cssi/SciSciGPT-SciSciNet huggingface dataset:
Linkage Disequilibrium and Inversion-Typing of the Drosophila melanogaster Genome Reference Panel

We calculated the linkage disequilibrium between all pairs of variants in the Drosophila Genome Reference Panel with minor allele count ≥5. We used r2 ≥ 0.5 as the cutoff for a highly correlated SNP. We make available the list of all highly correlated SNPs for use in association studies. Seventy-six percent of variant SNPs are highly correlated with at least one other SNP, and the mean number of highly correlated SNPs per variant over the whole genome is 83.9. Disequilibrium between distant SNPs is also common when minor allele frequency (MAF) is low: 37% of SNPs with MAF < 0.1 are highly correlated with SNPs more than 100 kb distant. Although SNPs within regions with polymorphic inversions are highly correlated with somewhat larger numbers of SNPs, and these correlated SNPs are on average farther away, the probability that a SNP in such regions is highly correlated with at least one other SNP is very similar to SNPs outside inversions. Previous karyotyping of the DGRP lines has been inconsistent, and we used LD and genotype to investigate these discrepancies. When previous studies agreed on inversion karyotype, our analysis was almost perfectly concordant with those assignments. In discordant cases, and for inversion heterozygotes, our results suggest errors in two previous analyses or discordance between genotype and karyotype. Heterozygosities of chromosome arms are, in many cases, surprisingly highly correlated, suggesting strong epsistatic selection during the inbreeding and maintenance of the DGRP lines.
Stable, Two-Coordinate, Open Shell (d0—d9) Transition Metal Complexes

Abstract Well characterized, stable, two-coordinate, open shell transition metal complexes are currently very rare species. The small number of known examples are limited to the first row metals Cr → Ni and the majority are derivatives of amide or modified amide ligands. A characteristic feature of the compounds is the small number of electrons in their valence shells, as low as eight in the case of the Cr complexes. The compounds are very reactive toward protic reagents and nucleophiles. However, this and many other aspects of their chemistry have not been well developed. Current data available are limited to structural (X-ray and electron diffraction) and some spectroscopic and magnetic studies.
Comparative evidence for the independent evolution of hair and sweat gland traits in primates

Humans differ in many respects from other primates, but perhaps no derived human feature is more striking than our naked skin. Long purported to be adaptive, humans' unique external appearance is characterized by changes in both the patterning of hair follicles and eccrine sweat glands, producing decreased hair cover and increased sweat gland density. Despite the conspicuousness of these features and their potential evolutionary importance, there is a lack of clarity regarding how they evolved within the primate lineage. We thus collected and quantified the density of hair follicles and eccrine sweat glands from five regions of the skin in three species of primates: macaque, chimpanzee and human. Although human hair cover is greatly attenuated relative to that of our close relatives, we find that humans have a chimpanzee-like hair density that is significantly lower than that of macaques. In contrast, eccrine gland density is on average 10-fold higher in humans compared to chimpanzees and macaques, whose density is strikingly similar. Our findings suggest that a decrease in hair density in the ancestors of humans and apes was followed by an increase in eccrine gland density and a reduction in fur cover in humans. This work answers long-standing questions about the traits that make human skin unique and substantiates a model in which the evolution of expanded eccrine gland density was exclusive to the human lineage.
Synthesis and Chemistry of Novel 2,2′-Binaphthyl-Substituted Organotin Lewis Acids

(±)-2,2'-Dibromo-1,1'-binaphthyl (3) was converted to the dilithio derivative, which was treated with trimethyltin chloride to yield 2,2'-bis(trimethylstannyl)-1,1'-binaphthyl (4) in excellent yield. Compound 4 then underwent highly selective methyl-Sn cleavage in the redistribution reactions with methyltin trichloride and tin tetrachloride to afford 2,2'-bis(monochlorodimethylstannyl)- and 2,2'-bis(dichloromethylstannyl-1,1'-binaphthyl, 2a and 2b, respectively. The chlorotins were then converted into the organotin triflates, 2c and 2d, by metathetic reactions with silver triflate. Interaction of the bis(cichlorotin) 2b and DMSO afforded a mono-DMSO
Preparation, structure, and chemistry of (O-acyl imidato)- and (O-alkyl imidato)carbene pentacarbonyl complexes of chromium

Premier exemple d'insertion d'organonitriles dans la liaison metal-carbone des complexes [(CO) 2 CrC(OMe)R], R=Ph, Me pour aboutir a des complexes ylidenes d'imides
The bulk-to-boundary propagator in black hole microstate backgrounds

First-quantized propagation in quantum gravitational AdS3 backgrounds can be exactly reconstructed using CFT2 data and Virasoro symmetry. We develop methods to compute the bulk-to-boundary propagator in a black hole microstate, $$ \left\langle {\phi}_L{\mathcal{O}}_L{\mathcal{O}}_H{\mathcal{O}}_H\right\rangle $$ , at finite central charge. As a first application, we show that the semiclassical theory on the Euclidean BTZ solution sharply disagrees with the exact description, as expected based on the resolution of forbidden thermal singularities, though this effect may appear exponentially small for physical observers.
CoGe LoadExp+: A web-based suite that integrates next-generation sequencing data analysis workflows and visualization

