12 results on '"Jefferson, Matthew P"'
Search Results
2. Regulation of Alternative Splicing in Drosophila Melanogaster
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Taliaferro, Jefferson Matthew
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Molecular biology ,Biochemistry ,Bioinformatics ,Alternative splicing ,Drosophila ,RNA - Abstract
The patterns and mechanisms by which eukaryotic cells regulate the expression of their genetic information are highly complex and intricate. The transmittance of this information from nuclear repository to cytoplasmic translation contains within it several steps, including the selective removal and concomitant joining of pieces of information in a process called alternative splicing. The projects detailed within this document describe the regulation of alternative splicing through the interaction of specific proteins with specific pre-mRNA transcripts.The Rio lab has studied PSI, a protein involved in the regulation of the P element transposase transcript, for many years. It has since been shown to regulate the splicing of hundreds of other transcripts. The experiments described here look at the organization of PSI and other proteins on the P element transcript by site-specific labeling of the transcript using radioactive 32P. We also investigate two phosphorylation events of PSI, identifying the kinases responsible and demonstrate that these events may change the protein-protein interaction partners of PSI.It has become increasingly apparent that alternative splicing may not only be regulated by protein/RNA interactions, but also by RNA/RNA interactions. To probe this, we designed experiments to test if some well-known small RNA-associated proteins are regulating alternative splicing. Using splice junction microarrays, we determined that Argonaute-2 (Ago-2) regulated the splicing of over 100 splice junctions, and further experiments using ChIP-seq and mRNA-seq of Ago-2 mutants revealed that Ago-2 also has a role in transcriptional repression, possibly through being incorporating in complexes composed of polycomb-group genes. We also used CLIP-seq to determine the RNA binding profile and preferences of Ago-2 in Drosophila tissue culture cells.Finally, we characterized the functions of a Drosophila specific splicing factor called LS2. LS2 is orthologous to the highly conserved splicing factor dU2AF50, but its origin through retroduplication and subsequent divergence to acquire distinct sequence specificity, expression pattern, and function show it to be an interesting case in the evolution of alternative splicing regulation. This may be a mechanism that underlies the existence of some members of the large families of splicing factors, including hnRNP proteins and SR proteins. That is, by duplicating functional copies of genes, cellular systems create new proteins to tinker with and acquire new functions while keeping the former functionality and stability of the parent protein.While these projects are essentially independent of each other, they all fall under the umbrella of protein regulation of RNA metabolism and hopefully contribute to a more complete understanding of the regulation of gene expression.
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- 2012
3. A bivalent conjugate vaccine in the treatment of biochemically relapsed prostate cancer: a study of glycosylated MUC-2-KLH and Globo H-KLH conjugate vaccines given with the new semi-synthetic saponin immunological adjuvant GPI-0100 OR QS-21
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Slovin, Susan F., Ragupathi, Govind, Fernandez, Celina, Jefferson, Matthew P., Diani, Meghan, Wilton, Andrew S., Powell, Shemeeakah, Spassova, Maria, Reis, Celso, Clausen, Henrick, Danishefsky, Samuel, Livingston, Philip, and Scher, Howard I.
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- 2005
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4. The WD Domain of Atg16l1Crucial for LC3-Associated Phagocytosis Is Not Required for Preserving Skin Barrier Function in Mice
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Conway, Shannon, Jefferson, Matthew, Warren, Derek T., Wileman, Thomas, and Morris, Christopher J.
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The skin is a multifunctional organ, forming a barrier between the external and internal environment, thereby functioning as a safeguard against extrinsic factors. Autophagy has been implicated in epidermal differentiation and in preserving skin homeostasis. LC3-associated phagocytosis (LAP) uses some but not all components of autophagy. The Atg16l1(ΔWD) mouse model lacks the WD40 domain required for LAP and has been widely used to study the effects of LAP deficiency and autophagy on tissue homeostasis and response to infection.
