Deletion of Serum Amyloid A3 Improves High Fat High Sucrose Diet-Induced Adipose Tissue Inflammation and Hyperlipidemia in Female Mice

Serum amyloid A (SAA) increases in response to acute inflammatory stimuli and is modestly and chronically elevated in obesity. SAA3, an inducible form of SAA, is highly expressed in adipose tissue in obese mice where it promotes monocyte chemotaxis, providing a mechanism for the macrophage accumulation that occurs with adipose tissue expansion in obesity. Humans do not express functional SAA3 protein, but instead express SAA1 and SAA2 in hepatic as well as extrahepatic tissues, making it difficult to distinguish between liver and adipose tissue-specific SAA effects. SAA3 does not circulate in plasma, but may exert local effects that impact systemic inflammation. We tested the hypothesis that SAA3 contributes to chronic systemic inflammation and adipose tissue macrophage accumulation in obesity using mice deficient for Saa3 (Saa3 ^−/−). Mice were rendered obese by feeding a pro-inflammatory high fat, high sucrose diet with added cholesterol (HFHSC). Both male and female Saa3 ^−/− mice gained less weight on the HFHSC diet compared to Saa3^+/+ littermate controls, with no differences in body composition or resting metabolism. Female Saa3 ^−/− mice, but not males, had reduced HFHSC diet-induced adipose tissue inflammation and macrophage content. Both male and female Saa3 ^−/− mice had reduced liver Saa1 and Saa2 expression in association with reduced plasma SAA. Additionally, female Saa3 ^−/− mice, but not males, showed improved plasma cholesterol, triglycerides, and lipoprotein profiles, with no changes in glucose metabolism. Taken together, these results suggest that the absence of Saa3 attenuates liver-specific SAA (i.e., SAA1/2) secretion into plasma and blunts weight gain induced by an obesogenic diet. Furthermore, adipose tissue-specific inflammation and macrophage accumulation are attenuated in female Saa3 ^−/− mice, suggesting a novel sexually dimorphic role for this protein. These results also suggest that Saa3 influences liver-specific SAA1/2 expression, and that SAA3 could play a larger role in the acute phase response than previously thought.     

Neighborhood influences on perceived social support among parents: findings from the project on human development in Chicago neighborhoods

Background

Social support is frequently linked to positive parenting behavior. Similarly, studies increasingly show a link between neighborhood residential environment and positive parenting behavior. However, less is known about how the residential environment influences parental social support. To address this gap, we examine the relationship between neighborhood concentrated disadvantage and collective efficacy and the level and change in parental caregiver perceptions of non-familial social support.

Methodology/Principal Findings

The data for this study came from three data sources, the Project on Human Development in Chicago Neighborhoods (PHDCN) Study''s Longitudinal Cohort Survey of caregivers and their offspring, a Community Survey of adult residents in these same neighborhoods and the 1990 Census. Social support is measured at Wave 1 and Wave 3 and neighborhood characteristics are measured at Wave 1. Multilevel linear regression models are fit. The results show that neighborhood collective efficacy is a significant (ß = .04; SE = .02; p = .03), predictor of the positive change in perceived social support over a 7 year period, however, not of the level of social support, adjusting for key compositional variables and neighborhood concentrated disadvantage. In contrast concentrated neighborhood disadvantage is not a significant predictor of either the level or change in social support.

Conclusion

Our finding suggests that neighborhood collective efficacy may be important for inducing the perception of support from friends in parental caregivers over time.     

Effect of aeration and agitation on yeast inulinase production: a biocalorimetric investigation

Bioprocess and Biosystems Engineering - Air flow rate and agitation speed for inulinase production by Kluyveromyces marxianus were optimized based on metabolic heat release profiles. Shear stress...     

Small-angle X-ray scattering studies of the intact eye lens: Effect of crystallin composition and concentration on microstructure

Background

The cortex and nucleus of eye lenses are differentiated by both crystallin protein concentration and relative distribution of three major crystallins (α, β, and γ). Here, we explore the effects of composition and concentration of crystallins on the microstructure of the intact bovine lens (37 °C) along with several lenses from Antarctic fish (− 2 °C) and subtropical bigeye tuna (18 °C).

Methods

Our studies are based on small-angle X-ray scattering (SAXS) investigations of the intact lens slices where we study the effect of crystallin composition and concentration on microstructure.