Summary To make genomic and epigenomic analyses more widely available to the biological research community, we have created LoadExp+, a suite of bioinformatics workflows integrated with the web-based comparative genomics platform, CoGe. LoadExp+ allows users to perform transcriptomic (RNA-seq), epigenomic (bisulfite-seq), chromatin-binding (ChIP-seq), variant identification (SNPs), and population genetics analyses against any genome in CoGe, including genomes integrated by users themselves. Through LoadExp+'s integration with CoGe's existing features, all analyses are available for visualization and additional downstream processing, and are available for export to CyVerse's data management and analysis platforms. LoadExp+ provides easy-to-use functionality to manage genomics and epigenomics data throughout its entire lifecycle using a publicly available web-based platform and facilitates greater accessibility of genomics analyses to researchers of all skill levels. LoadExp+ can be accessed at https://genomevolution.org.
Molten-Salt-Mediated Syntheses of Sr2FeReO6, Ba2FeReO6, and Sr2CrReO6: Particle Sizes, B/B′ Site Disorder, and Magnetic Properties

The half-metallic double-perovskites Sr2FeReO6, Ba2FeReO6, and Sr2CrReO6 were synthesized in high purity and homogeneity using a NaCl/KCl molten flux at 750–800 °C in as little as 3–6 h. The partic...
Synthesis of Heterocycles Using Tandem Cyclization Processes.

Various applications of the cycloaddition/N-acyliminium ion tandem cyclization cascade are outlined in this electronic symposium on synthetic organic chemistry. The key step in the process involves the generation of a reactive N-acyliminium ion by fragmentation of an amino substituted [4+2]-cycloadduct. The successful synthesis of a number of alkaloids by this sequence of reactions reveals the usefulness and importance of this unique domino cascade.
Hydrothermal growth of LiLuF4 crystals and new lithium lutetium fluorides LiKLuF5 and LiNaLu2F8

Abstract The hydrothermal synthesis and crystal growth of LiLuF 4 were investigated. Small crystals of LiLuF 4 were produced but while investigating various alkali fluoride mineralizers, a new series of alkali lithium lutetium fluorides, including, LiKLuF 5 and LiNaLu 2 F 8 , were synthesized under hydrothermal conditions (570 °C at 12.5 kpsi). The mineralizer KF leads to formation of a new compound LiKLuF 5 crystallized in the space group C 2/ m with the lattice parameters a = 6.2328(12), b = 11.709(2), c = 6.3986(13), β = 113.87(3). Tm and Yb analogs were also synthesized using the same conditions. Use of NaF as mineralizer leads to a new compound LiNaLu 2 F 8 , crystallized in space group Cmcm , a = 10.3181(21), b = 8.2393(16), c = 6.9565(14). Several doped compounds were also isolated and electronic spectra were obtained.
Signatures of Selection at Drug Resistance Loci in Mycobacterium tuberculosis.

ABSTRACT Tuberculosis (TB) is the leading cause of death by an infectious disease, and global TB control efforts are increasingly threatened by drug resistance in Mycobacterium tuberculosis . Unlike most bacteria, where lateral gene transfer is an important mechanism of resistance acquisition, resistant M. tuberculosis arises solely by de novo chromosomal mutation. Using whole-genome sequencing data from two natural populations of M. tuberculosis , we characterized the population genetics of known drug resistance loci using measures of diversity, population differentiation, and convergent evolution. We found resistant subpopulations to be less diverse than susceptible subpopulations, consistent with ongoing transmission of resistant M. tuberculosis . A subset of resistance genes (“sloppy targets”) were characterized by high diversity and multiple rare variants; we posit that a large genetic target for resistance and relaxation of purifying selection contribute to high diversity at these loci. For “tight targets” of selection, the path to resistance appeared narrower, evidenced by single favored mutations that arose numerous times in the phylogeny and segregated at markedly different frequencies in resistant and susceptible subpopulations. These results suggest that diverse genetic architectures underlie drug resistance in M. tuberculosis and that combined approaches are needed to identify causal mutations. Extrapolating from patterns observed for well-characterized genes, we identified novel candidate variants involved in resistance. The approach outlined here can be extended to identify resistance variants for new drugs, to investigate the genetic architecture of resistance, and when phenotypic data are available, to find candidate genetic loci underlying other positively selected traits in clonal bacteria. IMPORTANCE Mycobacterium tuberculosis , the causative agent of tuberculosis (TB), is a significant burden on global health. Antibiotic treatment imposes strong selective pressure on M. tuberculosis populations. Identifying the mutations that cause drug resistance in M. tuberculosis is important for guiding TB treatment and halting the spread of drug resistance. Whole-genome sequencing (WGS) of M. tuberculosis isolates can be used to identify novel mutations mediating drug resistance and to predict resistance patterns faster than traditional methods of drug susceptibility testing. We have used WGS from natural populations of drug-resistant M. tuberculosis to characterize effects of selection for advantageous mutations on patterns of diversity at genes involved in drug resistance. The methods developed here can be used to identify novel advantageous mutations, including new resistance loci, in M. tuberculosis and other clonal pathogens.
Methyl ketone production by Pseudomonas putida is enhanced by plant-derived amino acids.

