Investigation of the therapeutic potential of ES-62 in a murine model of SLE

Autoimmune inflammatory disorders such as systemic lupus erythematosus (SLE) remain debilitating conditions, as many patients are refractory to existing conventional and biologic therapies or suffer serious adverse effects, such as susceptibility to catastrophic infection. Therapies based on the actions of parasite- derived immunomodulators that dampen inflammation to promote the survival of the parasite without seriously immunocompromising the host, may therefore provide alternative strategies for the development of novel and safer drugs. One such molecule, ES-62, protects against disease in mouse models of rheumatoid arthritis and asthma; in both of these pathologies, suppression of disease is due to modulation of pathogenic IL-17A responses. As IL-17A has been implicated in the pathogenesis of SLE, in this thesis, the therapeutic potential of ES-62 is explored in the MRL/lpr mouse model of SLE. SLE is characterized by autoantibody responses to dsDNA, as well as other nuclear and cytoplasmic antigens, which result in the deposition of autoantibody- immune complexes that cause localized inflammation in tissues with dense capillary networks, most often the skin, joints and kidneys. The MRL/lpr mouse is genetically predisposed to develop lupus-like pathology displaying many of the characteristics of human disease, including the major cause of morbidity, glomerulonephritis. Twice weekly treatment of MRL/lpr mice with ES-62 significantly suppressed the development of proteinuria, a direct measure of renal dysfunction. Despite drastic improvement in renal function, the kidneys from ES-62 treated mice did not show substantial improvement in histopathology as indicated by the overall levels of glomeruloproliferation, cellular infiltration and complement or immunoglobulin deposition in the kidneys. However, exposure to ES-62 did reduce the expression of complement (C3aR and C5aR) and immunoglobulin receptors (FcγRI (CD64)), thus rendering renal cells hypo-responsive to these pro- inflammatory stimuli. Moreover, by modulating MyD88 signaling, ES-62 likely suppresses renal cell responsiveness to chronic DAMP and IL-1 signals as well as potentially promoting glomerular barrier stability. Consistent with their hypo-responsive phenotype, renal fibroblasts from ES-62 treated mice produced less MCP-1 in response to TLR stimulation and this was associated with reduced infiltration into the kidney by effector T and B cells and granulocytes; along with the ability of the parasite product to modulate the production of the pro-inflammatory cytokines IL-17A and IL-22. ES-62 suppressed the production of IL-22 both prior to and following onset of disease suggesting a key role for this cytokine in lupus pathogenesis, a proposal confirmed by neutralization studies which demonstrated that IL-22 played an essential role in the development of disease in the MRL/lpr mouse. This was further supported by studies showing that recombinant IL-22 significantly accelerated and exacerbated disease. By contrast, despite suppressing early IL-17A responses, the production of IL-17A was significantly increased in ES-62 treated mice during the established phase of disease, suggesting that IL-17A may promote pathogenesis during the initiation of pathology, yet act to resolve aberrant inflammation in the kidney. This potential dual role for IL-17A in the regulation of kidney inflammation was corroborated by studies using neutralizing antibodies and recombinant IL-17A, as the early neutralization of IL-17A production slowed the onset and severity of proteinuria and the late administration of rIL-17A suppressed disease severity. Aberrant B cell responses drive pathogenesis both in murine models of SLE and also in human disease: reflecting this, B cell depleting therapies have proved successful in the clinic. Thus, the effects of ES-62 on the population dynamics of effector and regulatory B cell subsets were investigated and these studies revealed that ES-62 induced a hypo-responsive B cell phenotype that was associated with modulated development, migration and/or activation of pathogenic effector B cells. Furthermore, the proportion of IL-10 producing ‘regulatory’ B cells were significantly elevated in the ES-62 treated MRL/lpr mice during the established phase of disease. Crucially, the protection afforded against the development of proteinuria by ES-62 was mimicked by the adoptive transfer of B cells from ES-62 treated MRL/lpr mice: moreover, such protection was associated with modulation of the IL-17A/IL-22 axis, as observed in MRL/lpr mice treated with ES-62. Together with previous reports on the therapeutic potential of ES-62 in arthritis and asthma, these studies suggest that therapies based on the parasite product have a future in the clinic. ES-62 itself is not suitable as a therapy, due to it immunogenic nature and the complexity of its biosynthesis: thus small molecular analogues (SMAs) of the parasite product have been synthesized. Two of these were tested in the MRL/lpr mouse and found to suppress the development of proteinuria, even when administered after the onset of pathology. This protection, as with that afforded by ES-62, was associated with a modulation of MyD88 signaling in the kidney and indicates that novel drugs, based on the safe modulation of the immune system by the parasite derived product, ES-62, have the potential to treat lupus nephritis in SLE patients

The Chemical Compositions of the Type II Cepheids -- The BL Her and W Vir Variables

