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Trends Mol Med,
2007]
Transforming growth factor beta1 (TGFbeta1), an important pleiotropic, immunoregulatory cytokine, uses distinct signaling mechanisms in lymphocytes to affect T-cell homeostasis, regulatory T (T(reg))-cell and effector-cell function and tumorigenesis. Defects in TGFbeta1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. TGFbeta1 prevents abnormal T-cell activation through the modulation of Ca(2+)-calcineurin signaling in a Caenorhabditis elegans Sma and Drosophila Mad proteins (SMAD)3 and SMAD4-independent manner; however, in T(reg) cells, its effects are mediated, at least in part, through SMAD signaling. TGFbeta1 also acts as a pro-inflammatory cytokine and induces interleukin (IL)-17-producing pathogenic T-helper cells (T(h) IL-17 cells) synergistically during an inflammatory response in which IL-6 is produced. Here, we will review TGFbeta1 and its signaling in T cells with an emphasis on the regulatory arm of immune tolerance.
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Exp Gerontol,
2006]
Caenorhabditis elegans has been used to model aspects of a number of age-associated neurodegenerative diseases, including Alzheimer''s, Parkinson''s and Huntington''s diseases. These models have typically involved the transgenic expression of disease-associated human proteins. Here I describe my laboratory''s specific experience engineering C. elegans models of Alzheimer''s disease, and give a general consideration of the advantages and disadvantages of these C. elegans models. The type of insights that might be gained from using these (relatively) simple models are highlighted. In particular, I consider the potential these models have for uncovering common and unique fundamental toxic mechanisms underlying human neurodegenerative diseases.
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Curr Biol,
2001]
When meiotic cells complete S phase, homologous chromosomes pair, synapse and undergo recombination. A checkpoint protein is somehow required for meiotic chromosome pairing in C. elegans, thus providing a direct link between S phase and the rest of the meiotic program.
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Toxins (Basel),
2016]
Staphylococcus aureus is an opportunistic pathogen and the leading cause of a wide range of severe clinical infections. The range of diseases reflects the diversity of virulence factors produced by this pathogen. To establish an infection in the host, S. aureus expresses an inclusive set of virulence factors such as toxins, enzymes, adhesins, and other surface proteins that allow the pathogen to survive under extreme conditions and are essential for the bacteria's ability to spread through tissues. Expression and secretion of this array of toxins and enzymes are tightly controlled by a number of regulatory systems. S. aureus is also notorious for its ability to resist the arsenal of currently available antibiotics and dissemination of various multidrug-resistant S. aureus clones limits therapeutic options for a S. aureus infection. Recently, the development of anti-virulence therapeutics that neutralize S. aureus toxins or block the pathways that regulate toxin production has shown potential in thwarting the bacteria's acquisition of antibiotic resistance. In this review, we provide insights into the regulation of S. aureus toxin production and potential anti-virulence strategies that target S. aureus toxins.
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Front Physiol,
2014]
The recent discovery of DNA methylation in the nematode T.spiralis may raise the possibility of using it as a potential model organism for epigenetic studies instead of C. elegans, which is deficient in this important epigenetic modification. In contrast to the free-living nematode C. elegans, T. spiralis is a parasitic worm that possesses a complicated life cycle and undergoes a complex developmental regulation of genes. We emphasize that the differential methylomes in the different life-history stages of T. spiralis can provide insight on how DNA methylation is triggered and regulated. In particular, we have demonstrated that DNA methylation is involved in the regulation of its parasitism-related genes. Further computational analyses indicated that the regulatory machinery for DNA methylation can also be found in the T. spiralis genome. By a logical extension of this point, we speculate that comprehensively addressing the epigenetic machinery of T. spiralis may help to understand epigenetics in invertebrates. Furthermore, considering the implication of epigenetics in metazoan parasitism, using T. spiralis as an epigenetic model organism may further contribute to drug development against metazoan parasites.
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WormBook,
2007]
Because of their free-living life cycle alternatives, Strongyloides and related nematode parasites may represent the best models for translating C. elegans science to the study of nematode parasitism. S. stercoralis, a significant pathogen of humans, can be maintained in laboratory dogs and gerbils. Biosafety precautions necessary for work with S. stercoralis, though unfamiliar to many C. elegans researchers, are straightforward and easily accomplished. Although specialized methods are necessary for large-scale culture of the free-living stages of S. stercoralis, small-scale cultures for experimental purposes may be undertaken using minor modifications of standard C. elegans methods. Similarly, the morphological similarities between C. elegans and the free-living stages of S. stercoralis allow investigational methods such as laser cell ablation and DNA transformation by gonadal microinjection to be easily adapted from C. elegans to S. stercoralis. Comparative studies employing these methods have yielded new insights into the neuronal control of the infective process in parasites and its similarity to regulation of dauer development in C. elegans. Furthermore, we have developed a practical method for transient transformation of S. stercoralis with vector constructs having various tissue- and cell-specific expression patterns and have assembled these into a modular vector kit for distribution to the community.