Plants are an attractive sourceof renewable carbon for conversion to biofuels and bio-based chemicals. Conversion strategies often use a fraction of the biomass, focusing on sugars from cellulose and hemicellulose. Strategies that use plant components, such as aromatics and amino acids, may improve the efficiency of biomass conversion. Pseudomonas putida is a promising host for its ability to metabolize a wide variety of organic compounds. P. putida was engineered to produce methyl ketones, which are promising diesel blendstocks and potential platform chemicals, from glucose and lignin-related aromatics. Unexpectedly, P. putida methyl ketone production using Arabidopsis thaliana hydrolysates was enhanced 2-5-fold compared with sugar controls derived from engineered plants that overproduce lignin-related aromatics. This enhancement was more pronounced (~seven-fold increase) with hydrolysates from nonengineered switchgrass. Proteomic analysis of the methyl ketone-producing P. putida suggested that plant-derived amino acids may be the source of this enhancement. Mass spectrometry-based measurements of plant-derived amino acids demonstrated a high correlation between methyl ketone production and amino acid concentration in plant hydrolysates. Amendment of glucose-containing minimal media with a defined mixture of amino acids similar to those found in the hydrolysates studied led to a nine-fold increase in methyl ketone titer (1.1 g/L).
New and Convenient Syntheses of Anhydro-2-alkyl-3-iminothiazolo-[3,2-a]pyridinium Hydroxide Derivatives

Abstract The 2-alkyl derivatives of anhydro-3-trifluoroacetyliminothiazolo[3,2- a ]pyridinium hydroxide were synthesized in quantitative yield by treatment of either 2-(pyridine-2-thiyl)-carboxamides or the corresponding nitriles with trifluoroacetic anhydride in dichloromethane. © 1997 Elsevier Science Ltd.
Development of Inflammatory Bowel Disease is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice

The gut microbiome is linked to inflammatory bowel disease (IBD) severity and altered in late-stage disease. However, it is unclear how gut microbial communities change over the course of IBD development, especially in regard to function. To investigate microbiome-mediated disease mechanisms and discover early biomarkers of IBD, we conducted a longitudinal metagenomic investigation in an established mouse model of IBD, where damped transforming growth factor β (TGF-β) signaling in T cells leads to peripheral immune activation, weight loss, and severe colitis. IBD development is associated with abnormal gut microbiome temporal dynamics, including damped acquisition of functional diversity and significant differences in abundance trajectories for KEGG modules such as glycosaminoglycan degradation, cellular chemotaxis, and type III and IV secretion systems. Most differences between sick and control mice emerge when mice begin to lose weight and heightened T cell activation is detected in peripheral blood. However, levels of lipooligosaccharide transporter abundance diverge prior to immune activation, indicating that it could be a predisease indicator or microbiome-mediated disease mechanism. Taxonomic structure of the gut microbiome also significantly changes in association with IBD development, and the abundances of particular taxa, including several species of Bacteroides, correlate with immune activation. These discoveries were enabled by our use of generalized linear mixed-effects models to test for differences in longitudinal profiles between healthy and diseased mice while accounting for the distributions of taxon and gene counts in metagenomic data. These findings demonstrate that longitudinal metagenomics is useful for discovering the potential mechanisms through which the gut microbiome becomes altered in IBD. IMPORTANCE IBD patients harbor distinct microbial communities with functional capabilities different from those seen with healthy people. But is this cause or effect? Answering this question requires data on changes in gut microbial communities leading to disease onset. By performing weekly metagenomic sequencing and mixed-effects modeling on an established mouse model of IBD, we identified several functional pathways encoded by the gut microbiome that covary with host immune status. These pathways are novel early biomarkers that may either enable microbes to live inside an inflamed gut or contribute to immune activation in IBD mice. Future work will validate the potential roles of these microbial pathways in host-microbe interactions and human disease. This study was novel in its longitudinal design and focus on microbial pathways, which provided new mechanistic insights into the role of gut microbes in IBD development.
Crystal Growth of Sr3NaNbO6 and Sr3NaTaO6: New Photoluminescent Oxides

Single crystals of Sr3NaNbO6 and Sr3NaTaO6 were grown out of high-temperature Sr(OH)2/NaOH melts contained in silver reaction vessels. Block- and rod-shaped crystals of Sr3NaNbO6 and Sr3NaTaO6 were isolated from sealed silver tubes and open crucibles, respectively. The structures were determined by single-crystal X-ray diffraction. Both Sr3NaNbO6 and Sr3NaTaO6 crystallize in the trigonal (rhombohedral) system, R-3c with a = 9.7853(12) A, c = 11.606(3) A, V = 962.4(3) A3, Z = 6 (Sr3NaNbO6), and a = 9.7867(4) A, c = 11.6109(7) A, V = 963.10(8) A3, Z = 6, (Sr3NaTaO6). The oxides are isostructural with the 2H-perovskite related K4CdCl6 structure type and consist of one-dimensional chains containing face-sharing NbO6 (TaO6) octahedra and NaO6 trigonal prisms. These chains in turn are separated from one another by infinite chains of strontium cations located in a distorted square antiprismatic environment. Interestingly, depending on the exact synthetic conditions, either green or brown crystals with distinct U...
Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1

Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no physical space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using solution nuclear magnetic resonance spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show that the putative canonical Nurr1 LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystallized conformation to allow binding of unsaturated fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinson's disease and schizophrenia.
Adaptation, specialization, and coevolution within phytobiomes.

