Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease

Aaron Copland's “Quiet City”: From the theater stage to the concert hall

Aaron Copland's Quiet City for Trumpet, English Horn, and String Orchestra has become a popular addition to the concert repertoire. Copland's original score, composed as incidental music for Irwin Shaw's stage production entitled Quiet City (1940), independently emerged as a piece for the concert stage. Aaron Copland began composing during childhood with a song written to his sister in-law. Copland eventually established his American-compositional identity, composing significant works throughout the nineteen-thirties, including: Short Symphony, El Salon México, and Billy the Kid, as well as references to various American folk-tunes. The score for Quiet City presented urban pastorals and nostalgia, among other elements to further reinforce Copland's emerging style. Attracting the attention of Harold Clurman, founding member of the Group Theatre in New York City, Aaron Copland agreed to write incidental music to the stage production of Irwin Shaw's Quiet City. Following the cancellation of Quiet City after only two performances, Copland's score continued as an independent work. The score to Quiet City has survived as a popular piece of solo literature. Featuring a duo of trumpet and English horn, Quiet City has been performed by musicians of the highest caliber, for example trumpeter Phil Smith and English horn-player Thomas Stacy. Quiet City has also been conducted by Leonard Bernstein, among other conductors. Modern performance practice of Quiet City provides the option for the trumpet and English horn to perform accompanied by either piano or string orchestra. Whether examining compositional elements or following the chronology of concerts where programmed, Aaron Copland's Quiet City has proven to survive its humble beginning, affirming its place among the concert stage repertoire

Molecular-Scale Perspective of Water-Catalyzed Methanol Dehydrogenation to Formaldehyde

Methanol steam reforming is a promising reaction for on-demand hydrogen production. Copper catalysts have excellent activity and selectivity for methanol conversion to hydrogen and carbon dioxide. This product balance is dictated by the formation and weak binding of formaldehyde, the key reaction intermediate. It is widely accepted that oxygen adatoms or oxidized copper are required to activate methanol. However, we show herein by studying a well-defined metallic copper surface that water alone is capable of catalyzing the conversion of methanol to formaldehyde. Our results indicate that six or more water molecules act in concert to deprotonate methanol to methoxy. Isolated palladium atoms in the copper surface further promote this reaction. This work reveals an unexpected role of water, which is typically considered a bystander in this key chemical transformation

Controlling Hydrogen Activation, Spillover, and Desorption with Pd–Au Single-Atom Alloys

Key descriptors in hydrogenation catalysis are the nature of the active sites for H₂ activation and the adsorption strength of H atoms to the surface. Using atomically resolved model systems of dilute Pd–Au surface alloys and density functional theory calculations, we determine key aspects of H₂ activation, diffusion, and desorption. Pd monomers in a Au(111) surface catalyze the dissociative adsorption of H₂ at temperatures as low as 85 K, a process previously expected to require contiguous Pd sites. H atoms preside at the Pd sites and desorb at temperatures significantly lower than those from pure Pd (175 versus 310 K). This facile H₂ activation and weak adsorption of H atom intermediates are key requirements for active and selective hydrogenations. We also demonstrate weak adsorption of CO, a common catalyst poison, which is sufficient to force H atoms to spill over from Pd to Au sites, as evidenced by low-temperature H₂ desorption

Effect of BN/CC Isosterism on the Thermodynamics of Surface and Bulk Binding: 1,2-Dihydro-1,2-azaborine vs Benzene

The chemistry of organoboron compounds has long been dominated by their high reactivity in synthetic organic chemistry. Recently, the incorporation of boron as a structural element in compounds has led to an increased diversity of organic compounds. A promising method of boron incorporation is BN/CC isosterism, where the replacement of a CC unit of the ubiquitous arene, benzene, with the isolectronic BN unit results in azaborine compounds whose properties are intermediate between benzene and borazine. These conjugated boron–nitrogen-containing heteroatom compounds show potential for use as charge transport materials in organic electronic devices in which the molecule–contact interface is a crucial factor of device performance. Therefore, to gain a fundamental understanding of the interaction of azaborines with two common metals, we examined 1,2-dihydro-1,2-azaborine and benzene desorption from Au(111) and Cu(111) by temperature-programmed desorption (TPD). Scanning tunneling microscopy imaging and theoretical calculations aided in the interpretation of the TPD results. Comparison between TPD spectra of 1,2-dihydro-1,2-azaborine and benzene allowed us to benchmark our experiments with literature values for benzene and to accurately quantify the magnitude of both molecule–molecule and molecule–surface interaction strengths. TPD spectra of 1,2-dihydro-1,2-azaborine show three well-defined adsorption states exist on each surface, assigned to mono-, bi-, and multilayers. The multilayer desorption energy of azaborine was found to be approximately 46 kJ/mol, about 4 kJ/mol larger than benzene and the increase is related to both dihydrogen bonding and dipole–dipole interactions. The bilayer formed by 1,2-dihydro-1,2-azaborine is less dense than that formed by benzene, with 0.7 molecules in the bilayer per each molecule in the monolayer on each surface. Importantly, in terms of application, azaborine did not decompose on either Cu or Au surfaces. Our data also reveal that a delicate balance of molecule–surface and molecule–molecule interactions dictate adsorption energetics in the submonolayer regime

Axonal spread of neuroinvasive viral infections

Neuroinvasive viral infections invade the nervous system, often eliciting serious disease and death. Members of four viral families are both neuroinvasive and capable of transmitting progeny virions or virion components within long neuronal extensions known as axons. Axons provide physical structures to spread of viral infection within the host while avoiding extracellular immune responses. Technological advances in analysis of in vivo neural circuits, neuronal culturing, and live imaging of fluorescent fusion proteins have enabled an unprecedented view into the steps of virion assembly, transport, and egress involved in axonal spread. In this review, we will summarize the literature supporting anterograde (axon to cell) spread of viral infection, describe the various strategies of virion transport, and discuss the effects of spread on populations of neuroinvasive viruses

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In &gt;400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency &lt; 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease