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.
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.
Lithium-sulfur (Li-S) batteries are expected to overcome the limit of current energy storage devices by delivering high specific energy with low material cost. However, the potential of Li-S batteries has not yet been realized because of several technical barriers. Poor electrochemical performance is mainly attributed to the low electrical conductivity of the fully charged and discharged species, the irreversible loss of polysulfide anions and the decrease in the number of electrochemically active reaction sites during battery operation. Here, we report that the introduction of graphene quantum dots (GQDs) into the sulfur cathode dramatically enhanced sulfur/sulfide utilization, yielding high performance. In addition, the GQDs induced structural integrity of the sulfur-carbon electrode composite by oxygen-rich functional groups. This hierarchical architecture enabled fast charge transfer while minimizing the loss of lithium polysulfides, which is attributed to the physicochemical properties of GQDs. The mechanisms through which excellent cycling and rate performance are achieved were thoroughly studied by analyzing capacity versus voltage profiles. Furthermore, experimental observations and theoretical calculations further clarified the role played by GQDs by proving that C-S bonding occurs. Thus, the introduction of GQDs into Li-S batteries will provide an important breakthrough allowing their use as high-performance and low-cost batteries for next-generation energy storage systems. INTRODUCTIONRechargeable lithium-ion batteries are widely used in various applications, such as portable devices, bio-medical implants and electric vehicles, because of their high energy and power density. 1,2 However, current lithium-ion batteries based on the graphite and transition metal oxide couple have nearly reached their ceiling with respect to storage capability because of the limitations associated with their electrical properties and crystal structure. Therefore, breakthroughs in new energy storage systems that can surpass the current performance barrier of lithium-ion batteries should be brought about in a timely manner. Recently, Li-S batteries that can operate by the reversible electrochemical transformation between sulfur (S 8 ) and dilithium sulfide (Li 2 S) have attracted great attention because they can deliver high energy with a moderate voltage owing to the direct use of
Ultraviolet photodepletion spectra of dibenzo-18-crown-6-ether complexes with alkali metal cations (M+-DB18C6, M = Cs, Rb, K, Na, and Li) were obtained in the gas phase using electrospray ionization quadrupole ion-trap reflectron time-of-flight mass spectrometry. The spectra exhibited a few distinct absorption bands in the wavenumber region of 35 450−37 800 cm−1. The lowest-energy band was tentatively assigned to be the origin of the S0-S1 transition, and the second band to a vibronic transition arising from the “benzene breathing” mode in conjunction with symmetric or asymmetric stretching vibration of the bonds between the metal cation and the oxygen atoms in DB18C6. The red shifts of the origin bands were observed in the spectra as the size of the metal cation in M+-DB18C6 increased from Li+ to Cs+. We suggested that these red shifts arose mainly from the decrease in the binding energies of larger-sized metal cations to DB18C6 at the electronic ground state. These size effects of the metal cations on the geometric and electronic structures, and the binding properties of the complexes at the S0 and S1 states were further elucidated by theoretical calculations using density functional and time-dependent density functional theories.
The glucagon-like peptide 1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) involved in insulin synthesis and regulation; therefore, it is an important drug target for treatment of diabetes. However, GLP1R is a member of the class B1 family of GPCRs for which there are no experimental structures. To provide a structural basis for drug design and to probe class B GPCR activation, we predicted the transmembrane (TM) bundle structure of GLP1R bound to the peptide Exendin-4 (Exe4; a GLP1R agonist on the market for treating diabetes) using the MembStruk method for scanning TM bundle conformations. We used protein-protein docking methods to combine the TM bundle with the X-ray crystal structure of the 143-aa N terminus coupled to the Exe4 peptide. This complex was subjected to 28 ns of full-solvent, full-lipid molecular dynamics. We find 14 strong polar interactions of Exe4 with GLP1R, of which 8 interactions are in the TM bundle (2 interactions confirmed by mutation studies) and 6 interactions involve the N terminus (3 interactions found in the crystal structure). We also find 10 important hydrophobic interactions, of which 4 interactions are in the TM bundle (2 interactions confirmed by mutation studies) and 6 interactions are in the N terminus (6 interactions present in the crystal structure). Thus, our predicted structure agrees with available mutagenesis studies. We suggest a number of mutation experiments to further validate our predicted structure. The structure should be useful for guiding drug design and can provide a structural basis for understanding ligand binding and receptor activation of GLP1R and other class B1 GPCRs.protein structure prediction | incretin receptors | peptide hormones G protein-coupled receptors (GPCRs) are the largest family of integral membrane proteins within the human genome, and they are all characterized by seven transmembrane (TM) helices, with the N terminus on the extracellular (EC) side and the C terminus on the intracellular (IC). This family of proteins senses molecules outside of the cell and activates signal transduction pathways to cause cellular responses. Because of this vital role in cellular signaling networks, GPCRs are involved in many diseases, and they are the target of ∼40% of all prescription pharmaceuticals on the market (1). Because of the importance of GPCRs as drug targets, it is vital to gain structural information for aiding in drug design. Unfortunately, GPCRs, like other membrane proteins, are difficult to crystallize. There are now X-ray crystal structures for more than 12 distinct receptors of the (at least) 800 human GPCRs (2-16). All of the crystallized receptors belong to the class A (rhodopsin-like) family of GPCRs. However, a phylogenetic analysis of GPCRs classifies them into different subfamilies: class A (rhodopsin-like), class B1 (secretin-like), class B2 (adhesionlike), class C (glutamate-like), and Frizzled/Taste2 (12).Class B1 (secretin-like) GPCRs are activated by peptide hormones. The large ectodomain of these receptors interacts...
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