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- 2024
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5. The ATG5-binding and coiled coil domains of ATG16L1 maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3-associated phagocytosis
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Rai, Shashank, Arasteh, Maryam, Jefferson, Matthew, Pearson, Timothy, Wang, Yingxue, Zhang, Weijiao, Bicsak, Bertalan, Divekar, Devina, Powell, Penny P., Naumann, Ronald, Beraza, Naiara, Carding, Simon R., Florey, Oliver, Mayer, Ulrike, and Wileman, Thomas
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ABSTRACTMacroautophagy/autophagy delivers damaged proteins and organelles to lysosomes for degradation, and plays important roles in maintaining tissue homeostasis by reducing tissue damage. The translocation of LC3 to the limiting membrane of the phagophore, the precursor to the autophagosome, during autophagy provides a binding site for autophagy cargoes, and facilitates fusion with lysosomes. An autophagy-related pathway called LC3-associated phagocytosis (LAP) targets LC3 to phagosome and endosome membranes during uptake of bacterial and fungal pathogens, and targets LC3 to swollen endosomes containing particulate material or apoptotic cells. We have investigated the roles played by autophagy and LAP in vivoby exploiting the observation that the WD domain of ATG16L1 is required for LAP, but not autophagy. Mice lacking the linker and WD domains, activate autophagy, but are deficient in LAP. The LAP−/-mice survive postnatal starvation, grow at the same rate as littermate controls, and are fertile. The liver, kidney, brain and muscle of these mice maintain levels of autophagy cargoes such as LC3 and SQSTM1/p62 similar to littermate controls, and prevent accumulation of SQSTM1 inclusions and tissue damage associated with loss of autophagy. The results suggest that autophagy maintains tissue homeostasis in mice independently of LC3-associated phagocytosis. Further deletion of glutamate E230 in the coiled-coil domain required for WIPI2 binding produced mice with defective autophagy that survived neonatal starvation. Analysis of brain lysates suggested that interactions between WIPI2 and ATG16L1 were less critical for autophagy in the brain, which may allow a low level of autophagy to overcome neonatal lethality.Abbreviations: CCD: coiled-coil domain; CYBB/NOX2: cytochrome b-245: beta polypeptide; GPT/ALT: glutamic pyruvic transaminase: soluble; LAP: LC3-associated phagocytosis; LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; NOD: nucleotide-binding oligomerization domain; NADPH: nicotinamide adenine dinucleotide phosphate; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing Beclin 1-interacting protein; SLE: systemic lupus erythematosus; SQSTM1/p62: sequestosome 1; TLR: toll-like receptor; TMEM: transmembrane protein; TRIM: tripartite motif-containing protein; UVRAG: UV radiation resistance associated gene; WD: tryptophan-aspartic acid; WIPI: WD 40 repeat domain: phosphoinositide interacting
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- 2019
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6. Single dose combination nanovaccine provides protection against influenza A virus in young and aged mice
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RossThese authors contributed equally to this work., Kathleen, Senapati, Sujata, Alley, Jessica, Darling, Ross, Goodman, Jonathan, Jefferson, Matthew, Uz, Metin, Guo, Baoqing, Yoon, Kyoung-Jin, Verhoeven, David, Kohut, Marian, Mallapragada, Surya, Wannemuehler, Michael, and Narasimhan, Balaji
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Immunosenescence poses a formidable challenge in designing effective influenza vaccines for aging populations. While approved vaccines against influenza viruses exist, their efficacy in older adults is significantly decreased due to the diminished capabilities of innate and adaptive immune responses. In this work, the ability of a combination nanovaccine containing both recombinant hemagglutinin and nucleoprotein to provide protection against seasonal influenza virus infection was examined in young and aged mice. Vaccine formulations combining two nanoadjuvants, polyanhydride nanoparticles and pentablock copolymer micelles, were shown to enhance protection against challenge compared to each adjuvant alone in young mice. Nanoparticles were shown to enhance in vitroactivation of dendritic cells isolated from aged mice, while both nanoadjuvants did not induce proinflammatory cytokine secretion which may be detrimental in aged individuals. In addition, the combination nanovaccine platform was shown to induce demonstrable antibody titers in both young and aged mice that correlated with the maintenance of body weight post-challenge. Collectively, these data demonstrate that the combination nanovaccine platform is a promising technology for influenza vaccines for older adults.
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- 2019
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7. A polyvalent vaccine for high-risk prostate patients: 'are more antigens better?'
