Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol L−1, p=3.4×10−12), T2D risk (OR[95%CI]=0.86[0.76-0.96], p=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose−1, p=0.048), but higher 2-h glucose (β=0.16±0.05 mmol L−1, p=4.3×10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8×10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol L−1, p=1.3×10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

As numerous diseases are associated with increased local inflammation, directing drugs to the inflamed sites can be a powerful therapeutic strategy. One of the common characteristics of inflamed endothelial cells is the up-regulation of vascular cell adhesion molecule–1 (VCAM-1). Here, the specific affinity between very late antigen–4 (VLA-4) and VCAM-1 is exploited to produce a biomimetic nanoparticle formulation capable of targeting inflammation. The plasma membrane from cells genetically modified to constitutively express VLA-4 is coated onto polymeric nanoparticle cores, and the resulting cell membrane–coated nanoparticles exhibit enhanced affinity to target cells that overexpress VCAM-1 in vitro. A model anti-inflammatory drug, dexamethasone, is encapsulated into the nanoformulation, enabling improved delivery of the payload to inflamed lungs and significant therapeutic efficacy in vivo. Overall, this work leverages the unique advantages of biological membrane coatings to engineer additional targeting specificities using naturally occurring target-ligand interactions.

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We use molecular dynamics (MD) simulations to understand the structure and stability of various paranemic crossover (PX) DNA molecules, synthesized recently by Seeman and co-workers at New York University. These studies include all atoms of the PX structures with an explicit description of solvent and ions. The average dynamics structures over the last 1 ns of the 3-ns simulation preserve the Watson-Crick hydrogen bonding as well as the helical structure. The root mean-square deviation in coordinates with respect to the MD averaged structure converges to 2-3 A for PX55, PX65, and PX85, but for PX75 and PX95 the root mean-square deviation in coordinates exhibits large fluctuations, indicating an intrinsic instability. The PX structures are structurally more rigid compared to the canonical B-DNA without crossover. We have developed a strain energy analysis method based on the nearest-neighbor interaction and computed the strain energy for the PX molecules compared to the B-DNA molecules of the same length and sequence. PX65 has the lowest calculated strain energy (approximately -0.77 kcal/mol/bp), and the strain increases dramatically for PX75, PX85, and PX95. PX55 has the highest strain energy (approximately 1.85 kcal/mol/bp) making it unstable, which is in accordance with the experimental results. We find that PX65 has helical twist and other helical structural parameters close to the values for normal B-DNA of similar length and sequence. Vibrational mode analysis shows that compared to other PX motifs, PX65 has the smallest population of the low-frequency modes that are dominant contributors for the conformational entropy of the PX DNA structures. All these results indicate that PX65 is structurally more stable compared to other PX motifs, in agreement with experiments. These results should aid in designing optimized DNA structures for use in nanoscale components and devices.

Actively phase-locked heterodyne-detected fifth-order nonresonant Raman scattering from room temperature CS2 has been measured. The experimental signals have similar magnitudes, shapes, and sign changes as calculated responses obtained via molecular dynamics simulations [S. Saito and I. Ohmine, Phys. Rev. Lett. 88, 207401 (2002)]. The measured signals contain sign changes that appear to be associated with the coupling of rotational motions both to each other and to translational motions.