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Ann Pharm Fr,
2006]
The Nematode Caenorhabditis elegans (C. elegans) is an established model increasingly used for studying human disease pathogenesis. C. elegans models are based on the mutagenesis of human disease genes conserved in this Nematode or on the transgenesis with disease genes not conserved in C. elegans. Genetic examinations will give new insights on the cellular and molecular mechanisms that are altered in some neurodegenerative diseases like Duchenne''s muscular dystrophy, Huntington''s disease and Alzheimer''s disease. C. elegans may be used for primary screening of new compounds that may be used as drugs in these diseases.
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J Biomed Sci,
2019]
MAP4K3 (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and proinflammatory cytokines. The data derived from GLK-overexpressing or shRNA-knockdown cell lines suggest that GLK may be involved in cell proliferation through mTOR signaling. GLK phosphorylates the transcription factor TFEB and retains TFEB in the cytoplasm, leading to inhibition of cell autophagy. After generating and characterizing GLK-deficient mice, the important in vivo roles of GLK in T-cell activation were revealed. In T cells, GLK directly interacts with and activates PKC through phosphorylating PKC at Ser-538 residue, leading to activation of IKK/NF-B. Thus, GLK-deficient mice display impaired T-cell-mediated immune responses and decreased inflammatory phenotypes in autoimmune disease models. Consistently, the percentage of GLK-overexpressing T cells is increased in the peripheral blood from autoimmune disease patients; the GLK-overexpressing T cell population is correlated with disease severity of patients. The pathogenic mechanism of autoimmune disease by GLK overexpression was unraveled by characterizing T-cell-specific GLK transgenic mice and using biochemical analyses. GLK overexpression selectively promotes IL-17A transcription by inducing the AhR-RORt complex in T cells. In addition, GLK overexpression in cancer tissues is correlated with cancer recurrence of human lung cancer and liver cancer; the predictive power of GLK overexpression for cancer recurrence is higher than that of pathologic stage. GLK directly phosphorylates and activates IQGAP1, resulting in induction of Cdc42-mediated cell migration and cancer metastasis. Furthermore, treatment of GLK inhibitor reduces disease severity of mouse autoimmune disease models and decreases IL-17A production of human autoimmune T cells. Due to the inhibitory function of HPK1/MAP4K1 in T-cell activation and the promoting effects of GLK on tumorigenesis, HPK1 and GLK dual inhibitors could be useful therapeutic drugs for cancer immunotherapy. In addition, GLK deficiency results in extension of lifespan in Caenorhabditis elegans and mice. Taken together, targeting MAP4K3 (GLK) may be useful for treating/preventing autoimmune disease, cancer metastasis/recurrence, and aging.
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IUBMB Life,
2007]
Most tRNAs share a common secondary structure containing a T arm, a D arm, an anticodon arm and an acceptor stem. However, there are some exceptions. Most nematode mitochondrial tRNAs and some animal mitochondrial tRNAs lack the T arm, which is necessary for binding to canonical elongation factor Tu (EF-Tu). The mitochondria of the nematode Caenorhabditis elegans have a unique EF-Tu, named EF-Tu1, whose structure has supplied clues as to how truncated tRNAs can work in translation. EF-Tu1 has a C-terminal extension of about 60 aa that is absent in canonical EF-Tu. Recent data from our laboratory strongly suggests that EF-Tu1 recognizes the D-arm instead of the T arm by a mechanism involving this C-terminal region. Further biochemical analysis of mitochondrial tRNAs and EF-Tu from the distantly related nematode Trichinella spp. and sequence information on nuclear and mitochondrial DNA in arthropods suggest that T-armless tRNAs may have arisen as a result of duplication of the EF-Tu gene. These studies provide valuable insights into the co-evolution of RNA and RNA-binding proteins. IUBMB Life, 59: 68-75, 2007.
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Mol Cell,
2004]
Applying a combination of innovative approaches to understanding neuronal gene regulation in C. elegans, an article in the latest Developmental Cell (Wenick and Hobert, 2004) gives hope that reading the genome''s transcriptional regulatory code may one day be possible.