scholarly journals Targeted genomic enrichment and sequencing of CyHV-3 from carp tissues confirms low nucleotide diversity and mixed genotype infections

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2516 ◽  
Author(s):  
Saliha Hammoumi ◽  
Tatiana Vallaeys ◽  
Ayi Santika ◽  
Philippe Leleux ◽  
Ewa Borzym ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Significant Proportion ◽  
Gill Tissue ◽  
Infected Fish ◽  
Genomic Diversity ◽  
Fish Tissues ◽  
Entire Genome ◽  
Koi Herpesvirus ◽  
Targeted Genomic Enrichment ◽  
New Strategy

Koi herpesvirus disease (KHVD) is an emerging disease that causes mass mortality in koi and common carp,Cyprinus carpioL. Its causative agent is Cyprinid herpesvirus 3 (CyHV-3), also known as koi herpesvirus (KHV). Although data on the pathogenesis of this deadly virus is relatively abundant in the literature, still little is known about its genomic diversity and about the molecular mechanisms that lead to such a high virulence. In this context, we developed a new strategy for sequencing full-length CyHV-3 genomes directly from infected fish tissues. Total genomic DNA extracted from carp gill tissue was specifically enriched with CyHV-3 sequences through hybridization to a set of nearly 2 million overlapping probes designed to cover the entire genome length, using KHV-J sequence (GenBank accession numberAP008984) as reference. Applied to 7 CyHV-3 specimens from Poland and Indonesia, this targeted genomic enrichment enabled recovery of the full genomes with >99.9% reference coverage. The enrichment rate was directly correlated to the estimated number of viral copies contained in the DNA extracts used for library preparation, which varied between ∼5000 and ∼2×107. The average sequencing depth was >200 for all samples, thus allowing the search for variants with high confidence. Sequence analyses highlighted a significant proportion of intra-specimen sequence heterogeneity, suggesting the presence of mixed infections in all investigated fish. They also showed that inter-specimen genetic diversity at the genome scale was very low (>99.95% of sequence identity). By enabling full genome comparisons directly from infected fish tissues, this new method will be valuable to trace outbreaks rapidly and at a reasonable cost, and in turn to understand the transmission routes of CyHV-3.

scholarly journals Cell signalling by reactive lipid species: new concepts and molecular mechanisms

2012 ◽  
Vol 442 (3) ◽  
pp. 453-464 ◽  
Author(s):  
Ashlee Higdon ◽  
Anne R. Diers ◽  
Joo Yeun Oh ◽  
Aimee Landar ◽  
Victor M. Darley-Usmar
Keyword(s):  
Cell Death ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Chemical Reactivity ◽  
Cell Signalling ◽  
Significant Proportion ◽  
Covalent Modification ◽  
Lipid Species ◽  
Electrophilic Stress ◽  
Cellular Antioxidants

The process of lipid peroxidation is widespread in biology and is mediated through both enzymatic and non-enzymatic pathways. A significant proportion of the oxidized lipid products are electrophilic in nature, the RLS (reactive lipid species), and react with cellular nucleophiles such as the amino acids cysteine, lysine and histidine. Cell signalling by electrophiles appears to be limited to the modification of cysteine residues in proteins, whereas non-specific toxic effects involve modification of other nucleophiles. RLS have been found to participate in several physiological pathways including resolution of inflammation, cell death and induction of cellular antioxidants through the modification of specific signalling proteins. The covalent modification of proteins endows some unique features to this signalling mechanism which we have termed the ‘covalent advantage’. For example, covalent modification of signalling proteins allows for the accumulation of a signal over time. The activation of cell signalling pathways by electrophiles is hierarchical and depends on a complex interaction of factors such as the intrinsic chemical reactivity of the electrophile, the intracellular domain to which it is exposed and steric factors. This introduces the concept of electrophilic signalling domains in which the production of the lipid electrophile is in close proximity to the thiol-containing signalling protein. In addition, we propose that the role of glutathione and associated enzymes is to insulate the signalling domain from uncontrolled electrophilic stress. The persistence of the signal is in turn regulated by the proteasomal pathway which may itself be subject to redox regulation by RLS. Cell death mediated by RLS is associated with bioenergetic dysfunction, and the damaged proteins are probably removed by the lysosome-autophagy pathway.

