Zinc tetrabenzotetraphenyl porphyrin (ZnTBTPP) covalently attached to four perylenediimide (PDI) acceptors self‐assembles into a π‐stacked, segregated columnar structure, as indicated by small‐ and ...wide‐angle X‐ray scattering. Photoexcitation of ZnTBTPP rapidly produces a long‐lived electron–hole pair having a 26 Å average separation distance, which is much longer than if the pair is confined within the covalent monomer. This implies that the charges are mobile within their respective segregated ZnTBTPP and PDI charge conduits.
Zinc tetrabenzotetraphenylporphyrin (ZnTBTPP) covalently attached to four perylenediimide (PDI) acceptors self‐assembles into a π‐stacked, segregated columnar structure. Photoexcitation of ZnTBTPP rapidly produces a long‐lived electron–hole pair with a 26 Å average separation distance, which is much longer than if the pair is confined within the covalent monomer. The charges are thus mobile within their respective segregated ZnTBTPP and PDI charge conduits.
The making of fetal surgery Deprest, Jan A.; Flake, Alan W.; Gratacos, Eduard ...
Prenatal diagnosis,
July 2010, Letnik:
30, Številka:
7
Journal Article
(-)-5-(18)F-fluoroethoxybenzovesamicol ((18)F-FEOBV) is a vesamicol derivative that binds selectively to the vesicular acetylcholine transporter (VAChT) and has been used in preclinical studies to ...quantify presynaptic cholinergic nerve terminals. This study presents, to our knowledge, the first-in-human experience with (18)F-FEOBV, including radiation dosimetry, biodistribution, tolerability and safety in human subjects, and brain kinetics and methods for quantitative analysis of (18)F-FEOBV.
Whole-body (18)F-FEOBV scans were obtained in 3 healthy human volunteers. Seven additional subjects underwent dynamic brain imaging 0-120, 150-180, and 210-240 min after bolus injection of (18)F-FEOBV. Arterial blood sampling was performed with chromatographic identification of authentic (18)F-FEOBV to determine the arterial plasma input function. Analysis methods included nonlinear least-squares fitting of a 2-tissue-compartmental model, reference tissue modeling, and late single-scan imaging.
No pharmacologic or physiologic changes were observed after intravenous administration of up to 1.3 μg of (18)F-FEOBV. Radiation dosimetry estimates indicate that more than 400 MBq may be administered without exceeding regulatory radiation dose limits. Kinetic analysis showed brain uptake to be relatively high with single-pass extraction of 25%-35%. VAChT binding estimates varied by a factor of greater than 30 between the striatum and cortex. Coefficients of variation in k3 estimates varied from 15% to 30%. Volume of distribution measures yielded a dynamic range of approximately 15 but with little reduction in variability. Reference tissue approaches yielded more stable estimates of the distribution volume ratio (1 + BPND), with coefficients of variation ranging from 20% in the striatum to 6%-12% in cortical regions. The late static distribution of (18)F-FEOBV correlated highly with the distribution volume ratio estimates from reference tissue models (r = 0.993).
(18)F-FEOBV PET confirms that the tracer binds to VAChT with the expected in vivo human brain distribution. Both reference tissue modeling and late static scanning approaches provide a robust index of VAChT binding.
Identifying
cis-regulatory elements is important to understanding how human pancreatic islets modulate gene expression in physiologic or pathophysiologic (e.g., diabetic) conditions. We conducted ...genome-wide analysis of DNase I hypersensitive sites, histone H3 lysine methylation modifications (K4me1, K4me3, K79me2), and CCCTC factor (CTCF) binding in human islets. This identified ∼18,000 putative promoters (several hundred unannotated and islet-active). Surprisingly, active promoter modifications were absent at genes encoding islet-specific hormones, suggesting a distinct regulatory mechanism. Of 34,039 distal (nonpromoter) regulatory elements, 47% are islet unique and 22% are CTCF bound. In the 18 type 2 diabetes (T2D)-associated loci, we identified 118 putative regulatory elements and confirmed enhancer activity for 12 of 33 tested. Among six regulatory elements harboring T2D-associated variants, two exhibit significant allele-specific differences in activity. These findings present a global snapshot of the human islet epigenome and should provide functional context for noncoding variants emerging from genetic studies of T2D and other islet disorders.