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Slovin, Susan F, Ragupathi, Govind, Fernandez, Celina, Diani, Meghan, Jefferson, Matthew P, Wilton, Andrew, Kelly, W Kevin, Morris, Michael, Solit, David, Clausen, Henrik, Livingston, Philip, Scher, Howard I, Slovin, Susan F, Ragupathi, Govind, Fernandez, Celina, Diani, Meghan, Jefferson, Matthew P, Wilton, Andrew, Kelly, W Kevin, Morris, Michael, Solit, David, Clausen, Henrik, Livingston, Philip, and Scher, Howard I
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Udgivelsesdato: 2007-Dec, We have shown the immunogenicity and safety of synthetic carbohydrate vaccines when conjugated to the carrier keyhole limpet hemocyanin (KLH) and given with the adjuvant, QS-21, in patients with biochemically relapsed prostate cancer. To determine whether immune response could be further enhanced with stimulation by multiple antigens, a hexavalent vaccine was prepared using previously determined doses and administered in a Phase II setting to 30 high-risk patients. The hexavalent vaccine included GM2, Globo H, Lewis(y), glycosylated MUC-1-32mer and Tn and TF in a clustered formation, conjugated to KLH and mixed with QS-21. Eight vaccinations were administered over 13 months. All 30 patients had significant elevations in antibody titers to at least two of the six antigens; 22 patients had increased reactivity with FACS. These serologic responses were lower than that seen previously in patients treated with the respective monovalent vaccines. The reciprocal median combined IgM and IgG antibody titers with ELISA against MUC1, Tn, TF, globo H and GM2 for these 30 patients were 640, 80, 120, 40 and 0, compared to 1280, 640, 1280, 320 and 160 seen in patients receiving individual monovalent vaccines. This hexavalent vaccine of synthetic "self" antigens broke immunologic tolerance against two or more antigens in all 30 vaccinated patients, was safe, but antibody titers against several of the antigens were lower than those seen in individual monovalent trials. No impact on PSA slope was detected. We address the relevance of the multivalent approach for prostate cancer treatment.
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- 2007
8. Autophagy and formation of tubulovesicular autophagosomes provide a barrier against nonviral gene delivery
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Roberts, Rebecca, Al-Jamal, Wafa’ T., Whelband, Matthew, Thomas, Paul, Jefferson, Matthew, van den Bossche, Jeroen, Powell, Penny P., Kostarelos, Kostas, and Wileman, Thomas
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Cationic liposome (lipoplex) and polymer (polyplex)-based vectors have been developed for nonviral gene delivery. These vectors bind DNA and enter cells via endosomes, but intracellular transfer of DNA to the nucleus is inefficient. Here we show that lipoplex and polyplex vectors enter cells in endosomes, activate autophagy and generate tubulovesicular autophagosomes. Activation of autophagy was dependent on ATG5, resulting in lipidation of LC3, but did not require the PtdIns 3-kinase activity of PIK3C3/VPS34. The autophagosomes generated by lipoplex fused with each other, and with endosomes, resulting in the delivery of vectors to large tubulovesicular autophagosomes, which accumulated next to the nucleus. The tubulovesicular autophagosomes contained autophagy receptor protein SQSTM1/p62 and ubiquitin, suggesting capture of autophagy cargoes, but fusion with lysosomes was slow. Gene delivery and expression from both lipoplex and polyplex increased 8-fold in atg5−/−cells unable to generate tubulovesicular autophagosomes. Activation of autophagy and capture within tubulovesicular autophagosomes therefore provides a new cellular barrier against efficient gene transfer and should be considered when designing efficient nonviral gene delivery vectors.
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- 2013
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9. LC3-Associated Phagocytosis in Bone Marrow Macrophages Suppresses AML Progression through Mitochondrial DAMP Induced Sting Activation
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Moore, Jamie A, Mistry, Jayna J, Hellmich, Charlotte, Horton, Rebecca H, Wojtowicz, Edyta, Jibril, Aisha, Wileman, Tom, Jefferson, Matthew, Beraza, Naiara, Bowles, Kristian M, and Rushworth, Stuart A
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The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for uncleared apoptotic debris in regulating the immunologic response to, and growth of, solid tumors. LC3-associated phagocytosis (LAP) maintains tissue homeostasis by regulating immune responses, such as tumor immunity. Here we investigate the role of LAP in macrophage within the BM microenvironment of AML.
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- 2021
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10. FGF‐4 signaling is involved in mir‐206 expression in developing somites of chicken embryos
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Sweetman, Dylan, Rathjen, Tina, Jefferson, Matthew, Wheeler, Guy, Smith, Terence G., Wheeler, Grant N., Münsterberg, Andrea, and Dalmay, Tamas
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The microRNAs (miRNAs) are recently discovered short, noncoding RNAs, that regulate gene expression in metazoans. We have cloned short RNAs from chicken embryos and identified five new chicken miRNA genes. Genome analysis identified 17 new chicken miRNA genes based on sequence homology to previously characterized mouse miRNAs. Developmental Northern blots of chick embryos showed increased accumulation of most miRNAs analyzed from 1.5 days to 5 days except, the stem cell–specific mir‐302, which was expressed at high levels at early stages and then declined. In situ analysis of mature miRNAs revealed the restricted expression of mir‐124 in the central nervous system and of mir‐206 in developing somites, in particular the developing myotome. In addition, we investigated how miR‐206 expression is controlled during somite development using bead implants. These experiments demonstrate that fibroblast growth factor (FGF) ‐mediated signaling negatively regulates the initiation of mir‐206 gene expression. This may be mediated through the effects of FGF on somite differentiation. These data provide the first demonstration that developmental signaling pathways affect miRNA expression. Thus far, miRNAs have not been studied extensively in chicken embryos, and our results show that this system can complement other model organisms to investigate the regulation of many other miRNAs. Developmental Dynamics 235:2185–2191, 2006. © 2006 Wiley‐Liss, Inc.
