Cerebral small vessel disease burden is associated with decreased abundance of gut Barnesiella intestinihominis bacterium in the Framingham Heart Study.

A bidirectional communication exists between the brain and the gut, in which the gut microbiota influences cognitive function and vice-versa. Gut dysbiosis has been linked to several diseases, including Alzheimer's disease and related dementias (ADRD). However, the relationship between gut dysbiosis and markers of cerebral small vessel disease (cSVD), a major contributor to ADRD, is unknown. In this cross-sectional study, we examined the connection between the gut microbiome, cognitive, and neuroimaging markers of cSVD in the Framingham Heart Study (FHS). Markers of cSVD included white matter hyperintensities (WMH), peak width of skeletonized mean diffusivity (PSMD), and executive function (EF), estimated as the difference between the trail-making tests B and A. We included 972 FHS participants with MRI scans, neurocognitive measures, and stool samples and quantified the gut microbiota composition using 16S rRNA sequencing. We used multivariable association and differential abundance analyses adjusting for age, sex, BMI, and education level to estimate the association between gut microbiota and WMH, PSMD, and EF measures. Our results suggest an increased abundance of Pseudobutyrivibrio and Ruminococcus genera was associated with lower WMH and PSMD (p values < 0.001), as well as better executive function (p values < 0.01). In addition, in both differential and multivariable analyses, we found that the gram-negative bacterium Barnesiella intestinihominis was strongly associated with markers indicating a higher cSVD burden. Finally, functional analyses using PICRUSt implicated various KEGG pathways, including microbial quorum sensing, AMP/GMP-activated protein kinase, phenylpyruvate, and ß-hydroxybutyrate production previously associated with cognitive performance and dementia. Our study provides important insights into the association between the gut microbiome and cSVD, but further studies are needed to replicate the findings.

Profiling the sulfation specificities of glycosaminoglycan interactions with growth factors and chemotactic proteins using microarrays.

We report a carbohydrate microarray-based approach for the rapid, facile analysis of glycosaminoglycan-protein interactions. The key structural determinants responsible for protein binding, such as sulfate groups that participate in the interactions, were elucidated. Specificities were also readily compared across protein families or functional classes, and comparisons among glycosaminoglycan subclasses provided a more comprehensive understanding of protein specificity. To validate the approach, we showed that fibroblast growth factor family members have distinct sulfation preferences. We also demonstrated that heparan sulfate and chondroitin sulfate interact in a sulfation-dependent manner with various axon guidance proteins, including slit2, netrin1, ephrinA1, ephrinA5, and semaphorin5B. We anticipate that these microarrays will accelerate the discovery of glycosaminoglycan-binding proteins and provide a deeper understanding of their roles in regulating diverse biological processes.

Dynamic properties of the G93A mutant of copper-zinc superoxide dismutase as detected by NMR spectroscopy: implications for the pathology of familial amyotrophic lateral sclerosis.

The backbone assignment of the copper-zinc superoxide dismutase amyotrophic lateral sclerosis G93A mutant was performed on an (15)N-enriched protein sample. (15)N R(1), R(2), and R(1)(rho) and (15)N-(1)H NOE experiments were then carried out at 600 MHz on G93A Cu(2)Zn(2)SOD and the values compared to the dynamics data for the "wild-type" protein. In addition, (15)N and (1)H chemical shift comparisons between wild-type Cu(2)Zn(2)SOD and its G93A mutant were also made. G93A exhibits a higher mobility than wild-type Cu(2)Zn(2)SOD, particularly in loops III and V, on a time scale faster than the rate of protein tumbling. There are also distinct chemical shift and NOE differences in residues 35-42 and 92-95, which comprise these loops. These two regions of Cu(2)Zn(2)SOD form the end of the beta-barrel termed the "beta-barrel plug" [Tainer, J. A., Getzoff, E. D., Beem, K. M., Richardson, J. S., and Richardson, D. C. (1982) J. Mol. Biol. 160, 181-217]. The increased mobility and reduction of the number of observed NOEs in this region indicate an opening of the beta-barrel that may lead to amyloid fibrillogenesis. Alternatively, a motor neuron-specific substrate may bind this region of the protein, leading to deleterious modifications and/or reactions.