► ∼18,000 promoters and ∼34,000 distal regulatory elements are predicted in human islets ► Six nonpromoter regulatory elements harbor type 2 diabetes-associated variants ► Reporter assays verify 40% of putative enhancers and detect allele-specific effects ► Islet hormone genes lack typical active histone modifications of expressed genes
TNFα is an important cytokine in inflammatory bowel disease. V565 is a novel anti-TNFα domain antibody developed for oral administration in IBD patients, derived from a llama domain antibody and ...engineered to enhance intestinal protease resistance. V565 activity was evaluated in TNFα-TNFα receptor-binding ELISAs as well as TNFα responsive cellular assays and demonstrated neutralisation of both soluble and membrane TNFα with potencies similar to those of adalimumab. Although sensitive to pepsin, V565 retained activity after lengthy incubations with trypsin, chymotrypsin, and pancreatin, as well as mouse small intestinal and human ileal and faecal supernatants. In orally dosed naïve and DSS colitis mice, high V565 concentrations were observed in intestinal contents and faeces and immunostaining revealed V565 localisation in mouse colon tissue. V565 was detected by ELISA in post-dose serum of colitis mice, but not naïve mice, demonstrating penetration of disrupted epithelium. In an ex vivo human IBD tissue culture model, V565 inhibition of tissue phosphoprotein levels and production of inflammatory cytokine biomarkers was similar to infliximab, demonstrating efficacy when present at the disease site. Taken together, results of these studies provide confidence that oral V565 dosing will be therapeutic in IBD patients where the mucosal epithelial barrier is compromised.
Monocyte activation and migration into the arterial wall are key events in atherogenesis associated with hypercholesterolemia. CD11c/CD18, a beta2 integrin expressed on human monocytes and a subset ...of mouse monocytes, has been shown to play a distinct role in human monocyte adhesion on endothelial cells, but the regulation of CD11c in hypercholesterolemia and its role in atherogenesis are unknown.
Mice genetically deficient in CD11c were generated and crossbred with apolipoprotein E (apoE)-/- mice to generate CD11c-/-/apoE-/- mice. Using flow cytometry, we examined CD11c on blood leukocytes in apoE-/- hypercholesterolemic mice and found that compared with wild-type and apoE-/- mice on a normal diet, apoE-/- mice on a Western high-fat diet had increased CD11c+ monocytes. Circulating CD11c+ monocytes from apoE-/- mice fed a high-fat diet exhibited cytoplasmic lipid vacuoles and expressed higher levels of CD11b and CD29. Deficiency of CD11c decreased firm arrest of mouse monocytes on vascular cell adhesion molecule-1 and E-selectin in a shear flow assay, reduced monocyte/macrophage accumulation in atherosclerotic lesions, and decreased atherosclerosis development in apoE-/- mice on a high-fat diet.
CD11c, which increases on blood monocytes during hypercholesterolemia, plays an important role in monocyte recruitment and atherosclerosis development in an apoE-/- mouse model of hypercholesterolemia.
Background Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for ...heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Blocker-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non-COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years;
<0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NT-proBNP (N-terminal pro-B-type natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%;
<0.001) and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (73 versus 81;
<0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for beta-blockade (87% versus 94%;
<0.001) and diuretics (85% versus 80%;
<0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio HR, 1.32; 95% CI, 1.13-1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05-1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94-1.30), or all-cause mortality (HR, 1.14; 95% CI, 0.99-1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05-1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29-1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points. Conclusions In PARADIGM-HF, COPD was associated with lower use of beta-blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high-risk subgroup. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01035255.
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