Abundance analyses from high-resolution optical spectra are presented for 19 Type II Cepheids in the Galactic field. The sample includes both short-period (BL Her) and long-period (W Vir) stars. This is the first extensive abundance analysis of these variables. The C, N, and O abundances with similar spreads for the BL Her and W Vir show evidence for an atmosphere contaminated with $3\alpha$-process and CN-cycling products. A notable anomaly of the BL Her stars is an overabundance of Na by a factor of about five relative to their presumed initial abundances. This overabundance is not seen in the W Vir stars. The abundance anomalies running from mild to extreme in W Vir stars but not seen in the BL Her stars are attributed to dust-gas separation that provides an atmosphere deficient in elements of high condensation temperature, notably Al, Ca, Sc, Ti, and $s$-process elements. Such anomalies have previously been seen among RV Tau stars which represent a long-period extension of the variability enjoyed by the Type II Cepheids. Comments are offered on how the contrasting abundance anomalies of BL Her and W Vir stars may be explained in terms of the stars' evolution from the blue horizontal branch.Comment: 41 pages including 11 figures and 4 tables; Accepted for publication in Ap

Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation

ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed

The enthalpies of combustion and formation of [2.2]-paracyclophane and triptycene

The enthalpies of combustion, ΔHoc, for crystalline [2.2]-paracyclophane (C16H16) and triptycene (C20H14) have been measured by oxygen combustion calorimetry. The derived standard enthalpies of formation at 298.15 K in the crystalline state are (34.59±0.19) and (51.87±0.20) kcalth mol-1. The strain present in these molecular systems is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33825/1/0000082.pd

Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation

ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed

A fixed sublithospheric source for the late Neogene track of the Yellowstone hotspot: Implications of the Heise and Picabo volcanic fields

The Heise and Picabo volcanic fields of eastern Idaho are part of the more extensive time-transgressive Yellowstone-Snake River Plain hotspot track. Calderas associated with these two silicic volcanic fields are buried under 1 to 3 km of younger basalt, so their locations and eruption record histories have been based on analysis of silicic units along the margins of the eastern Snake River Plain along with some limited geophysical data. A 1.5 km borehole penetrating through basalt into underlying silicic rocks provides new data we used to reassess caldera locations and the timing of eruptions of these volcanic fields. Using these new caldera locations, we calculate an extension-adjusted rate of 2.35 cm/yr for the North American plate over the last 6.66 m.y. and a velocity of 2.30 cm/yr over the 10.27 m.y. Recalculation of a previously determined plate velocity-based migration of the deformation field surrounding the eastern Snake River Plain yields an extension-adjusted rate of 2.38 ± 0.21 cm/yr. These migration rates all fall within the previously published range of North American plate velocities of 2.2 ± 0.8 cm/yr, 2.4 cm/yr, and 2.68 ± 0.78 cm/yr based on a global hot spot reference frame. The consistency of these rates suggest that over the last 10 m.y., the Yellowstone hot spot is fixed with respect to the motion of the North American plate and therefore consistent with a classical deep-sourced hotspot model

Methane observations from the Greenhouse Gases Observing SATellite: Comparison to ground‐based TCCON data and model calculations

We report new short-wave infrared (SWIR) column retrievals of atmospheric methane (X_(CH4)) from the Japanese Greenhouse Gases Observing SATellite (GOSAT) and compare observed spatial and temporal variations with correlative ground-based measurements from the Total Carbon Column Observing Network (TCCON) and with the global 3-D GEOS-Chem chemistry transport model. GOSAT X_(CH4) retrievals are compared with daily TCCON observations at six sites between April 2009 and July 2010 (Bialystok, Park Falls, Lamont, Orleans, Darwin and Wollongong). GOSAT reproduces the site-dependent seasonal cycles as observed by TCCON with correlations typically between 0.5 and 0.7 with an estimated single-sounding precision between 0.4–0.8%. We find a latitudinal-dependent difference between the X_(CH4) retrievals from GOSAT and TCCON which ranges from 17.9 ppb at the most northerly site (Bialystok) to −14.6 ppb at the site with the lowest latitude (Darwin). We estimate that the mean smoothing error difference included in the GOSAT to TCCON comparisons can account for 15.7 to 17.4 ppb for the northerly sites and for 1.1 ppb at the lowest latitude site. The GOSAT X_(CH4) retrievals agree well with the GEOS-Chem model on annual (August 2009 – July 2010) and monthly timescales, capturing over 80% of the zonal variability. Differences between model and observed X_(CH4) are found over key source regions such as Southeast Asia and central Africa which will be further investigated using a formal inverse model analysis

Homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium

Interferon-lambda (IFN-λ) protects intestinal epithelial cells (IECs) from enteric viruses by inducing expression of antiviral IFN-stimulated genes (ISGs). Here, we find that bacterial microbiota stimulate a homeostatic ISG signature in the intestine of specific pathogen-free mice. This homeostatic ISG expression is restricted to IECs, depends on IEC-intrinsic expression of IFN-λ receptor

Microbiota-produced indole metabolites disrupt mitochondrial function and inhibit Cryptosporidium parvum growth

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. To explore microbial influences on susceptibility, we screened 85 microbiota-associated metabolites for their effects on Cryptosporidium parvum growth in vitro. We identify eight inhibitory metabolites in three main classes: secondary bile salts/acids, a vitamin