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- 2006
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11. Salmonella as a biological "Trojan horse" for neoplasia: Future possibilities including brain cancer.
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Mlynarczyk, Gregory S.A., Berg, Carrie A., Withrock, Isabelle C., Fick, Meghan E., Anderson, Stephen J., Laboissonniere, Lauren A., Jefferson, Matthew A., Brewer, Matthew T., Stock, Matthew L., Lange, Jennifer K., Luna, K. C., Acharya, Sreemoyee, Kanuri, Sriharsha, Sharma, Shaunik, Kondru, Naveen C., McCormack, Garrett R., and Carlson, Steve A.
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SALMONELLA ,DRUG administration ,TREATMENT of brain cancer ,LIPOPOLYSACCHARIDES ,SEPSIS ,SEPTIC shock - Abstract
This manuscript considers available evidence that a specific Salmonella strain could be used as an effective orally-administered option for cancer therapy involving the brain. It has been established that Salmonella preferentially colonizes neoplastic tissue and thrives as a facultative anaerobe in the intra-tumor environment. Although Salmonella accumulates in tumors by passive processes, it is still possible for lipopolysaccharide to cause sepsis and endotoxic shock during the migration of bacteria to the tumor site. An LPS-free version of a recently identified Salmonella isolate may have the capability to circumvent the blood brain barrier and provide a safer method of reaching brain tumors. This isolate merits further research as a "Trojan horse" for future oral biotherapy of brain cancer. [ABSTRACT FROM AUTHOR]
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- 2014
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12. Integrative analysis of Paneth cell proteomic and transcriptomic data from intestinal organoids reveals functional processes dependent on autophagy
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Jones, Emily J., Matthews, Zoe J., Gul, Lejla, Sudhakar, Padhmanand, Treveil, Agatha, Divekar, Devina, Buck, Jasmine, Wrzesinski, Tomasz, Jefferson, Matthew, Armstrong, Stuart D., Hall, Lindsay J., Watson, Alastair J. M., Carding, Simon R., Haerty, Wilfried, Di Palma, Federica, Mayer, Ulrike, Powell, Penny P., Hautefort, Isabelle, Wileman, Tom, and Korcsmaros, Tamas
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Paneth cells are key epithelial cells that provide an antimicrobial barrier and maintain integrity of the small-intestinal stem cell niche. Paneth cell abnormalities are unfortunately detrimental to gut health and are often associated with digestive pathologies such as Crohn's disease or infections. Similar alterations are observed in individuals with impaired autophagy, a process that recycles cellular components. The direct effect of autophagy impairment on Paneth cells has not been analysed. To investigate this, we generated a mouse model lacking Atg16l1 specifically in intestinal epithelial cells, making these cells impaired in autophagy. Using three-dimensional intestinal organoids enriched for Paneth cells, we compared the proteomic profiles of wild-type and autophagy-impaired organoids. We used an integrated computational approach combining protein-protein interaction networks, autophagy-targeted proteins and functional information to identify the mechanistic link between autophagy impairment and disrupted pathways. Of the 284 altered proteins, 198 (70%) were more abundant in autophagy-impaired organoids, suggesting reduced protein degradation. Interestingly, these differentially abundant proteins comprised 116 proteins (41%) that are predicted targets of the selective autophagy proteins p62, LC3 and ATG16L1. Our integrative analysis revealed autophagy-mediated mechanisms that degrade key proteins in Paneth cell functions, such as exocytosis, apoptosis and DNA damage repair. Transcriptomic profiling of additional organoids confirmed that 90% of the observed changes upon autophagy alteration have effects at the protein level, not on gene expression. We performed further validation experiments showing differential lysozyme secretion, confirming our computationally inferred downregulation of exocytosis. Our observations could explain how protein-level alterations affect Paneth cell homeostatic functions upon autophagy impairment. This article has an associated First Person interview with the joint first authors of the paper.
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- 2019
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