Growth patterns of individual plants and evolutionary trajectories of plant communities are intimately linked with and are critically affected by host-associated microbiomes. Research across systems has begun to shed light on how these phytobiomes are established under laboratory and natural conditions, and have cultivated hope that a better understanding of the governing principles for host–microbe interactions can guide attempts to engineer microbiomes to boost agricultural yields. One important, yet relatively understudied, parameter in regards to phytobiome membership is the degree to which specialization and coevolution between plant species and microbes provides structure to these communities. In this article, I provide an overview of mechanisms enabling adaptation and specialization of phytobiome communities to host plants as well as the potential for plants themselves to recruit and cultivate beneficial interactions. I further explore the possibility of host-beneficial microbe coevolution and suggest particular situations that could promote the evolution of such close-knit partnerships. It is my hope that this overview will encourage future experiments that can begin to fill in this black box of ecological and evolutionary interactions across phytobiomes.
Synthesis of 2-Deoxy-2-halo-L-ascorbic Acids.

2-Iodo- and 2-bromo-2-deoxy-l-ascorbic acids (2 and 3) were prepared by facile halogenation of 2-deoxy-l-ascorbic acid (6) with NIS and NBS, respectively. Likewise, chlorination with NCS produced 2-chloro-2-deoxy-l-ascorbic acid (4), but formation of 4 was accompanied by formation of the dichloro hemiketal 9. Direct fluorination of 6 with 1-chloro-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA−BF4) gave only the difluoro hemiketal 10. A convenient synthesis of 2-deoxy-2-fluoro-l-ascorbic acid (5) was achieved by an indirect route. Fluorination of 2-bromo-2-deoxy-l-ascorbic acid (3) with F-TEDA−BF4 produced the bromofluoro hemiketal 16 as a mixture of diastereoisomers. Debromination with tributyltin hydride gave 5 in good yield.
Recent Outbreaks of Shigellosis in California Caused by Two Distinct Populations of Shigella sonnei with either Increased Virulence or Fluoroquinolone Resistance.

Shigella sonnei has caused unusually large outbreaks of shigellosis in California in 2014 and 2015. Preliminary data indicated the involvement of two distinct bacterial populations, one from San Diego and San Joaquin (SDi/SJo) and one from the San Francisco (SFr) Bay area. Whole-genome analysis and antibiotic susceptibility testing of 68 outbreak and archival isolates of S. sonnei were performed to investigate the microbiological factors related to these outbreaks. Both SDi/SJo and SFr populations, as well as almost all of the archival S. sonnei isolates belonged to sequence type 152 (ST152). Genome-wide single nucleotide polymorphism (SNP) analysis clustered the majority of California (CA) isolates to an earlier described lineage III. Isolates in the SDi/SJo population had a novel lambdoid bacteriophage carrying genes encoding Shiga toxin (STX) that were most closely related to that found in Escherichia coli O104:H4. However, the STX genes (stx1A and stx1B) from this novel phage had sequences most similar to the phages from Shigella flexneri and S. dysenteriae. The isolates in the SFr population were resistant to ciprofloxacin due to point mutations in gyrA and parC genes and were related to the fluoroquinolone-resistant S. sonnei clade within lineage III that originated in South Asia. The emergence of a highly virulent S. sonnei strain and introduction of a fluoroquinolone-resistant strain reflect the changing traits of this pathogen in California. An enhanced monitoring is advocated for early detection of future outbreaks caused by such strains. IMPORTANCE Shigellosis is an acute diarrheal disease causing nearly half a million infections, 6,000 hospitalizations, and 70 deaths annually in the United States. S. sonnei caused two unusually large outbreaks in 2014 and 2015 in California. We used whole-genome sequencing to understand the pathogenic potential of bacteria involved in these outbreaks. Our results suggest the persistence of a local S. sonnei SDi/SJo clone in California since at least 2008. Recently, a derivative of the original clone acquired the ability to produce Shiga toxin (STX) via exchanges of bacteriophages with other bacteria. STX production is connected with more severe disease, including bloody diarrhea. A second population of S. sonnei that caused an outbreak in the San Francisco area was resistant to fluoroquinolones and showed evidence of connection to a fluoroquinolone-resistant lineage from South Asia. These emerging trends in S. sonnei populations in California must be monitored for future risks of the spread of increasingly virulent and resistant clones.
Fleas (Siphonaptera) are Cretaceous, and evolved with Theria.

