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1.
Elife ; 92020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31958057

RESUMO

The RAS proteins are GTP-dependent switches that regulate signaling pathways and are frequently mutated in cancer. RAS proteins concentrate in the plasma membrane via lipid-tethers and hypervariable side-chain interactions in distinct nano-domains. However, little is known about RAS membrane dynamics and the details of RAS activation of downstream signaling. Here we characterize RAS in live human and mouse cells using single molecule tracking methods and estimate RAS mobility parameters. KRAS4b exhibits confined mobility with three diffusive states distinct from the other RAS isoforms (KRAS4a, NRAS, and HRAS); and although most of the amino acid differences between RAS isoforms lie within the hypervariable region, the additional confinement of KRAS4b is largely determined by the protein's globular domain. To understand the altered mobility of an oncogenic KRAS4b we used complementary experimental and molecular dynamic simulation approaches to reveal a detailed mechanism.

2.
J Fish Dis ; 43(1): 39-48, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31726482

RESUMO

Hydrogen peroxide (H2 O2 ) is a commonly used treatment for a range of parasitic diseases of marine finfish, including amoebic gill disease (AGD). While this treatment is partially effective at reducing parasite load, H2 O2 can have detrimental effects on the host under certain conditions. Treatment temperature and dose concentration are two factors that are known to influence the toxicity of H2 O2 ; however, their impact on the outcome of AGD treatment remains unclear. Here, we investigated the effects of treatment temperature (8, 12 or 16°C) and dose concentration (750, 1,000, 1,250 mg/L) on the efficacy of H2 O2 to treat AGD. We demonstrated that a 20-min bath treatment of H2 O2 at all doses reduced both parasite load and gross gill score significantly. Parasite load and gross gill score were lowest in the 1,000 mg/L treatment performed at 12°C. At the high dose and temperature combinations, H2 O2 caused moderate gill damage and a significant increase in the plasma concentration of electrolytes (sodium, chloride and potassium). Taken together, our study demonstrates that higher H2 O2 treatment temperatures can adversely affect the host and do not improve the effectiveness of the treatment.

3.
J Proteomics ; 209: 103488, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31445215

RESUMO

Today we have unprecedented access to human genomic and proteomic data that appear to be rapidly approaching our current understanding of comprehensive coverage. Combining genomic information with shotgun proteomics remains challenging due to the large increase in proteomics search space. However, making this connection between genomic and proteomic information is critical for cancer studies to vaccine development. Furthermore, as we progress towards personalized medicine, it will be essential for proteomics analysis to identify individual mutations and variants in order to fully understand protein networks and to develop personalized therapies. While these advantages are well-established, only a few studies have demonstrated the successful integration of proteomic data with large genomic input. We present and examine the abilities of Bolt, a new cloud-based proteomics search engine to search for the presence of over 2.3 million known cancer mutations in a matter of minutes while still performing a standard proteomics search that includes 31 post translational modifications. We use previously published proteomics data sets and identify mutations that are verified using genomic studies as well as previous proteomics efforts. Our results also emphasize the need to search for mutations in a comprehensive manner while still searching for both common and rare PTMs. SIGNIFICANCE: We present and examine the abilities of Bolt, a new cloud-based proteomics search engine to search for the presence of over 2.3 million known cancer mutations in a matter of minutes while still performing a standard proteomics search that includes 31 post translational modifications. No other proteomics search software can do so.

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