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Patrick Chang

Publications and source records attributed to Patrick Chang.

8 recordsLinked to original sources
PubMed2025

Nanobioreactor detection of space-associated hematopoietic stem and progenitor cell aging.

Human hematopoietic stem and progenitor cell (HSPC) fitness declines following exposure to stressors that reduce survival, dormancy, telomere maintenance, and self-renewal, thereby accelerating aging. While previous National Aeronautics and Space Administration (NASA) research revealed immune dysfunction in low-earth orbit (LEO), the impact of spaceflight on human HSPC aging had not been studied. To study HSPC aging, our NASA-supported Integrated Space Stem Cell Orbital Research (ISSCOR) team developed bone marrow niche nanobioreactors with lentiviral bicistronic fluorescent, ubiquitination-based cell-cycle indicator (FUCCI2BL) reporter for real-time HSPC tracking in artificial intelligence (AI)-driven CubeLabs. In month-long International Space Station (ISS) missions (SpX-24, SpX-25, SpX-26, and SpX-27) compared with ground controls, FUCCI2BL reporter, whole-genome and transcriptome sequencing, and cytokine arrays demonstrated cell-cycle, inflammatory cytokine, mitochondrial gene, human repetitive element, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) deregulation together with clonal hematopoietic mutations. Furthermore, HSPC functionally organized multi-omics aging (HSPC-FOMA) analyses revealed reduced telomere maintenance, adenosine deaminase acting on RNA1 (ADAR1) p150 self-renewal gene expression, and replating capacity indicative of space-associated HSPC aging that may limit long-duration spaceflight.

Humans↗
PubMed2006

Muscle development in Ciona intestinalis requires the b-HLH myogenic regulatory factor gene Ci-MRF.

The activity of myogenic regulatory factor (MRF) genes is essential for vertebrate muscle development, whereas invertebrate muscle development is largely independent of MRF function. This difference indicates that myogenesis is controlled by distinct regulatory mechanisms in these two groups of animals. Here we used overexpression and gene knockdown to investigate the role in embryonic myogenesis of the single MRF gene of the invertebrate chordate Ciona intestinalis (Ci-MRF). Injection of Ci-MRF mRNA into eggs resulted in increased embryonic muscle-specific gene activity and revealed the myogenic activity of Ci-MRF by inducing the expression of four muscle marker genes, Acetylcholinesterase, Actin, Troponin I, and Myosin Light Chain in non-muscle lineages. Conversely, inhibiting Ci-MRF activity with antisense morpholinos down-regulated the expression of these genes. Consistent with the effects of morpholinos on muscle gene activity, larvae resulting from morpholino injection were paralyzed and their "muscle" cells lacked myofibrils. We conclude that Ci-MRF is required for larval tail muscle development and thus that an MRF-dependent myogenic regulatory network probably existed in the ancestor of tunicates and vertebrates. This possibility raises the question of whether the earliest myogenic regulatory networks were MRF-dependent or MRF-independent.

Animals↗
PubMed2006

Hypocatalasemic fibroblasts accumulate hydrogen peroxide and display age-associated pathologies.

Human epidemiological studies point to an association of hypocatalasemia and an increased risk of age-related disease. Unfortunately, the cellular and molecular manifestations of hypocatalasemia are only poorly understood. In this analysis, we have extensively characterized hypocatalasemic human fibroblasts and report that they amass hydrogen peroxide and are oxidatively damaged. Protein and DNA alike are affected, as are functioning and biogenesis of peroxisomes - the subcellular organelles which normally house catalase. Despite these pathologies and their relative inability to grow, the cells do not appear to be intrinsically senescent. With the goal of restoring oxidative balance and perhaps reversing some of the accumulated damage to critical cellular components, we transduced hypocatalasemic fibroblasts with a form of catalase specifically designed to efficiently traffic to peroxisomes. We show the strategy is extremely effective, with dramatic reductions seen in cellular hydrogen peroxide levels. Future longitudinal studies aimed at examining the effects of a more continuous and long-term protein therapy may now commence.

Age Factors↗
PubMed2005

Xenopus Xpat protein is a major component of germ plasm and may function in its organisation and positioning.