Abstract Fleas (order Siphonaptera) are highly-specialized, diverse blood-feeding ectoparasites of mammals and birds with an enigmatic evolutionary history and obscure origin. We here present a molecular phylogenetic study based on a comprehensive taxon sampling of 259 flea taxa, representing 16 of the 18 extant families of this order. A Bayesian phylogenetic tree with strong nodal support was recovered, consisting of seven sequentially derived lineages with Macropsyllidae as the earliest divergence, followed by Stephanocircidae. Divergence times of flea lineages were estimated based on fossil records and host specific associations to bats (Chiroptera), suggesting that the common ancestor of extant Siphonaptera diversified during the Cretaceous. However, most of the intraordinal divergence into extant lineages took place after the K-Pg boundary. Ancestral states of host association and biogeographical distribution were reconstructed, suggesting with high likelihood that fleas originated in the southern continents (Gondwana) and migrated from South America to their extant distributions in a relatively short time frame. Theria (placental mammals and marsupials) represent the most likely ancestral host group of extant Siphonaptera, with marsupials occupying a more important role than previously assumed. Major extant flea families evolved in connection to post K-Pg diversification of Placentalia. The association of fleas with monotremes and birds is likely due to later secondary host association. These results suggest caution in casually interpreting recently discovered Mesozoic fossil “dinosaur fleas” of Northeast Asia as part of what we currently consider Siphonaptera.
Asymmetric Catalysis for the Synthesis of Spirocyclic Compounds

Spirocycles provide an exciting platform to develop and understand the reactivity and selectivity for a wide variety of catalysts while affording diverse strategies to access molecules with importa...
Synthesis of a Tetradentate Oxorhenium(V) Complex Mimic of a Steroidal Estrogen

We are developing oxometal(V) complexes as high affinity ligands for the estrogen receptor. When labeled with technetium-99m, these complexes might be used as imaging agents for estrogen receptor-positive breast tumors. We describe the synthesis of a tetradentate oxorhenium(V) amino amido thioether thiol (AATT) complex in which the metal complex replaces the CD ring portion of estradiol. This complex is a close steric congener of the steroid and has a similar molecular volume. It was synthesized from norphenylephrine via an efficient Pictet−Spengler cyclization to give a tetrahydroisoquinoline that was then readily elaborated into the tetradentate chelate system. Treatment with an oxorhenium(V) salt led to the formation of the desired complex as a mixture of two diastereomers in modest yield. The relative stereochemistry of these isomers was easily assigned from their NMR spectra. On the basis of their octanol−water partition coefficients, these complexes are considerably more hydrophilic than is estradio...
An investigation of temperature and pressure dependence of the reaction of CF2ClO2 radicals with nitrogen dioxide by flash photolysis and time resolved mass spectrometry

Rate coefficients of the termolecular reaction were determined over the temperature range of 248–324 K and at pressures from 1 to 10 torr by time resolved mass spectrometry. CF2ClO2 radicals were generated by flash photolysis of CF2ClBr in the presence of oxygen. Their rate of decay was measured by following (CF2O2)+ fragment ions formed in the ion source. With 2 to 40 mtorr of NO2 present the dominant removal pathway is addition to form the peroxynitrate. The third order rate coefficients are wholly within the falloff over the experimental pressure range, and have a negative temperature coefficient. Rate constants for the reverse reaction, the unimolecular dissociation of CF2ClO2NO2, D. Koppenkastrop and F. Zabel, Int. J. Chem. Kinet., 23, 1 (1991) were employed to calculate equilibrium constants, from which a 600 torr value of the combination rate coefficient was obtained at each temperature. From the temperature dependence of the equilibrium constants, the average enthalpy of reaction over the experimental temperature range was found to be 106.1 ± 0.3 kJ/mol. Extrapolation of the combination rate constants to lower and higher pressures, and estimates of low and high pressure limiting rate coefficients, k0 and k∞ were done by nonlinear least squares fit of the experimental data, using the empirical Fc equations developed by Troe.
Haloacetal Radical Cyclizations of α- and β-Hydroxyhydrazones

Haloacetal radical cyclizations of α- and β-hydroxyhydrazones provide a direct access to aminosugarlike compounds. Stereocontrol of this process is influenced by stereogenic centers of both the hydroxyhydrazone and the acetal. The outcomes are consistent with chair and twist transition states with the anomeric alkoxy group in pseudoaxial orientations.
Synthesis and oxygen-atom transfer reactions of 3-hydroperoxy-3,4,4,5,5-pentasubstituted-1,2-dioxolanes

A series of 3-hydroperoxy-3,4,4,5,5-pentasubstituted-1,2-dioxolanes 2a-d were synthesized in good yield from the corresponding 3-hydroxy-1,2-dioxolanes by reaction with concentrated hydrogen peroxide in acetonitrile with p-toluenesulfonic acid as catalyst. The 3-hydroperoxy-1,2-dioxolanes were effective oxygen-atom transfer reagents for the oxidation of thioanisole, triethylamine and 2,3-dimethyl-2-butene to the sulfoxide, N-oxide and epoxide, respectively. The reactions occurred under mild conditions and were found to be of the second order overall. The second order rate constants (k2) were determined for oxidation of thioanisole by 2a-d in deuteriochloroform. For 2a, k2 values for N-oxidation and epoxidation were also measured. The 3-hydroperoxy-1,2-dioxolanes were found to be less reactive than the structurally similar cyclic α-azohydroperoxides but much more reactive than simple hydroperoxides. The mechanism of oxygen-atom transfer is postulated to occur via nucleophilic attack of the substrate on the terminal oxygen of the hydroperoxide. Intramolecular hydrogen bonding of the hydroperoxy proton to a dioxolane oxygen appears to account for the reaction order in aprotic media.
The reaction of nitrogen dioxide with sea salt aerosol

