Faculty Bibliography

While researchers have extensively characterized functional connectivity between brain regions, the characterization of functional homogeneity within a region of the brain connectome is in early stages of development. Several functional homogeneity measures were proposed previously, among which regional homogeneity (ReHo) was most widely used as a measure to characterize functional homogeneity of resting state fMRI (R-fMRI) signals within a small region (Zang et al., 2004). Despite a burgeoning literature on ReHo in the field of neuroimaging brain disorders, its test-retest (TRT) reliability remains unestablished. Using two sets of public R-fMRI TRT data, we systematically evaluated the ReHo's TRT reliability and further investigated the various factors influencing its reliability and found: 1) nuisance (head motion, white matter, and cerebrospinal fluid) correction of R-fMRI time series can significantly improve the TRT reliability of ReHo while additional removal of global brain signal reduces its reliability, 2) spatial smoothing of R-fMRI time series artificially enhances ReHo intensity and influences its reliability, 3) surface-based R-fMRI computation largely improves the TRT reliability of ReHo, 4) a scan duration of 5min can achieve reliable estimates of ReHo, and 5) fast sampling rates of R-fMRI dramatically increase the reliability of ReHo. Inspired by these findings and seeking a highly reliable approach to exploratory analysis of the human functional connectome, we established an R-fMRI pipeline to conduct ReHo computations in both 3-dimensions (volume) and 2-dimensions (surface).

Genome-wide association studies (GWAS) have identified hundreds of genetic variants that are associated with lipid phenotypes. However, data supporting a functional role for these variants in the context of lipid metabolism are scarce. We investigated the association of the lipoprotein lipase (LPL) variant rs13702 with plasma lipids and explored its potential for functionality. The rs13702 minor allele had been predicted to disrupt a microRNA (miR) recognition element (MRE) seed site (MRESS) for the human microRNA-410 (miR-410). Furthermore, rs13702 is in linkage disequilibrium (LD) with several SNPs identified by GWAS. We performed a meta-analysis across ten cohorts of participants that showed a statistically significant association of rs13702 with triacylglycerols (TAG) (p = 3.18 x 10(-42)) and high-density lipoprotein cholesterol (HDL-C) (p = 1.35 x 10(-32)) with each copy of the minor allele associated with 0.060 mmol/l lower TAG and 0.041 mmol/l higher HDL-C. Our data showed that an LPL 3' UTR luciferase reporter carrying the rs13702 major T allele was reduced by 40% in response to a miR-410 mimic. We also evaluated the interaction between intake of dietary fatty acids and rs13702. Meta-analysis demonstrated a significant interaction between rs13702 and dietary polyunsaturated fatty acid (PUFA) with respect to TAG concentrations (p = 0.00153), with the magnitude of the inverse association between dietary PUFA intake and TAG concentration showing -0.007 mmol/l greater reduction. Our results suggest that rs13702 induces the allele-specific regulation of LPL by miR-410 in humans. This work provides biological and potential clinical relevance for previously reported GWAS variants associated with plasma lipid phenotypes.

When ether vapor was allowed to diffuse into a CH(2)Cl(2) solution of an enantiomer of a hexa-peri-hexabenzocoronene (HBC) derivative carrying a chiral (BINAP)Pt(II)-appended coordination metallacycle (HBC(Py)([(R)-Pt]) or HBC(Py)([(S)-Pt])), screw-sense-selective assembly took place to give optically active nanotubes (NT(Py)([(R)-Pt]) or NT(Py)([(S)-Pt])) with helical chirality, which were enriched in either left-handed (M)-NT(Py)([(R)-Pt]) or right-handed (P)-NT(Py)([(S)-Pt]), depending on the absolute configuration of the (BINAP)Pt(II) pendant. When MeOH was used instead of ether for the vapor-diffusion-induced assembly, nanocoils formed along with the nanotubes. As determined by scanning electron microscopy, the diastereomeric excess of the nanocoils was 60% (80:20 diastereomeric ratio). Removal of the (BINAP)Pt(II) pendants from NT(Py)([(R)-Pt]) or NT(Py)([(S)-Pt]) with ethylenediamine yielded metal-free nanotubes (NT(Py)) that remained optically active even upon heating without any change in the circular dichroism spectral profile. No helical inversion took place when NT(Py) derived from HBC(Py)([(R)-Pt]) or HBC(Py)([(S)-Pt]) was allowed to complex with (BINAP)Pt(II) with an absolute configuration opposite to the original one.

