Med One最新文献

Precision medicine informatics is a field of research that incorporates learning systems that generate new knowledge to improve individualized treatments using integrated data sets and models. Given the ever-increasing volumes of data that are relevant to patient care, artificial intelligence (AI) pipelines need to be a central component of such research to speed discovery. Applying AI methodology to complex multidisciplinary information retrieval can support efforts to discover bridging concepts within collaborating communities. This dovetails with precision medicine research, given the information rich multi-omic data that are used in precision medicine analysis pipelines. In this perspective article we define a prototype AI pipeline to facilitate discovering research connections between bioinformatics and clinical researchers. We propose building knowledge representations that are iteratively improved through AI and human-informed learning feedback loops supported through crowdsourcing. To illustrate this, we will explore the specific use case of nonalcoholic fatty liver disease, a growing health care problem. We will examine AI pipeline construction and utilization in relation to bench-to-bedside bridging concepts with interconnecting knowledge representations applicable to bioinformatics researchers and clinicians.

Peroxynitrite (ONOO^-, PN) has long been considered a potent nitrating agent implicated in numerous inflammation-mediated diseases. The current work highlights an unexplored oxidation chemistry initiated under conditions of sustained PN exposure. Impetus for this investigation developed from mass spectral results that suggested dimerization of a model peptide with a single tyrosine residue that was first nitrated following extended exposure to PN generated in situ. In attempts to substantiate this dimerization event and divulge the possible mode of linkage between the tyrosine derivatives of the peptide monomers, 3-nitrotyrosine (3-NT) was exposed to sustained fluxes of PN in a two-component PN-generating platform developed in this laboratory. Such exposure afforded products with tandem mass spectrometry and fluorescence spectroscopy profiles indicative of C-O coupling between 3-NT moieties. Synthesis and comparative analysis of the C-C coupled 3-NT isomer corroborated these findings. Most notably, the mass spectral data of the C-C coupled 3-NT dimer displayed a 226.80 m/z peak following exposure to high collision energy, corresponding to symmetric cleavage of the parent dimer peak (m/z = 453) along with a fragmentation product at m/z = 180.04 (-NO₂ species). This fragmentation profile was distinct from the C-O coupled 3-NT dimer that exhibited a predominant 209.14 m/z peak with a small secondary 226.15 m/z peak indicative of asymmetric cleavage of the parent dimer. Results of this study indicate that formation of C-O coupled 3-NT dimer is promoted by elevated levels of 3-NT formed under high and sustained flux of PN.

Stem cell therapy has emerged as one of the topics in tissue engineering where undifferentiated and multipotent cells are strategically placed/ injected in tissue structure for cell regeneration. Over the years, stem cells have shown promising results in skin repairs for non-healing and/or chronic wounds. The addition of the stem cells around the wound site promotes signaling pathways for growth factors that regulate tissue reconstruction. However, injecting stem cells around the wound site has its drawbacks, including cell death due to lack of microenvironment cues. This particular issue is resolved when biomaterial scaffolds are involved in the cultivation and mechanical support of the stem cells. In this review, we describe the current models of stem cell therapy by injections and those that are done through cell cultures using electrospun fiber scaffolds. Electrospun fibers are considered as an ideal candidate for cell cultures due to their surface properties. Through the control of fiber morphology and fiber structure, cells are able to proliferate and differentiate into keratinocytes for skin tissue regeneration. Furthermore, we provide another perspective of using electrospun fibers and stem cells in a layer-by-layer structure for skin substitutes (dressing). Finally, electrospun fibers have the potential to incorporate bioactive agents to achieve controlled release properties, which is beneficial to the survival of the delivered stem cells or the recruitment of the cells. Overall, our work illustrates that electrospun fibers are ideal for stem cell cultures while serving as cell carriers for wound dressing materials.

A large body of in vivo and in vitro evidence indicates that Manuka honey resolves inflammation and promotes healing when applied topically to a wound. In this study, the effect of two different concentrations (0.5% and 3% v/v) of Manuka honey on the release of cytokines, chemokines, and matrix-degrading enzymes from neutrophils was examined using a differentiated HL-60 cell line model in the presence of inflammatory stimuli. The results indicate that 0.5% honey decreased TNF-α, IL-1β, MIP-1α, MIP-1β, IL-12 p70, MMP-9, MMP-1, FGF-13, IL-1ra, and IL-4 release, but increased MIP-3α, Proteinase 3, VEGF, and IL-8 levels. In contrast, 3% honey reduced the release of all analytes except TNF-α, whose release was increased. Together, these results demonstrate a dose-dependent ability of Manuka honey to modify the release of cytokines, chemokines, and matrix-degrading enzymes that promote or inhibit inflammation and/or healing within a wound. The findings of this study provide further guidance for the future use of Manuka honey in wounds or tissue engineering templates. Future in vivo investigation is warranted to validate the in vitro results and translate these results to physiologically relevant environments.

