The supramolecular modification of trans-resveratrol and related antioxidant molecules

The naturally occurring phytoalexin trans-Resveratrol (RES) is known to be a powerful antioxidant and is used as a nutraceutical. It is considered to be one of the factors contributing to the beneficial effects of red wine. The phenolic hydroxycinnamic acids caffeic acid (CAF), ferulic acid (FA), p-coumaric acid (PCA) and sinapic acid (SA) are found in a wide variety of plants and also have antioxidant activity. The acetophenone derivatives paeonol (2H4M) and vanillin (4H3M) display antioxidant, anti-inflammatory and antihypertensive activity. The use of these compounds as food fortifiers and nutraceuticals is limited as they exhibit adverse physical properties such as low aqueous solubility and low bioavailability. These properties may be improved by inclusion complex formation with cyclodextrins (CDs) and by cocrystallisation with generally regarded as safe (GRAS) coformers. A study of the CD complexation of RES, CAF, FA, PCA, SA, 2H4M and 4H3M was carried out both in solution and in the solid state. The solubility enhancement of the nutraceuticals by CD inclusion and by cocrystallisation was evaluated. The compounds hydrocaffeic acid (HCA), hydroferulic acid (FA), 2-hydroxy-5-methoxy acetophenone (2H5M) and 2-hydroxy-6-methoxy acetophenone (2H6M) have little or no known bioactivity but were included in the study as structural analogues for comparative purposes. Inclusion complexes were formed with the nutraceuticals and the native CDs (β- and γ-CD) by kneading and coprecipitation, as well as with methylated CDs by coprecipitation. The resulting inclusion complexes were characterised using powder X-ray diffraction (PXRD), ¹H nuclear magnetic resonance spectroscopy (¹H-NMR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and hot stage microscopy (HSM). Single crystal X-ray diffraction was used to elucidate inclusion complex structures. Three novel RES inclusion complexes were formed with methylated CDs having common modes of inclusion and hydrogen bonding motifs. Inclusion complex formation with the methylated CDs also produced six new hydroxycinnamic acid complexes and five new hydroxyacetophenone complexes. While attempting to produce native CD inclusion complexes with the hydroxycinnamic acid compounds, crystals of SA were isolated, the structure of which had not been reported previously. The results of phase solubility studies revealed that, in general, CD inclusion complex formation improves the aqueous solubility of RES [randomly methylated CD (RAMEB) effecting a maximum increase of 63 times that of free RES] and hydroxycinnamic acids. The thermodynamic parameters and association constants for complexation between hydroxycinnamic acids and both β- and γ-CD were determined by isothermal titration calorimetry (ITC). For β-CD a 1:1 host-guest ratio was found with association constants in the range 246-774 M⁻¹. The interactions between the guests and β-CD were found to be enthalpy-driven, except for that of SA and β-CD which was entropy-driven. With γ-CD a 1:1 host to CAF ratio was found while PCA, FA and SA interact with γ-CD in a 2:1 molar ratio. The association constants were in the range 228-543 M⁻¹. The formation of 2:1 complexes in solution was found to be enthalpy-driven while that of 1:1 complexes was entropydriven. ¹H NMR spectroscopy was used to study the interaction of the acetophenone derivatives with β- and γ-CD in solution. Job plot analyses confirmed 1:1 host-guest complex ratios. The association constants spanned the range 145-336 M⁻¹. Similarly for γ-CD, complex stoichiometries were confirmed to be 1:1 with 2H6M and 4H3M with association constants 67 and 125 M⁻¹, respectively. Eight cocrystals were prepared with hydroxycinnamic acids and the GRAS compounds nicotinamide (NIC) and isonicotinamide (ISO) by coprecipitation, and were fully characterised. Single crystal X-ray diffraction confirmed the formation of cocrystals rather than salts. Analysis using ¹H NMR spectroscopy for quantitation revealed that the aqueous solubilities of FA and PCA were enhanced approximately ten-fold when tested in the form of their cocrystals with the coformer NIC

Exploring How We Teach: Lived Experiences, Lessons, and Research about Graduate Instructors by Graduate Instructors

This book combines the knowledge of 30 graduate student instructors sharing about how they teach and how they’ve learned how to teach

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

Immune Activation, Cd4+ T Cell Counts, and Viremia Exhibit Oscillatory Patterns over Time in Patients with Highly Resistant HIV Infection

The rates of immunologic and clinical progression are lower in patients with drug-resistant HIV compared to wild-type HIV. This difference is not fully explained by viral load. It has been argued that reductions in T cell activation and/or viral fitness might result in preserved target cells and an altered relationship between the level of viremia and the rate of CD4+ T cell loss. We tested this hypothesis over time in a cohort of patients with highly resistant HIV. Fifty-four antiretroviral-treated patients with multi-drug resistant HIV and detectable plasma HIV RNA were followed longitudinally. CD4+ T cell counts and HIV RNA levels were measured every 4 weeks and T cell activation (CD38/HLA-DR) was measured every 16 weeks. We found that the levels of CD4+ T cell activation over time were a strong independent predictor of CD4+ T cell counts while CD8+ T cell activation was more strongly associated with viremia. Using spectral analysis, we found strong evidence for oscillatory (or cyclic) behavior in CD4+ T cell counts, HIV RNA levels, and T cell activation. Each of the cell populations exhibited an oscillatory behavior with similar frequencies. Collectively, these data suggest that there may be a mechanistic link between T cell activation, CD4+ T cell counts, and viremia and lends support for the hypothesis of altered predator-prey dynamics as a possible explanation of the stability of CD4+ T cell counts in the presence of sustained multi-drug resistant viremia

MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis, by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation (MTsat) and neurite orientation dispersion and density imaging (NODDI) diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 vs 0.57, difference 0.036, 95% CI 0.029 to 0.043, p < 0.001). Lesion volume (Spearman’s rho rs= 0.38, p < 0.001) and g-ratio (rs= 0.24 p < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) (11/23 [48%] versus 2/15 [13%] p < 0.05). These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity, and help to identify individuals with a high degree of axonal damage at disease onset. York, Martin et al. simultaneously measured g-ratio and plasma neurofilament in 73 relapsing-remitting multiple sclerosis patients at diagnosis using advanced MRI and single molecule ELISA. They demonstrate that g-ratio of cerebral white matter lesions varies at diagnosis, and show that high g-ratio of lesions is associated with elevated plasma neurofilament

Impact of HIV on CD8+ T Cell CD57 Expression Is Distinct from That of CMV and Aging

Background: Chronic antigenic stimulation by cytomegalovirus (CMV) is thought to increase ‘‘immunosenesence’’ of aging, characterized by accumulation of terminally differentiated CD28- CD8+ T cells and increased CD57, a marker of proliferative history. Whether chronic HIV infection causes similar effects is currently unclear. Methods: We compared markers of CD8+ T cell differentiation (e.g., CD28, CD27, CCR7, CD45RA) and CD57 expression on CD28- CD8+ T cells in healthy HIV-uninfected adults with and without CMV infection and in both untreated and antiretroviral therapy (ART)-suppressed HIV-infected adults with asymptomatic CMV infection. Results: Compared to HIV-uninfected adults without CMV (n = 12), those with asymptomatic CMV infection (n = 31) had a higher proportion of CD28-CD8+ T cells expressing CD57 (P = 0.005). Older age was also associated with greater proportions of CD28-CD8+ T cells expressing CD57 (rho: 0.47, P = 0.007). In contrast, untreated HIV-infected CMV+ participants (n = 55) had much lower proportions of CD28- CD8+ cells expressing CD57 than HIV-uninfected CMV+ participants (P,0.0001) and were enriched for less well-differentiated CD28- transitional memory (TTR) CD8+ T cells (P,0.0001). Chronically HIV-infected adults maintaining ART-mediated viral suppression (n = 96) had higher proportions of CD28-CD8+ T cells expressing CD57 than untreated patients (P,0.0001), but continued to have significantly lower levels than HIV-uninfected controls (P = 0.001). Among 45 HIV-infected individuals initiating their first ART regimen, the proportion of CD28-CD8+ T cells expressing CD57 declined (P,0.0001), which correlated with a decline in percent of transitional memory CD8+ T cells, and appeared to be largely explained by a decline in CD28-CD57- CD8+ T cell counts rather than an expansion of CD28-CD57+ CD8+ T cell counts. Conclusions: Unlike CMV and aging, which are associated with terminal differentiation and proliferation of effector memory CD8+ T cells, HIV inhibits this process, expanding less well-differentiated CD28- CD8+ T cells and decreasing the proportion of CD28- CD8+ T cells that express CD57

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology

Genome-wide association studies have uncovered hundreds of DNA changes associated with complex disease. The ultimate promise of these studies is the understanding of disease biology; this goal, however, is not easily achieved because each disease has yielded numerous associations, each one pointing to a region of the genome, rather than a specific causal mutation. Presumably, the causal variants affect components of common molecular processes, and a first step in understanding the disease biology perturbed in patients is to identify connections among regions associated to disease. Since it has been reported in numerous Mendelian diseases that protein products of causal genes tend to physically bind each other, we chose to approach this problem using known protein–protein interactions to test whether any of the products of genes in five complex trait-associated loci bind each other. We applied several permutation methods and find robustly significant connectivity within four of the traits. In Crohn's disease and rheumatoid arthritis, we are able to show that these genes are co-expressed and that other proteins emerging in the network are enriched for association to disease. These findings suggest that, for the complex traits studied here, associated loci contain variants that affect common molecular processes, rather than distinct mechanisms specific to each association.Massachusetts Institute of Technology (MIT IDEA2 Program)Harvard University. Biological and Biomedical Sciences ProgramEunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (NICHD RO1 grant HD055150-03)National Institute of Arthritis and Musculoskeletal and Skin Diseases (U.S.) (K08 NIH-NIAMS career development award (AR055688))National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (DK083756)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (DK086502)Denmark. Forskningsradet for Sundhed og SygdomCenter for the Study of Inflammatory Bowel Diseas