In many animals, including Drosophila, C. elegans, zebrafish and Xenopus, the germ line is specified by maternal determinants localised in a distinct cytoplasmic structure called the germ plasm. This is consists of dense granules, mitochondria, and specific localised RNAs. We have characterised the expression and properties of the protein encoded by Xpat, an RNA localised to the germ plasm of Xenopus. Immunofluorescence and immunoblotting showed that this novel protein is itself a major constituent of germ plasm throughout oogenesis and early development, although it is also present in other regions of oocytes and embryos, including their nuclei. We found that an Xpat-GFP fusion protein can localise correctly in cultured oocytes, in early oocytes to the 'mitochondrial cloud', from which germ plasm originates, and in later oocytes to the vegetal cortex. The localisation process was microtubule-dependent, while cortical anchoring required microfilaments. Xpat-GFP expressed in late stage oocytes assembled into circular fields of multi-particulate structures resembling endogenous fields of germ plasm islands. Furthermore these structures could be induced to form at ectopic sites by manipulation of culture conditions. Ectopic Xpat-GFP islands were able to recruit mitochondria, a major germ plasm component. These data suggest that Xpat protein has an important role in Xenopus germ plasm formation, positioning and maintenance.

Actin Cytoskeleton↗
PubMed2004

Localization of RNAs to the mitochondrial cloud in Xenopus oocytes through entrapment and association with endoplasmic reticulum.

The germ cell lineage in Xenopus is specified by the inheritance of germ plasm, which originates within a distinct "mitochondrial cloud" (MC) in previtellogenic oocytes. Germ plasm contains localized RNAs implicated in germ cell development, including Xcat2 and Xdazl. To understand the mechanism of the early pathway through which RNAs localize to the MC, we applied live confocal imaging and photobleaching analysis to oocytes microinjected with fluorescent Xcat2 and Xdazl RNA constructs. These RNAs dispersed evenly throughout the cytoplasm through diffusion and then became progressively immobilized and formed aggregates in the MC. Entrapment in the MC was not prevented by microtubule disruption and did not require localization to germinal granules. Immobilized RNA constructs codistributed and showed coordinated movement with densely packed endoplasmic reticulum (ER) concentrated in the MC, as revealed with Dil16(3) labeling and immunofluorescence analysis. Vg1RBP/Vera protein, which has been implicated in linking late pathway RNAs to vegetal ER, was shown to bind specifically both wild-type Xcat2 3' untranslated region and localization-defective constructs. We found endogenous Vg1RBP/Vera and Vg1RBP/Vera-green fluorescent protein to be largely excluded from the MC but subsequently to codistribute with Xcat2 and ER at the vegetal cortex. We conclude that germ line RNAs localize into the MC through a diffusion/entrapment mechanism involving Vg1RBP/Vera-independent association with ER.

Animals↗
PubMed2004

New anticoagulants for venous thromboembolic disease.

Venous thromboembolic disease, including deep vein thrombosis and pulmonary embolism, is a cause of significant mortality and morbidity. In the US, approximately 260000 cases are diagnosed annually. Current drugs for the prevention and treatment of venous thromboembolism (VTE) include heparin, low-molecular-weight heparins and warfarin. Since they possess several disadvantages, researchers are investigating improved anticoagulants. To understand how any promising anticoagulant would work, a review of the pathophysiology and regulation of the coagulation cascade is provided. The more prominent drugs reviewed include tissue factor pathway inhibitor protein, nematode anticoagulant protein, Factor IX inhibitors, anti-Factor Xa inhibitors (DX-9065a (Daiichi Seiyaku Co Ltd), YM-60828 (Yamanouchi Pharmaceutical Co Ltd), fondaparinux, idraparinux (Sanofi-Synthelabo/NV Organon)), selective thrombin inhibitors (oral heparin, ximelagatran (AstraZeneca plc)) and enhancers of natural anticoagulants (activated protein C, ART-123 (Asahi Kasei Pharma Corp)).

Animals↗
PubMed2003

Pre-M phase-promoting factor associates with annulate lamellae in Xenopus oocytes and egg extracts.

We have used complementary biochemical and in vivo approaches to study the compartmentalization of M phase-promoting factor (MPF) in prophase Xenopus eggs and oocytes. We first examined the distribution of MPF (Cdc2/CyclinB2) and membranous organelles in high-speed extracts of Xenopus eggs made during mitotic prophase. These extracts were found to lack mitochondria, Golgi membranes, and most endoplasmic reticulum (ER) but to contain the bulk of the pre-MPF pool. This pre-MPF could be pelleted by further centrifugation along with components necessary to activate it. On activation, Cdc2/CyclinB2 moved into the soluble fraction. Electron microscopy and Western blot analysis showed that the pre-MPF pellet contained a specific ER subdomain comprising "annulate lamellae" (AL): stacked ER membranes highly enriched in nuclear pores. Colocalization of pre-MPF with AL was demonstrated by anti-CyclinB2 immunofluorescence in prophase oocytes, in which AL are positioned close to the vegetal surface. Green fluorescent protein-CyclinB2 expressed in oocytes also localized at AL. These data suggest that inactive MPF associates with nuclear envelope components just before activation. This association may explain why nuclei and centrosomes stimulate MPF activation and provide a mechanism for targeting of MPF to some of its key substrates.

Animals↗