Inadequate tissue perfusion is a key contributor to early complications following reconstructive procedures. Accurate and reliable intraoperative evaluation of tissue perfusion is critical to reduce complications and improve clinical outcomes. Clinical judgment is the most commonly used method for evaluating blood supply, but when used alone, is not always completely reliable. A variety of other methodologies have been evaluated, including Doppler devices, tissue oximetry, and fluorescein, among others. However, none have achieved widespread acceptance. Recently, intraoperative laser angiography using indocyanine green was introduced to reconstructive surgery. This vascular imaging technology provides real-time assessment of tissue perfusion that correlates with clinical outcomes and can be used to guide surgical decision making. Although this technology has been used for decades in other areas, surgeons may not be aware of its utility for perfusion assessment in reconstructive surgery. A group of experts with extensive experience with intraoperative laser angiography convened to identify key issues in perfusion assessment, review available methodologies, and produce initial recommendations for the use of this technology in reconstructive procedures.

TGF-beta and its signaling pathways are important mediators in the suppression of cancers of the gastrointestinal tract. TGF-beta is released from cells in a latent complex consisting of TGF-beta, the TGF-beta propeptide [latency associated protein (LAP)], and a latent TGF-beta binding protein (LTBP). We previously generated mice in which the LTBP-binding cysteine residues in LAP TGF-beta1 were mutated to serine precluding covalent interactions with LTBP. These Tgfb1(C33S/C33S) mice develop multiorgan inflammation and tumors consistent with reduced TGF-beta1 activity. To test whether further reduction in active TGF-beta levels would yield additional tumors and a phenotype more similar to Tgfb1(-/-) mice, we generated mice that express TGF-beta1(C33S) and are deficient in either integrin beta8 or TSP-1, known activators of latent TGF-beta1. In addition, we generated mice that have one mutant allele and one null allele at the Tgfb1 locus, reasoning that these mice should synthesize half the total amount of TGF-beta1 as Tgfb1(C33S/C33S) mice, and the amount of active TGF-beta1 would be correspondingly decreased compared with Tgfb1(C33S/C33S) mice. These compound-mutant mice displayed more severe inflammation and higher tumor numbers than the parental Tgfb1(C33S/C33S) animals. The level of active TGF-beta1 in compound mutant mice seemed to be decreased compared with Tgfb1(C33S/C33S) mice as determined from analyses of surrogate markers of active TGF-beta, such as P-Smad2, C-Myc, KI-67, and markers of cell-cycle traverse. We conclude that these mutant mice provide a useful system for modulating TGF-beta levels in a manner that determines tumor number and inflammation within the gastrointestinal tract. Cancer Res; 73(1); 459-68. (c)2012 AACR.

We have recently shown that Toll-like receptor (TLR) signaling exacerbates pancreatic fibro-inflammation and promotes carcinogenesis in mice. Paradoxically, inhibition of the TLR-MYD88 signaling pathway is pro-tumorigenic owing to the dendritic cell-mediated TH2-polarization of CD4+ T cells. TLR signaling appears to be central in pancreatic cancer-associated inflammation.

ATP-sensitive K(+) (K(ATP) ) channels are expressed ubiquitously, but have diverse roles in various organs and cells. Their diversity can partly be explained by distinct tissue-specific compositions of four copies of the pore-forming inward rectifier potassium channel subunits (Kir6.1 and/or Kir6.2) and four regulatory sulfonylurea receptor subunits (SUR1 and/or SUR2). Channel function and/or subcellular localization also can be modified by the proteins with which they transiently or permanently interact to generate even more diversity. We performed a quantitative proteomic analysis of K(ATP) channel complexes in the heart, endothelium, insulin-secreting min6 cells (pancreatic beta-cell like), and the hypothalamus to identify proteins with which they interact in different tissues. Glycolysis is an overrepresented pathway in identified proteins of the heart, min6 cells, and the endothelium. Proteins with other energy metabolic functions were identified in the hypothalamic samples. These data suggest that the metabolo-electrical coupling conferred by K(ATP) channels is conferred partly by proteins with which they interact. A large number of identified cytoskeletal and trafficking proteins suggests endocytic recycling may help control K(ATP) channel surface density and/or subcellular localization. Overall, our data demonstrate that K(ATP) channels in different tissues may assemble with proteins having common functions, but that tissue-specific complex organization also occurs.