scholarly journals Tetracycline Analogs Inhibit Osteoclast Differentiation by Suppressing MMP-9-Mediated Histone H3 Cleavage

2019 ◽  
Vol 20 (16) ◽  
pp. 4038 ◽  
Author(s):  
Yeojin Kim ◽  
Jinman Kim ◽  
Hyerim Lee ◽  
Woo-Ri Shin ◽  
Sheunghun Lee ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Osteoclast Differentiation ◽  
Histone H3 ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Receptor Activator ◽  
New Strategy ◽  
Docking Approach ◽  
Metalloproteinase 9

Osteoporosis is a common disorder of bone remodeling, caused by the imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Recently, we reported that matrix metalloproteinase-9 (MMP-9)-dependent histone H3 proteolysis is a key event for proficient osteoclast formation. Although it has been reported that several MMP-9 inhibitors, such as tetracycline and its derivatives, show an inhibitory effect on osteoclastogenesis, the molecular mechanisms for this are not fully understood. Here we show that tetracycline analogs, especially tigecycline and minocycline, inhibit osteoclast formation by blocking MMP-9-mediated histone H3 tail cleavage. Our molecular docking approach found that tigecycline and minocycline are the most potent inhibitors of MMP-9. We also observed that both inhibitors significantly inhibited H3 tail cleavage by MMP-9 in vitro. These compounds inhibited receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast formation by blocking the NFATc1 signaling pathway. Furthermore, MMP-9-mediated H3 tail cleavage during osteoclast differentiation was selectively blocked by these compounds. Treatment with both tigecycline and minocycline rescued the osteoporotic phenotype induced by prednisolone in a zebrafish osteoporosis model. Our findings demonstrate that the tetracycline analogs suppress osteoclastogenesis via MMP-9-mediated H3 tail cleavage, and suggest that MMP-9 inhibition could offer a new strategy for the treatment of glucocorticoid-induced osteoporosis.

scholarly journals The Role of Polycomb Repressive Complex in Malignant Peripheral Nerve Sheath Tumor

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 287 ◽  
Author(s):  
Xiyuan Zhang ◽  
Béga Murray ◽  
George Mo ◽  
Jack F. Shern
Keyword(s):  
Peripheral Nerve ◽  
Transcriptional Repression ◽  
Molecular Mechanisms ◽  
Significant Proportion ◽  
Soft Tissue Sarcomas ◽  
Nerve Sheath Tumor ◽  
Polycomb Repressive Complex ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath ◽  
Recurrent Mutations

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that can arise most frequently in patients with neurofibromatosis type 1 (NF1). Despite an increasing understanding of the molecular mechanisms that underlie these tumors, there remains limited therapeutic options for this aggressive disease. One potentially critical finding is that a significant proportion of MPNSTs exhibit recurrent mutations in the genes EED or SUZ12, which are key components of the polycomb repressive complex 2 (PRC2). Tumors harboring these genetic lesions lose the marker of transcriptional repression, trimethylation of lysine residue 27 on histone H3 (H3K27me3) and have dysregulated oncogenic signaling. Given the recurrence of PRC2 alterations, intensive research efforts are now underway with a focus on detailing the epigenetic and transcriptomic consequences of PRC2 loss as well as development of novel therapeutic strategies for targeting these lesions. In this review article, we will summarize the recent findings of PRC2 in MPNST tumorigenesis, including highlighting the functions of PRC2 in normal Schwann cell development and nerve injury repair, as well as provide commentary on the potential therapeutic vulnerabilities of a PRC2 deficient tumor cell.

scholarly journals Molecular mechanisms of telomere biology disorders

2020 ◽  
pp. jbc.REV120.014017
Author(s):  
Sherilyn Grill ◽  
Jayakrishnan Nandakumar
Keyword(s):  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Wide Spectrum ◽  
Significant Proportion ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Genetic Mutations ◽  
Hematopoietic Stem ◽  
Telomere Biology ◽  
Underlying Mechanisms

Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita (DC), pulmonary fibrosis (PF) and aplastic anemia (AA), is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin, and the telomerase RNA maturation component PARN, affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of DC mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pin-point disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease.

