Dendrimers as artificial enzymes

Dendrimers are regular tree-like macromolecules accessible by chemical synthesis from a variety of building blocks. Their topology enforces a globular shape that offers a unique opportunity to design artificial enzymes. Catalytic groups such as metal complexes and cofactors can be placed at the dendrimer core to exploit microenvironment and selectivity effects of the dendritic shell. In a second approach, attaching catalytic groups in multiple copies at the end of the dendritic branches may lead to cooperativity effects. Finally, exploration of dendritic structural space by screening combinatorial libraries of peptide dendrimers for catalytic activity can lead to discovery of functional dendrimers with enzyme-like properties, in a process mimicking natural selection.     

Glycopeptide dendrimer colchicine conjugates targeting cancer cells

Screening of a 65,536-member one-bead-one-compound (OBOC) combinatorial library of glycopeptide dendrimers of structure ((βGal)_n + 1X⁸X⁷X⁶X⁵)₂DapX⁴X³X²X¹(β-Gal)_m (βGal = β-galactosyl-thiopropionic acid, X^8–1 = variable amino acids, Dap = l-2,3-diaminopropionic acid, n, m = 0, or 1 if X⁸ = Lys resp. X¹ = Lys) for binding of Jurkat cells to the library beads in cell culture, resynthesis and testing lead to the identification of dendrimer J1 (βGal-Gly-Arg-His-Ala)₂Dap-Thr-Arg-His-Asp-CysNH₂ and related analogues as delivery vehicles. Cell targeting is evidenced by FACS with fluorescein conjugates such as J1F. The colchicine conjugate J1C is cytotoxic with LD₅₀ = 1.5 μM. The β-galactoside groups are necessary for activity, as evidenced by the absence of cell-binding and cytotoxicity in the non-galactosylated, acetylated analogue AcJ1F and AcJ1C, respectively. The pentagalactosylated dendrimer J4 βGal₄(Lys-Arg-His-Leu)₂Dap-Thr-Tyr-His-Lys(βGal)-Cys) selectively labels Jurkat cell as the fluorescein derivative J4F, but its colchicine conjugate J4C lacks cytotoxicity. Tubulin binding assays show that the colchicine dendrimer conjugates do not bind to tubulin, implying intracellular degradation of the dendrimers releasing the active drug.

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Influence of segmentation on morphological parameters and computed hemodynamics in cerebral aneurysms

This article focuses on the effects of segmentation on cerebral aneurysm's morphological parameters and on blood flow patterns computed using computational fluid dynamics. Segmentation is a non-negligible source of uncertainty that may have a consequent impact on the morphological assessment and the resulting hemodynamical simulations, the latter potentially being a key element in the decision-making therapeutic armamentarium for neuroradiologists and neurosurgeons. From the three patient-specific cases investigated, medical imaging data sets were collected, and four different three-dimensional segmentations were generated by the same senior technician. Morphological parameters were measured, and the aspect ratio was derived. Numerical simulations were performed; flow pattern changes, their impact on wall shear stress (WSS) and their sensitivity within the four reconstructed geometries were analyzed. Aneurysm velocity, vorticity and shear magnitudes were computed and compared. The morphological parameters having the highest variability were the aneurysm lobe dimensions (20 %). The neck length was the second parameter presenting the highest variability (21 %). The neck width variability reached 13.8 %, and the aspect ratio variability reached 14.2 %. The artery height and the artery width presented a variability of 13.7 and 10.8 %, respectively. Finally, the aneurysm depth, aneurysm height and aneurysm width presented variabilities of 12.8, 9.4 and 7.3 %, respectively. Differences in the flow path lines, velocity magnitude, wall shear stress and vorticity are also reported and discussed. The average variability reached 15.6 % for velocity, 25.2 % for vorticity and 25.2 % for shear, these parameters being computed inside the aneurysm. The maximum variability reached 31.0 % for velocity, 54.8 % for vorticity and 58.1 % for shear. A segmentation process reconstructing anatomies that is less sensitive to human intervention would be a future goal worth pursuing.     

Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets

Stimulated CD4(+) T lymphocytes can differentiate into effector T cell (Teff) or inducible regulatory T cell (Treg) subsets with specific immunological roles. We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic. Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufficient to decrease Glut1 and increase Treg generation in an asthma model. These data demonstrate that CD4(+) T cell subsets require distinct metabolic programs that can be manipulated in vivo to control Treg and Teff development in inflammatory diseases.