scholarly journals A VLP-based vaccine targeting ANGPTL3 lowers plasma triglycerides in mice

2021 ◽  
Author(s):  
Alexandra Fowler ◽  
Maureen Sampson ◽  
Alan T. Remaley ◽  
Bryce Chackerian
Keyword(s):  
Steady State ◽  
Lipoprotein Lipase ◽  
High Titer ◽  
Lipoprotein Metabolism ◽  
List Type ◽  
Loss Of Function ◽  
Igg Antibody ◽  
Plasma Triglycerides ◽  
Binding Domains ◽  
Steady State Levels

AbstractElevated triglycerides (TGs) are an important risk factor for the development of coronary heart disease (CHD) and in acute pancreatitis. Angiopoietin-like proteins 3 (ANGPTL3) and 4 (ANGPTL4) are critical regulators of TG metabolism that function by inhibiting the activity of lipoprotein lipase (LPL), which is responsible for hydrolyzing triglycerides in lipoproteins into free fatty acids. Interestingly, individuals with loss-of-function mutations in ANGPTL3 and ANGPTL4 have low plasma TG levels, have a reduced risk of CHD, and are otherwise healthy. Consequently, interventions targeting ANGPTL3 and ANGPTL4 have emerged as promising new approaches for reducing elevated TGs. Here, we developed virus-like particle (VLP) based vaccines that target the LPL binding domains of ANGPTL3 and ANGPTL4. ANGPTL3 VLPs and ANGPTL4 VLPs are highly immunogenic in mice and vaccination with ANGPTL3 VLPs, but not ANGPTL4 VLPs, was associated with reduced steady state levels of TGs. Immunization with ANGPTL3 VLPs rapidly cleared circulating TG levels following an oil gavage challenge and enhanced plasma LPL activity. These data indicate that targeting ANGPTL3 by active vaccination is potential alternative to other ANGPTL3-inhibiting therapies.HighlightsANGPTL3 and ANGPTL4 are mediators of lipoprotein metabolism that inhibit lipoprotein lipase (LPL) activity.Vaccination using virus-like particles (VLPs) targeting ANGPTL3 and ANGPTL4 elicits high-titer IgG antibody responses.Immunization with ANGPTL3 VLPs lowers steady-state plasma triglycerides and enhances LPL activity.

scholarly journals UBA1 and UBA2, Two Proteins That Interact with UBP1, a Multifunctional Effector of Pre-mRNA Maturation in Plants

2002 ◽  
Vol 22 (12) ◽  
pp. 4346-4357 ◽  
Author(s):  
Mark H. L. Lambermon ◽  
Yu Fu ◽  
Dominika A. Wieczorek Kirk ◽  
Marcel Dupasquier ◽  
Witold Filipowicz ◽  
...  
Keyword(s):  
Steady State ◽  
Rna Binding ◽  
Rna Recognition Motif ◽  
Dependent Manner ◽  
Binding Domains ◽  
Mrna Maturation ◽  
Associated Proteins ◽  
Steady State Levels ◽  
Transient Overexpression

ABSTRACT Nicotiana plumbaginifolia UBP1 is an hnRNP-like protein associated with the poly(A)+ RNA in the cell nucleus. Consistent with a role in pre-mRNA processing, overexpression of UBP1 in N. plumabaginifolia protoplasts enhances the splicing of suboptimal introns and increases the steady-state levels of reporter mRNAs, even intronless ones. The latter effect of UBP1 is promoter specific and appears to be due to UBP1 binding to the 3′ untranslated region (3′-UTR) and protecting the mRNA from exonucleolytic degradation (M. H. L. Lambermon, G. G. Simpson, D. A. Kirk, M. Hemmings-Mieszczak, U. Klahre, and W. Filipowicz, EMBO J. 19:1638-1649, 2000). To gain more insight into UBP1 function in pre-mRNA maturation, we characterized proteins interacting with N. plumbaginifolia UBP1 and one of its Arabidopsis thaliana counterparts, AtUBP1b, by using yeast two-hybrid screens and in vitro pull-down assays. Two proteins, UBP1-associated proteins 1a and 2a (UBA1a and UBA2a, respectively), were identified in A. thaliana. They are members of two novel families of plant-specific proteins containing RNA recognition motif-type RNA-binding domains. UBA1a and UBA2a are nuclear proteins, and their recombinant forms bind RNA with a specificity for oligouridylates in vitro. As with UBP1, transient overexpression of UBA1a in protoplasts increases the steady-state levels of reporter mRNAs in a promoter-dependent manner. Similarly, overexpression of UBA2a increases the levels of reporter mRNAs, but this effect is promoter independent. Unlike UBP1, neither UBA1a nor UBA2a stimulates pre-mRNA splicing. These and other data suggest that UBP1, UBA1a, and UBA2a may act as components of a complex recognizing U-rich sequences in plant 3′-UTRs and contributing to the stabilization of mRNAs in the nucleus.