Time for a New Strategy in the War on Alzheimer’s Disease

2019 ◽  
Vol 29 (4) ◽  
pp. 119-122
Author(s):  
Matt Kaeberlein
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Well Being ◽  
Developed Countries ◽  
Biological Aging ◽  
Root Cause ◽  
New Strategy ◽  
New Strategies ◽  
Made In

Abstract Alzheimer’s disease is a growing threat to the economic and social well-being of developed countries around the globe, but efforts to delay, prevent, or cure this disorder have yet to yield success. I believe the lack of progress largely results from approaches that ignore the most important component of Alzheimer’s disease: biological aging. Major advances have been made in understanding the molecular mechanisms that link biological aging to disease. These mechanisms have been formalized as nine hallmarks, or pillars, of aging. Here, I discuss the barriers that have impaired progress and propose specific steps that can be taken to overcome these barriers. The time has come to adopt bold new strategies that tackle biological aging as the root cause of Alzheimer’s disease.

scholarly journals Comparative Transcriptome Analysis of Gill Tissue in Response to Hypoxia in Silver Sillago (Sillago sihama)

Animals ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 628
Author(s):  
Wanida Saetan ◽  
Changxu Tian ◽  
Jiawang Yu ◽  
Xinghua Lin ◽  
Feixiang He ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Molecular Mechanisms ◽  
Gill Tissue ◽  
Gene Families ◽  
Glutathione Metabolism ◽  
Glutathione S Transferase ◽  
Treatment Groups ◽  
Hypoxia Stress ◽  
Group A ◽  
Sillago Sihama

Silver sillago (Sillago sihama) is a commercially important marine fish species in East Asia. In this study, we compared the transcriptome response to hypoxia stress in the gill tissue of S. sihama. The fish were divided into four groups, such as 1 h of hypoxia (hypoxia1h, DO = 1.5 ± 0.1 mg/L), 4 h of hypoxia (hypoxia4h, DO = 1.5 ± 0.1 mg/L), 4 h of reoxygen (reoxygen4h, DO = 8.0 ± 0.2 mg/L) after 4 h of hypoxia (DO = 1.5 mg/L), and normoxia or control (DO = 8.0 ± 0.2 mg/L) groups. Compared to the normoxia group, a total of 3550 genes were identified as differentially expressed genes (DEGs) (log2foldchange > 1 and padj < 0.05), including 1103, 1451 and 996 genes in hypoxia1h, hypoxia4h and reoxygen4h groups, respectively. Only 247 DEGs were differentially co-expressed in all treatment groups. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, DEGs were significantly enriched in steroid biosynthesis, biosynthesis of amino acids, glutathione metabolism and metabolism of xenobiotics by cytochrome P450, ferroptosis and drug metabolism—cytochrome P450 pathways. Of these, the cytochrome P450 (CYP) and glutathione S-transferase (GST) gene families were widely expressed. Our study represents the insights into the underlying molecular mechanisms of hypoxia stress.

scholarly journals A network view of microRNA and gene interactions in different pathological stages of colon cancer

2019 ◽  
Vol 12 (S7) ◽  
Author(s):  
Jia Wen ◽  
Benika Hall ◽  
Xinghua Shi
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Clinical Information ◽  
The Cancer Genome Atlas ◽  
Gene Interactions ◽  
New Strategy ◽  
Pathological Stages

Abstract Background Colon cancer is one of the common cancers in human. Although the number of annual cases has decreased drastically, prognostic screening and translational methods can be improved. Hence, it is critical to understand the molecular mechanisms of disease progression and prognosis. Results In this study, we develop a new strategy for integrating microRNA and gene expression profiles together with clinical information toward understanding the regulation of colon cancer. Particularly, we use this approach to identify microRNA and gene expression networks that are specific to certain pathological stages. To demonstrate the application of our method, we apply this approach to identify microRNA and gene interactions that are specific to pathological stages of colon cancer in The Cancer Genome Atlas (TCGA) datasets. Conclusions Our results show that there are significant differences in network connections between miRNAs and genes in different pathological stages of colon cancer. These findings point to a hypothesis that these networks signify different roles of microRNA and gene regulation in the pathogenesis and tumorigenesis of colon cancer.