It is estimated that sea salt is the largest source of tropospheric aerosol particulate matter with 10{sup 12} kg introduced into the atmosphere from wave action over the oceans each year. Recently, considerable attention has been given to heterogeneous reactions between salts and nitrogen oxides and their possible roles in atmospheric chemistry, primarily as potential sources of tropospheric halogens. The reaction of sea salt aerosol with NO{sub 2} under ambient conditions was explored using particles that were generated by atomizing an aqueous solution of synthetic sea salt. The aerosol at 9--30% relative humidity, was mixed with 1--3 mbar of NO{sub 2} and then passed through an optical cell where reactants and products were monitored by infrared spectroscopy. The duration times of the reaction, partial pressure of NO{sub 2}, and relative humidity were systematically varied in order to explore the aerosol heterogeneous chemistry. Infrared spectra of the aerosol revealed that a substantial fraction of the particulate Cl{sup {minus}} was replaced by NO{sub 3}{sup {minus}} and that there was a significant production of ClNO, consistent with the stoichiometry 2 NO{sub 2} + Cl{sup {minus}} {yields} NO{sub 3}{sup {minus}} + ClNO. The rate of the reaction was found to increase both with NO{submore » 2} pressure and relative humidity. The infrared spectra also revealed that, even under arid conditions, the sea salt aerosol particles contain more water than can be explained by the various hydrates in sea salt, suggesting that the particles possess a complex structure. This complex structure involves microcrystalline and amorphous regions with pockets for water inclusions.« less
Conjugate Addition of a Cyano-Gilman Cuprate to an Acrylic Acid: Homologation of Artemisinic Acid and Subsequent Conversion to 16-Butylartemisinin

Abstract Conjugate addition to the acrylic acid moiety of artemisinic acid 2 was made possible by in situ protection as a silyl ester, treatment with a cyano-Gilman cuprate [Bu2CuLi·LiCN] to facilitate 1,4-addition, and deprotective workup affording the homologated carboxylic acid 9. Photoxygenation and acid treatment of 9 then led to the facile preparation of potent antimalarial 9-modified analogs of artemisinin.
Descriptions of reactions: Their logic and applications

Three systems of reaction description, from Ugi, Fujita, and Hendrickson, are examined and compared. They are shown to be essentially identical, and are rationalized here into a single simplified representation. The application of these systems to reaction retrieval, synthesis, and the invention of new reactions is also described.
Relative Basicities of Some Endo and Exo Norbornylamines.

A series of endo- and exo-norbornylamines were synthesized and their relative basicities determined in acetonitrile and dimethylformamide solvents. The exo isomer is always more basic than the corresponding endo isomer in either solvent. All of the bicyclic amines studied have higher pKa's in acetonitrile solvent than in dimethylformamide except for the 2-morpholinonorbornanes which are just the reverse. This effect is explained by the ability of the morpholine group to disperse a positive charge and the relative polarizabilities of the solvents. Semiempirical AM1 and PM3 methods along with ab initio HF/STO-3G, HF/3-21G*, and HF/6-31G* methods were used to calculate proton affinities and dipole moments for each of the amines. The results of the theoretical calculations correspond well with the experimental observations.
Structural, magnetic, and ion-exchange properties of a new layered alkaline/alkaline earth iron phosphate: NaBaFe4(HPO4)3(PO4)3.H2O.

A new mixed alkali/alkaline earth iron phosphate, NaBaFe4(HPO4)3(PO4)3·H2O, has been synthesized hydrothermally and structurally characterized by single-crystal X-ray diffraction, magnetic suscepti...
TET-mediated epimutagenesis of the Arabidopsis thaliana methylome

DNA methylation in the promoters of plant genes sometimes leads to transcriptional repression, and the loss of DNA methylation in methyltransferase mutants results in altered gene expression and severe developmental defects. However, many cases of naturally occurring DNA methylation variations have been reported, whereby altered expression of differentially methylated genes is responsible for agronomically important traits. The ability to manipulate plant methylomes to generate epigenetically distinct individuals could be invaluable for breeding and research purposes. Here, we describe "epimutagenesis," a method to rapidly generate DNA methylation variation through random demethylation of the Arabidopsis thaliana genome. This method involves the expression of a human ten-eleven translocation (TET) enzyme, and results in widespread hypomethylation that can be inherited to subsequent generations, mimicking mutants in the maintenance of DNA methyltransferase met1. Application of epimutagenesis to agriculturally significant plants may result in differential expression of alleles normally silenced by DNA methylation, uncovering previously hidden phenotypic variations.
An Efficient Synthesis of 4(5)-Benzyl-L-Histidines Employing Catalytic Transfer Hydrogenolysis at Elevated Temperatures.

An efficient two-step synthesis of 4(5)-benzyl- l -histidine from l -histidine was developed. A Pictet–Spengler reaction between l -histidine and benzaldehyde in the presence of excess strong base yielded 4- l -phenylspinacine within one hour. Catalytic transfer hydrogenolysis in methanol at reflux using ammonium formate rapidly converted 4- l -phenylspinacine to 4(5)-benzyl- l -histidine within five minutes. No racemization of the final product 4(5)-benzyl- l -histidine was observed using the Marfey reagent. To show the utility of this method, a series of fluorinated benzylhistidines were prepared.
BAR scaffolds drive membrane fission by crowding disordered domains.

