miR-22 attenuated the gain of fat mass and prevented dyslipidemia induced by HF diet, although the body weight gain, or glucose intolerance and insulin resistance did not seem to be affected. Mechanistically, loss of miR-22 attenuated the increased expression of genes involved in lipogenesis and inflammation mediated by HF diet. Similarly, we found that miR-22 mediates metabolic alterations and inflammation induced by obesity in the liver. However, loss of miR-22 did not appear to alter HF diet induced cardiac hypertrophy or fibrosis in the heart. Our study therefore establishes miR-22 as an important regulator of dyslipidemia and suggests it may serve as a potential candidate in the treatment of dyslipidemia associated with obesity. [ABSTRACT FROM AUTHOR]

Aims: Ischemic cardiomyopathy (ICM) resulting from myocardial infarction is a major cause of heart failure (HF). Recently, thousands of long non-coding RNAs (lncRNAs) have been discovered and implicated in a variety of biological processes. However, the role of most lncRNAs in HF remains largely unknown. The aim of this study is to test the hypothesis that the expression and function of lncRNAs are differentially regulated in diseased hearts. Methods and results: In this study, we performed RNA deep sequencing of protein-coding and non-coding RNAs from cardiac samples of patients with ICM (n?15) and controls (n=15). Genome-wide transcriptome analysis confirmed that many protein-coding genes previously known to be involved in HF were altered in ICM hearts. Among the 145 differentially expressed lncRNAs identified in ICM hearts, we found a set of 35 lncRNAs that display strong positive expression correlation. Expression correlation coefficient analyses of differentially expressed lncRNAs and proteincoding genes revealed a strong association between lncRNAs and extracellular matrix (ECM) protein-coding genes. We overexpressed or knocked down selected lncRNAs in cardiac fibroblasts and our results suggest that lncRNAs are important regulators of fibrosis and the expression of ECM synthesis genes. Moreover, we show that lncRNAs participate in the TGF-α pathway to modulate the expression of ECM genes and myofibroblast differentiation. Conclusion: Our studies demonstrate that the expression of many lncRNAs is dynamically regulated in ICM. lncRNAs regulate the expression and function of ECM and cardiac fibrosis during the development of ICM. Our results further indicate that lncRNAs may represent novel regulators of heart function and cardiac disorders, including ICM. [ABSTRACT FROM AUTHOR]