Histopathology of Sanguinicola inermis infection in carp, Cyprinus carpio

1998 ◽  
Vol 72 (1) ◽  
pp. 33-38 ◽  
Author(s):  
R.S. Kirk ◽  
J.W. Lewis
Keyword(s):  
Egg Production ◽  
Mechanical Damage ◽  
Gill Tissue ◽  
Infected Fish ◽  
Epithelial Tissue ◽  
Histopathological Response ◽  
Vascular Integrity ◽  
Invasion And Migration ◽  
Organ Systems ◽  
Partially Occluded

AbstractThe histopathological response of carp to Sanguinicola inermis was investigated by serial sectioning laboratory infected fish up to 90 days post infection (d p.i.). Juvenile flukes and adults caused mechanical damage to tissues during invasion and migration up to 28 d p.i. Adults partially occluded blood vessels and may have reduced blood circulation. In the initial phase of egg production (28–42 d p.i.), eggs and emigrating miracidia in gill tissue caused breakdown of vascular integrity, necrosis, hyperplasia, haemorrhage and eosinophilic infiltration of epithelial tissue. After 42 d p.i. the host granulomatous inflammatory response encapsulated eggs lodged in the gills, visceral sites and connective tissue displacing normal tissue. Encapsulation and subsequent degradation of eggs and miracidia within granulomata was highly developed by 90 d p.i. Laboratory infections of S. inermis can induce respiratory distress and therefore impair respiration of fish. The parasite also caused pathological changes in osmoregulatory, excretory and haemopoietic tissue and may impair function in these organ systems.

Genomic Comparison Of Clonal B-Cells In Waldenstrom Macroglobulinemia (WM) Versus IgM MGUS

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 400-400
Author(s):  
Bruno Paiva ◽  
Luis A Corchete ◽  
Norma Gutierrez ◽  
María-Belén Vidriales ◽  
Irene Aires-Mejia ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Significant Proportion ◽  
Molecular Profile ◽  
Healthy Donors ◽  
Myd88 L265p