Cellular membranes are continuously remodeled. The crescent-shaped bin-amphiphysin-rvs (BAR) domains remodel membranes in multiple cellular pathways. Based on studies of isolated BAR domains in vitro, the current paradigm is that BAR domain–containing proteins polymerize into cylindrical scaffolds that stabilize lipid tubules. But in nature, proteins that contain BAR domains often also contain large intrinsically disordered regions. Using in vitro and live cell assays, here we show that full-length BAR domain–containing proteins, rather than stabilizing membrane tubules, are instead surprisingly potent drivers of membrane fission. Specifically, when BAR scaffolds assemble at membrane surfaces, their bulky disordered domains become crowded, generating steric pressure that destabilizes lipid tubules. More broadly, we observe this behavior with BAR domains that have a range of curvatures. These data suggest that the ability to concentrate disordered domains is a key driver of membrane remodeling and fission by BAR domain–containing proteins.
Avoiding math on a rapid timescale: Emotional responsivity and anxious attention in math anxiety.

Abstract Math anxiety (MA) is characterized by negative feelings towards mathematics, resulting in avoidance of math classes and of careers that rely on mathematical skills. Focused on a long timescale, this research may miss important cognitive and affective processes that operate moment-to-moment, changing rapid reactions even when a student simply sees a math problem. Here, using fMRI with an attentional deployment paradigm, we show that MA influences rapid spontaneous emotional and attentional responses to mathematical stimuli upon brief presentation. Critically, participants viewed but did not attempt to solve the problems. Indicating increased threat reactivity to even brief presentations of math problems, increased MA was associated with increased amygdala response during math viewing trials. Functionally and anatomically defined amygdala ROIs yielded similar results, indicating robustness of the finding. Similar to the pattern of vigilance and avoidance observed in specific phobia, behavioral results of the attentional paradigm demonstrated that MA is associated with attentional disengagement for mathematical symbols. This attentional avoidance is specific to math stimuli; when viewing negatively-valenced images, MA is correlated with attentional engagement, similar to other forms of anxiety. These results indicate that even brief exposure to mathematics triggers a neural response related to threat avoidance in highly MA individuals.
A Unified Strategy for the Synthesis of Phenanthroizidine Alkaloids: Preparation of Sterically Congested Pyridines

Total syntheses of the representative phenanthroizidine alkaloids, tylophorine and antofine, and of their seco congeners, septicine and julandine, have been completed from sterically congested 3,4-diarylpyridines prepared by a modified Knoevenagel−Stobbe synthesis. Central to the success of this effort was the ability of α-dicarbonyl enones to combine in a formal [4 + 2]-cycloaddition with sterically demanding vinyl ethers.
TIGAR: An Improved Bayesian Tool for Transcriptomic Data Imputation Enhances Gene Mapping of Complex Traits

The transcriptome-wide association studies (TWASs) that test for association between the study trait and the imputed gene expression levels from cis-acting expression quantitative trait loci (cis-eQTL) genotypes have successfully enhanced the discovery of genetic risk loci for complex traits. By using the gene expression imputation models fitted from reference datasets that have both genetic and transcriptomic data, TWASs facilitate gene-based tests with GWAS data while accounting for the reference transcriptomic data. The existing TWAS tools like PrediXcan and FUSION use parametric imputation models that have limitations for modeling the complex genetic architecture of transcriptomic data. Therefore, to improve on this, we employ a nonparametric Bayesian method that was originally proposed for genetic prediction of complex traits, which assumes a data-driven nonparametric prior for cis-eQTL effect sizes. The nonparametric Bayesian method is flexible and general because it includes both of the parametric imputation models used by PrediXcan and FUSION as special cases. Our simulation studies showed that the nonparametric Bayesian model improved both imputation R2 for transcriptomic data and the TWAS power over PrediXcan when ≥1% cis-SNPs co-regulate gene expression and gene expression heritability ≤0.2. In real applications, the nonparametric Bayesian method fitted transcriptomic imputation models for 57.8% more genes over PrediXcan, thus improving the power of follow-up TWASs. We implement both parametric PrediXcan and nonparametric Bayesian methods in a convenient software tool "TIGAR" (Transcriptome-Integrated Genetic Association Resource), which imputes transcriptomic data and performs subsequent TWASs using individual-level or summary-level GWAS data.
Black Adult Patients With Acute Liver Failure Are Sicker and More Likely to Undergo Liver Transplantation Than White Patients.

Racial and ethnic differences in the presentation and outcomes of patients wait-listed with acute liver failure (ALF) have not been explored. Adult patients with ALF wait-listed for liver transplantation (LT) from 2002 to 2016 were investigated using the United Network for Organ Sharing database. Clinical characteristics and causative etiologies were compared between white, black, Hispanic, and Asian patients with ALF who were wait-listed as status 1. A competing risk analysis was used to explore differences in LT and wait-list removal rates. Kaplan-Meier survival curves were used to explore differences in 1-year posttransplant survival. There were 8208 patients wait-listed with a primary diagnosis of ALF; 4501 were wait-listed as status 1 (55.3% of whites, 64.4% of blacks, 51.6% of Hispanics, 40.7% of Asians; P < 0.001). Black patients had higher bilirubin and Model for End-Stage Liver Disease at wait-listing than other groups. White patients were the most likely to have acetaminophen toxicity as a causative etiology, whereas black patients were the most likely to have autoimmune liver disease. Black patients were significantly more likely to undergo LT than white patients (hazard ratio, 1.20; 95% confidence interval, 1.08-1.30). There was no difference in wait-list removal because of death or clinical deterioration among racial/ethnic groups. The 1-year posttransplant survival was lowest in black patients (79.6%) versus white (82.8%), Hispanic (83.9%), and Asian (89.3%) patients (P = 0.02). In conclusion, etiologies of ALF vary by race and ethnicity. Black patients with ALF were more likely to be wait-listed as status 1 and undergo LT than white patients, but they were sicker at presentation. The 1-year posttransplant survival rate was lowest among black patients.
Learning Classifiers for Target Domain with Limited or No Labels