Results

We are able to distinguish the nuclear and cortical regions by the development of a characteristic peak in the intensity of scattered X-rays. For both the bovine and fish lenses, the peak corresponds to that expected for dense suspensions of α-crystallins.

Conclusions

The absence of the scattering peak in the nucleus indicates that there is no characteristic wavelength for density fluctuations in the nucleus although there is liquid-like order in the packing of the different crystallins. The loss in peak is due to increased polydispersity in the sizes of the crystallins and due to the packing of the smaller γ-crystallins in the void space of α-crystallins.

General significance

Our results provide an understanding for the low turbidity of the eye lens that is a mixture of different proteins. This will inform design of optically transparent suspensions that can be used in a number of applications (e.g., artificial liquid lenses) or to better understand human diseases pathologies such as cataract.     

On the impact of correlation between collaterally consanguineous cells on lymphocyte population dynamics

During an adaptive immune response, lymphocytes proliferate for five to twenty-five cell divisions, then stop and die over a period of weeks. Based on extensive flow cytometry data, Hawkins et al. (Proc Natl Acad Sci USA 104:5032–5037, 2007) introduced a cell-level stochastic model of lymphocyte population dynamics, called the Cyton Model, that accurately captures mean lymphocyte population size as a function of time. In Subramanian et al. (J Math Biol 56(6):861–892, 2008), we performed a branching process analysis of the Cyton Model and deduced from parameterizations for in vitro and in vivo data that the immune response is predictable despite each cell’s fate being highly variable. One drawback of flow cytometry data is that individual cells cannot be tracked, so that it is not possible to investigate dependencies in the fate of cells within family trees. In the absence of this information, while the Cyton Model abandons one of the usual assumptions of branching processes (the independence of lifetime and progeny number), it adopts another of the standard branching processes hypotheses: that the fates of progeny are stochastically independent. However, new experimental observations of lymphocytes show that the fates of cells in the same family tree are not stochastically independent. Hawkins et al. (2008, submitted) report on ciné lapse photography experiments where every founding cell’s family tree is recorded for a system of proliferating lymphocytes responding to a mitogenic stimulus. Data from these experiments demonstrate that the death-or-division fates of collaterally consanguineous cells (those in the same generation within a founding cell’s family tree) are strongly correlated, while there is little correlation between cells of distinct generations and between cells in distinct family trees. As this finding contrasts with one of the assumptions of the Cyton Model, in this paper we introduce three variants of the Cyton Model with increasing levels of collaterally consanguineous correlation structure to incorporate these new found dependencies. We investigate their impact on the predicted expected variability of cell population size. Mathematically we conclude that while the introduction of correlation structure leaves the mean population size unchanged from the Cyton Model, the variance of the population size distribution is typically larger. Biologically, through comparison of model predictions for Cyton Model parameterizations determined by in vitro and in vivo experiments, we deduce that if collaterally consanguineous correlation extends beyond cousins, then the immune response is less predictable than would be concluded from the original Cyton Model. That is, some of the variability seen in data that we previously attributed to experimental error could be due to intrinsic variability in the cell population size dynamics.      

The Role of Jasmonates in Floral Nectar Secretion

Plants produce nectar in their flowers as a reward for their pollinators and most of our crops depend on insect pollination, but little is known on the physiological control of nectar secretion. Jasmonates are well-known for their effects on senescence, the development and opening of flowers and on plant defences such as extrafloral nectar. Their role in floral nectar secretion has, however, not been explored so far. We investigated whether jasmonates have an influence on floral nectar secretion in oil-seed rape, Brassica napus. The floral tissues of this plant produced jasmonic acid (JA) endogenously, and JA concentrations peaked shortly before nectar secretion was highest. Exogenous application of JA to flowers induced nectar secretion, which was suppressed by treatment with phenidone, an inhibitor of JA synthesis. This effect could be reversed by additional application of JA. Jasmonoyl-isoleucine and its structural mimic coronalon also increased nectar secretion. Herbivory or addition of JA to the leaves did not have an effect on floral nectar secretion, demonstrating a functional separation of systemic defence signalling from reproductive nectar secretion. Jasmonates, which have been intensively studied in the context of herbivore defences and flower development, have a profound effect on floral nectar secretion and, thus, pollination efficiency in B. napus. Our results link floral nectar secretion to jasmonate signalling and thereby integrate the floral nectar secretion into the complex network of oxylipid-mediated developmental processes of plants.     

The amino and carboxyl termini of perilipin a facilitate the storage of triacylglycerols

Perilipin A is the most abundant lipid droplet-associated protein in adipocytes and serves important functions in regulating triacylglycerol levels by reducing rates of basal lipolysis and facilitating hormonally stimulated lipolysis. We have previously shown that the central region of perilipin A targets and anchors it to lipid droplets, at least in part via three moderately hydrophobic sequences that embed the protein into the hydrophobic core of the droplet. The current study examines the roles of the amino and carboxyl termini of perilipin A in facilitating triacylglycerol storage. Amino- and carboxyl-terminal truncation mutations of mouse perilipin A were stably expressed in 3T3-L1 preadipocytes, which lack perilipins. Triacylglycerol content of the cells was quantified as a measure of perilipin function and was compared with that of cells expressing full-length perilipin A or control cells lacking perilipins. The amino-terminal sequence between amino acids 122 and 222, including four 10-11-amino acid sequences predicted to form amphipathic beta-strands and a consensus site for cAMP-dependent protein kinase, and the carboxyl terminus of 112 amino acids that is unique to perilipin A were critical to facilitate triacylglycerol storage. The precocious expression of full-length perilipin A in 3T3-L1 preadipocytes aided more rapid storage of triacylglycerol during adipose differentiation. By contrast, the expression of highly truncated amino- or carboxyl-terminal mutations of perilipin failed to serve a dominant negative function in lowering triacylglycerol storage during adipose differentiation. We conclude that the amino and carboxyl termini are critical to the function of perilipin A in facilitating triacylglycerol storage.     

Monomeric recombinant TCR ligand reduces relapse rate and severity of experimental autoimmune encephalomyelitis in SJL/J mice through cytokine switch

Our previous studies demonstrated that oligomeric recombinant TCR ligands (RTL) can treat clinical signs of experimental autoimmune encephalomyelitis (EAE) and induce long-term T cell tolerance against encephalitogenic peptides. In the current study, we produced a monomeric I-A(s)/PLP 139-151 peptide construct (RTL401) suitable for use in SJL/J mice that develop relapsing disease after injection of PLP 139-151 peptide in CFA. RTL401 given i.v. or s.c. but not empty RTL400 or free PLP 139-151 peptide prevented relapses and significantly reduced clinical severity of EAE induced by PLP 139-151 peptide in SJL/J or (C57BL/6 x SJL)F(1) mice, but did not inhibit EAE induced by PLP 178-191 or MBP 84-104 peptides in SJL/J mice, or MOG 35-55 peptide in (C57BL/6 x SJL/J)F(1) mice. RTL treatment of EAE caused stable or enhanced T cell proliferation and secretion of IL-10 in the periphery, but reduced secretion of inflammatory cytokines and chemokines. In CNS, there was a modest reduction of inflammatory cells, reduced expression of very late activation Ag-4, lymphocyte function-associated Ag-1, and inflammatory cytokines, chemokines, and chemokine receptors, but enhanced expression of Th2-related factors, IL-10, TGF-beta3, and CCR3. These results suggest that monomeric RTL therapy induces a cytokine switch that curbs the encephalitogenic potential of PLP 139-151-specific T cells without fully preventing their entry into CNS, wherein they reduce the severity of inflammation. This mechanism differs from that observed using oligomeric RTL therapy in other EAE models. These results strongly support the clinical application of this novel class of peptide/MHC class II constructs in patients with multiple sclerosis who have focused T cell responses to known encephalitogenic myelin peptides.     

N-Phthaloyl gamma-aminobutyric acid affects biochemical circadian rhythms in Wistar rats

N-Phthaloyl gamma-aminobutyric acid (P-GABA) was administered to Wistar rats and 24 hr rhythms of glucose, cholesterol, total protein and lactic acid levels in blood were studied under semi-natural light dark conditions. P-GABA administration caused desynchronisation of the rhythms; while glucose and lactic acid rhythms were advanced, cholesterol and total protein rhythms were delayed. Since GABA is being involved in conveying dark information to the clock, exogenous administration of P-GABA may reduce the photic information received by the clock. The results could be explained by slightly less than 1 hr daily delays (or) advances respectively which would bring the peak times to the points 21 days after the start of administration.