Abstract It is hypothesized that similarly to multiple myeloma, also in WM there may be a continuum between IgM MGUS, smoldering (SWM) and symptomatic WM, rather than these entities being considered as separate. The very low frequency of MYD88 L265P initially reported in IgM MGUS suggested that this could be implicated in disease transformation. However, using sensitive ASO-PCR a significant proportion of patients of patients with IgM MGUS already harbors the MYD88 mutation. Thus, the molecular mechanisms driving the malignant transformation of WM remain largely unknown. Here, we used high-sensitive 8-color multidimensional flow cytometry (MFC) to detect and sort the specific B-cell clone in BM samples (N=31) from a total of 22 newly-diagnosed WM patients (8 symptomatic, 14 SWM) as well as 9 patients with IgM MGUS. The later 9 cases had negative BM biopsy, but light-chain restricted clonal B-cells (typically CD22low, CD25+, sIgM+, LAIR1-) were identified by MFC (median 1.74%, range 0.2%-7.04%). MYD88 L265P was detected on FACS-sorted (purity ≥97%) clonal B-cells from 9/9, 13/14 and 7/8 IgM MGUS, SWM and WM patients, respectively. We first compared the genomic profile of clonal B-cells through high density Cytoscan750K array. Overall, IgM MGUS, SWM and WM patients showed a median of 2, 1.5, and 3 copy number abnormalities (CNA)/case, respectively [defined by >25 consecutive imbalanced markers/segment, >100Kb genomic size and <50% overlapping variants with patient-paired control DNA (n=6), or unpaired DNA from BM normal B-cells from 20 healthy donors]. Whole chromosomal imbalances were detected in IgM MGUS (+18), SWM (+3, +12) and WM patients (+4, +12, +18, +19). Gain and deletion of chromosomal arms was also detected in the 3 disease stages: 3q+, 6q-, 8p-, 13q-, 17p-, 18q+ in IgM MGUS; 11q- in SWM; and 6q-, 17p-, 18q+, 22q- in WM. Thus, genomic imbalances typically observed in WM (3q+,6q- or 18q+) were already detectable in clonal B-cells from IgM MGUS patients. Trisomy 4 was not present, nor CNA at 4q33-34 (previously ascribed with increased susceptibility for IgM MGUS and WM). One minimal amplified region at 8q11.23 was noted in 6 of the 31 patients (19%). Median number of copy-number-neutral loss of heterozygosity (CNN-LOH) was also similar between IgM MGUS, SWM and WM (median of 3, 2, and 3 CNN-LOH/case, respectively). Of note, two IgM MGUS patients showed CNN-LOH in minimal deleted regions often detected in the aggressive forms of the disease such as 6q16.1and 6q25.3. In accordance to the genomic profiles, preliminary analysis of gene expression profiles (GEP; HumanGene 1.0ST) between FACS-sorted clonal B-cells from IgM MGUS, SWM and WM patients showed virtually no deregulated genes (SAM Excel add-in with a FDR q-value<10-5). Consequently, we grouped patients together (n=14) and compared them to normal BM B-cells from healthy donors. Moreover, taking into consideration the aberrant phenotypes of the Waldenström’s clone, a specific comparison was made between the GEP of clonal B-cells vs CD22+/CD25- normal B-cells (n=6) as well as the small subset of normal BM B-cells that display the typical CD22low/CD25+ WM phenotype (n=4). Clonal B-cells showed de-regulation of 776 genes (92 down- and 684 up-regulated) as compared to CD22+/CD25- normal B-cells. By enrichment analysis (Ingenuity Pathways), top upstream regulators such as IFNg, the B-cell receptor (BCR) complex, and the synovial apoptosis inhibitor 1 (SYVN1) were activated in clonal B-cells, while the IL1 receptor antagonist (IL1RN) was inhibited. Well-known genes such as PRDM1, CD27, IL2Rα (CD25) or TRAF3 were also up-regulated in clonal B-cells. Noteworthy, up to 27 genes over-expressed by clonal B-cells were already up-regulated in normal BM CD22low/CD25+ B-cells vs CD22+/CD25- normal B-cells. Accordingly, when compared to the CD22low/CD25+ normal B-cell counterpart, GEP of clonal B-cells was far less deregulated (185 genes being infra-expressed). In fact, genes such as IL1R2, TLR4, TNFRSF1A, IGF1R, FCER1G or TNFSF13B (target molecules of the NFKB and IL-6 pathways) were down-regulated in the WM clone vs CD22low/CD25+ normal B-cells. In summary, our results show that clonal B-cells from IgM MGUS patients already show a molecular profile that overlaps with that of WM, and suggest that the Waldenström’s clone may arise from normal CD22low/CD25+ BM B-cells. Disclosures: No relevant conflicts of interest to declare.

Thyroid Cancer—Risks and Causes

2014 ◽  
Vol 10 (02) ◽  
pp. 144
Author(s):  
Simon Bonnefond ◽  
Terry F Davies ◽  
◽  
Keyword(s):  
Thyroid Cancer ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Significant Proportion ◽  
Precipitating Factors ◽  
Local Tumor ◽  
Cancer Risks ◽  
The Us ◽  
Different Types ◽  
Metastatic Thyroid Cancer

The incidence of thyroid cancer has almost doubled in recent years and over 60,000 people will be diagnosed in the US in 2015. While the prognosis for most such patients is excellent, a significant proportion die of thyroid cancer from local tumor progression and above all from metastases. Here we review the different types of thyroid cancers and their molecular changes with a special emphasis on the currently known susceptibility and precipitating factors. With the recent clinical introduction of tyrosine kinase inhibitors for the treatment of metastatic thyroid cancer it is clear that a simple cure is not at hand and further understanding of the molecular mechanisms of these tumors is urgently needed.

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