The DAL81 gene product is required for induced expression of two differently regulated nitrogen catabolic genes in Saccharomyces cerevisiae

1991 ◽  
Vol 11 (2) ◽  
pp. 1161-1166 ◽  
Author(s):  
P A Bricmont ◽  
J R Daugherty ◽  
T G Cooper
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Steady State ◽  
Amino Acid ◽  
The Other ◽  
Loss Of Function ◽  
Induced Expression ◽  
Catabolic Genes ◽  
Acid Protein ◽  
Steady State Levels ◽  
Amino Acid Protein

We demonstrate that the DAL81 gene, previously thought to be specifically required for induced expression of the allantoin pathway genes in Saccharomyces cerevisiae, functions in a more global manner. The data presented show it to be required for utilization of 4-aminobutyrate as a nitrogen source and for 4-aminobutyrate-induced increases in the steady-state levels of UGA1 mRNA. The DAL81 gene encodes a 970-amino-acid protein containing sequences homologous to the Zn(II)2Cys6 motif and two stretches of polyglutamine residues. Deletion of sequences homologous to the Zn(II)2Cys6 motif did not result in a detectable loss of function. On the other hand, loss of one of the polyglutamine stretches, but not the other, resulted in a 50% loss of DAL81 function.

scholarly journals The DAL81 gene product is required for induced expression of two differently regulated nitrogen catabolic genes in Saccharomyces cerevisiae.

1991 ◽  
Vol 11 (2) ◽  
pp. 1161-1166 ◽  
Author(s):  
P A Bricmont ◽  
J R Daugherty ◽  
T G Cooper
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Steady State ◽  
Amino Acid ◽  
The Other ◽  
Loss Of Function ◽  
Induced Expression ◽  
Catabolic Genes ◽  
Acid Protein ◽  
Steady State Levels ◽  
Amino Acid Protein

We demonstrate that the DAL81 gene, previously thought to be specifically required for induced expression of the allantoin pathway genes in Saccharomyces cerevisiae, functions in a more global manner. The data presented show it to be required for utilization of 4-aminobutyrate as a nitrogen source and for 4-aminobutyrate-induced increases in the steady-state levels of UGA1 mRNA. The DAL81 gene encodes a 970-amino-acid protein containing sequences homologous to the Zn(II)2Cys6 motif and two stretches of polyglutamine residues. Deletion of sequences homologous to the Zn(II)2Cys6 motif did not result in a detectable loss of function. On the other hand, loss of one of the polyglutamine stretches, but not the other, resulted in a 50% loss of DAL81 function.

scholarly journals The critical role of T cells in glucocorticoid-induced osteoporosis

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Song ◽  
Lijuan Cao ◽  
Rui Liu ◽  
Hui Ma ◽  
Yanan Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Steady State ◽  
Side Effects ◽  
Critical Role ◽  
Wild Type ◽  
Receptor Activator ◽  
Steady State Levels ◽  
Induced Apoptosis

AbstractGlucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.

The Olympic Games as a News Shock

2017 ◽  
Vol 19 (6) ◽  
pp. 884-906 ◽  
Author(s):  
Viktoria C. E. Langer ◽  
Wolfgang Maennig ◽  
Felix Richter
Keyword(s):  
Steady State ◽  
Olympic Games ◽  
Structural Models ◽  
Adjustment Process ◽  
Dynamic Adjustment ◽  
Economic Variables ◽  
Long Run ◽  
News Shock ◽  
Steady State Levels ◽  
The Olympic Games

The awarding of the Olympic Games to a certain city or the announcement of a city’s Olympic bid may be considered as a news shock that affects agents’ market expectations. A news shock implies potential impacts on the dynamic adjustment process that change not only the volatility but also the long-run steady-state levels of endogenous economic variables. In this study, we contribute to and extend previous researchers’ attempts to empirically test for the Olympic Games as a news shock by implementing full structural models and by matching Olympic hosts and bidders to structurally similar countries.

Quantitative assessment of ground squirrel mRNA levels in multiple stages of hibernation

2002 ◽  
Vol 10 (2) ◽  
pp. 93-102 ◽  
Author(s):  
L. Elaine Epperson ◽  
Sandra L. Martin
Keyword(s):  
Steady State ◽  
Core Body Temperature ◽  
Ground Squirrels ◽  
Apolipoprotein A1 ◽  
Mrna Levels ◽  
Cdna Subtraction ◽  
Global Issues ◽  
Α2 Macroglobulin ◽  
Steady State Levels ◽  
Molecular Components

Hibernators in torpor dramatically reduce their metabolic, respiratory, and heart rates and core body temperature. These extreme physiological conditions are frequently and rapidly reversed during the winter hibernation season via endogenous mechanisms. This phenotype must derive from regulated expression of the hibernator’s genome; to identify its molecular components, a cDNA subtraction was used to enrich for seasonally upregulated mRNAs in liver of golden-mantled ground squirrels. The relative steady-state levels for seven mRNAs identified by this screen, plus five others, were measured and analyzed for seasonal and stage-specific differences using kinetic RT-PCR. Four mRNAs show seasonal upregulation in which all five winter stages differ significantly from and are higher than summer (α2-macroglobulin, apolipoprotein A1, cathepsin H, and thyroxine-binding globulin). One of these mRNAs, α2-macroglobulin, varies during the winter stages with significantly lower levels at late torpor. None of the 12 mRNAs increased during torpor. The implications for these newly recognized upregulated mRNAs for hibernation as well as more global issues of maintaining steady-state levels of mRNA during torpor are discussed.

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