In computer vision applications, such as domain adaptation (DA), few shot learning (FSL) and zero-shot learning (ZSL), we encounter new objects and environments, for which insufficient examples exist to allow for training "models from scratch," and methods that adapt existing models, trained on the presented training environment, to the new scenario are required. We propose a novel visual attribute encoding method that encodes each image as a low-dimensional probability vector composed of prototypical part-type probabilities. The prototypes are learnt to be representative of all training data. At test-time we utilize this encoding as an input to a classifier. At test-time we freeze the encoder and only learn/adapt the classifier component to limited annotated labels in FSL; new semantic attributes in ZSL. We conduct extensive experiments on benchmark datasets. Our method outperforms state-of-art methods trained for the specific contexts (ZSL, FSL, DA).
A reinforcement learning approach to weaning of mechanical ventilation in intensive care units

The management of invasive mechanical ventilation, and the regulation of sedation and analgesia during ventilation, constitutes a major part of the care of patients admitted to intensive care units. Both prolonged dependence on mechanical ventilation and premature extubation are associated with increased risk of complications and higher hospital costs, but clinical opinion on the best protocol for weaning patients off of a ventilator varies. This work aims to develop a decision support tool that uses available patient information to predict time-to-extubation readiness and to recommend a personalized regime of sedation dosage and ventilator support. To this end, we use off-policy reinforcement learning algorithms to determine the best action at a given patient state from sub-optimal historical ICU data. We compare treatment policies from fitted Q-iteration with extremely randomized trees and with feedforward neural networks, and demonstrate that the policies learnt show promise in recommending weaning protocols with improved outcomes, in terms of minimizing rates of reintubation and regulating physiological stability.
Neural optimizer search with reinforcement learning

We present an approach to automate the process of discovering optimization methods, with a focus on deep learning architectures. We train a Recurrent Neural Network controller to generate a string in a specific domain language that describes a mathematical update equation based on a list of primitive functions, such as the gradient, running average of the gradient, etc. The controller is trained with Reinforcement Learning to maximize the performance of a model after a few epochs. On CIFAR-10, our method discovers several update rules that are better than many commonly used optimizers, such as Adam, RMSProp, or SGD with and without Momentum on a ConvNet model. These optimizers can also be transferred to perform well on different neural network architectures, including Google's neural machine translation system.
A Method of Moments for Mixture Models and Hidden Markov Models

Mixture models are a fundamental tool in applied statistics and machine learning for treating data taken from multiple subpopulations. The current practice for estimating the parameters of such models relies on local search heuristics (e.g., the EM algorithm) which are prone to failure, and existing consistent methods are unfavorable due to their high computational and sample complexity which typically scale exponentially with the number of mixture components. This work develops an ecient method of moments approach to parameter estimation for a broad class of high-dimensional mixture models with many components, including multi-view mixtures of Gaussians (such as mixtures of axis-aligned Gaussians) and hidden Markov models. The new method leads to rigorous unsupervised learning results for mixture models that were not achieved by previous works; and, because of its simplicity, it oers a viable alternative to EM for practical deployment.
Sparse Inverse Covariance Selection via Alternating Linearization Methods

Gaussian graphical models are of great interest in statistical learning. Because the conditional independencies between different nodes correspond to zero entries in the inverse covariance matrix of the Gaussian distribution, one can learn the structure of the graph by estimating a sparse inverse covariance matrix from sample data, by solving a convex maximum likelihood problem with an l1-regularization term. In this paper, we propose a first-order method based on an alternating linearization technique that exploits the problem's special structure; in particular, the subproblems solved in each iteration have closed-form solutions. Moreover, our algorithm obtains an e-optimal solution in O(1/e) iterations. Numerical experiments on both synthetic and real data from gene association networks show that a practical version of this algorithm outperforms other competitive algorithms.
Bonding and electronic properties of ice at high pressure

The properties of water ice at megabar pressure are characterized with ab initio computer simulations. The focus lies on the metallic Cmcm phase and its insulating distorted analogue with Pnma symmetry. Both phases were recently predicted to occur at 15.5 and 12.5 Mbar, respectively (Militzer and Wilson, Phys Rev Lett, 2010, 105, 195701). The Fermi surface of the Cmcm phase is analyzed and possibility of Fermi nesting to occur is discussed. The Wannier orbital are computed for the Pnma structure and compared to ice X. While ice X shows typical sp3 hybridization, in the Pnma structure, the orbitals are deforms and no longer all aligned with the hydrogen bonds.