Collateral-dependent blood flow is capable of significantly lessening the severity of stroke. Unfortunately, collateral flow varies widely in patients for reasons that remain unclear. Studies in mice have shown that the number and diameter of cerebral collaterals vary widely due primarily to polymorphisms in genes, e.g., Rabep2, involved in their formation during development. However, understanding how variation in collateral abundance affects stroke progression has been hampered by lack of a method to reversibly ligate the distal middle cerebral artery (MCAO) in mice. Here we present a method and examine infarct volume 24 h after transient (tMCAO, 90 min) versus permanent occlusion (pMCAO) in mice with good versus poor collaterals. Wildtype C57BL/6 mice (have abundant collaterals) sustained small infarctions following tMCAO that increased 2.1-fold after pMCAO, reflecting significant penumbra present at 90 min. Mutant C57BL/6 mice lacking Rabep2 (have reduced collaterals) sustained a 4-fold increase in infarct volume over WT following tMCAO and a smaller additional increase (0.4-fold) after pMCAO, reflecting reduced penumbra. Wildtype BALB/cBy (have a deficient Rabep2 variant and poor collaterals) had large infarctions following tMCAO that increased less (0.6-fold) than the above wildtype C57BL/6 mice following pMCAO. Mutant BALB/cBy mice (have deficient Rabep2 replaced with the C57BL/6 variant thus increased collaterals) sustained smaller infarctions after tMCAO. However, unlike C57BL/6 versus Rabep2 mice, penumbra was not increased since infarct volume increased only 0.3-fold following pMCAO. These findings present a murine model of tMCAO and demonstrate that neuroprotective mechanisms, in addition to collaterals, also vary with genetic background and affect the evolution of stroke.

Tissue transglutaminase (tTG), also referred to as type 2 transglutaminase or Gα_h, can bind and hydrolyze GTP, as well as function as a protein crosslinking enzyme. tTG is widely expressed and can be detected both inside cells and in the extracellular space. In contrast to many enzymes, the active and inactive conformations of tTG are markedly different. The catalytically inactive form of tTG adopts a compact "closed-state" conformation, while the catalytically active form of the protein adopts an elongated "open-state" conformation. tTG has long been appreciated as an important player in numerous diseases, including celiac disease, neuronal degenerative diseases, and cancer, and its roles in these diseases often depend as much upon its conformation as its catalytic activity. While its ability to promote these diseases has been traditionally thought to be dependent on its protein crosslinking activity, more recent findings suggest that the conformational state tTG adopts is also important for mediating its effects. In particular, we and others have shown that the closed-state of tTG is important for promoting cell growth and survival, while maintaining tTG in the open-state is cytotoxic. In this review, we examine the two unique conformations of tTG and how they contribute to distinct biological processes. We will also describe how this information can be used to generate novel therapies to treat diseases, with a special focus on cancer.

Transglutaminases (TGs) and especially TG2 play important roles in neurotransmitter and receptor signaling pathways. Three different mechanisms by which TG2 interacts with neurotransmitter and receptor signaling systems will be discussed in this review. The first way in which TG2 interacts with receptor signaling is via its function as a guanine nucleotide binding protein (G-protein) coupling to G-protein coupled receptors (GPCRs) to activate down-stream signaling pathways. TG2 can exist in a least two conformations, a closed GTP-bound conformation and an open calcium-bound conformation. In the closed GTP-bound conformation, TG2 is capable of functioning as a G-protein for GPCRs. In the open calcium-bound conformation, TG2 catalyzes a transamidation reaction cross-linking proteins or catalyzing the covalent binding of a mono- or polyamine to a protein. The second mechanism is regulation of the transamidation reaction catalyzed by TG2 via receptor stimulation which can increase local calcium concentrations and thereby increase transamidation reactions. The third way in which TG2 plays a role in neurotransmitter and receptor signaling systems is via its use of monoamine neurotransmitters as a substrate. Monoamine neurotransmitters including serotonin can be substrates for transamidation to a protein often a small G-protein (also known as a small GTPase) resulting in activation of the small G-protein. The transamidation of a monoamine neurotransmitter or serotonin has been designated as monoaminylation or more specifically serotonylation, respectively. Other proteins are also targets for monoaminylation such as fibronectin and cytoskeletal proteins. These receptor and neurotransmitter-regulated reactions by TG2 play roles in physiological and key pathophysiological processes.