cssi/SciSciGPT-SciSciNet huggingface dataset:
Tumor Incidence Experiments

This article describes a variety of methods for analyzing data from animal tumorigenesis experiments. The primary endpoint of interest is the tumor incidence rate. Both the estimation of tumor incidence rates and the comparison of these rates across treatment groups are discussed. Analyses are complicated by the fact that all onset times are censored when tumors are occult, censoring is informative unless tumors are completely nonlethal, and biases arise if proper adjustment is not made for survival differences across groups. Existing methods address such concerns by assuming a particular level of tumor lethality, assigning individual causes of death, requiring some animals to be sacrificed, specifying parametric models, or imposing functional restrictions. This article describes each of these approaches and summarizes the associated advantages and disadvantages. Keywords: cause of death; competing risks; differential mortality; fatal tumors; incidental tumors; survival/sacrifice study; tumor lethality; tumor onset
A Scalable Hybrid Research Paper Recommender System for Microsoft Academic

We present the design and methodology for the large scale hybrid paper recommender system used by Microsoft Academic. The system provides recommendations for approximately 160 million English research papers and patents. Our approach handles incomplete citation information while also alleviating the cold-start problem that often affects other recommender systems. We use the Microsoft Academic Graph (MAG), titles, and available abstracts of research papers to build a recommendation list for all documents, thereby combining co-citation and content based approaches. Tuning system parameters also allows for blending and prioritization of each approach which, in turn, allows us to balance paper novelty versus authority in recommendation results. We evaluate the generated recommendations via a user study of 40 participants, with over 2400 recommendation pairs graded and discuss the quality of the results using P@10 and nDCG scores. We see that there is a strong correlation between participant scores and the similarity rankings produced by our system but that additional focus needs to be put towards improving recommender precision, particularly for content based recommendations. The results of the user survey and associated analysis scripts are made available via GitHub and the recommendations produced by our system are available as part of the MAG on Azure to facilitate further research and light up novel research paper recommendation applications.
Effect of physician gender on the prescription of estrogen replacement therapy.

OBJECTIVE: To determine if women cared for by female physicians are more likely to receive postmenopausal estrogen replacement therapy than women cared for by male physicians.
Localized homology

In this paper, we provide the theoretical foundation and an effective algorithm for localizing topological attributes such as tunnels and voids. Unlike previous work that focused on 2-manifolds with restricted geometry, our theory is general and localizes arbitrary-dimensional attributes in arbitrary spaces. We implement our algorithm to validate our approach in practice.
Supersymmetric microring laser arrays

A coherent combination of emission power from an array of coupled semiconductor lasers operating on the same chip is of fundamental and technological importance. In general, the nonlinear competition among the array supermodes can entail incoherence and spectral broadening, leading to a spatiotemporally unstable and multimode emission pattern and thus poor beam quality. Here, by harnessing notions from supersymmetric (SUSY) quantum mechanics, we report that the strategic coupling between a class III-V semiconductor microring laser array with its dissipative superpartner can be used to limit the number of supermodes available for laser actions to one. We introduce a novel approach based on second-order SUSY transformation in order to drastically simplify the superpartner array engineering. Compared to a conventional laser array, which has a multimode spectrum, a SUSY laser array is observed to be capable of operating in a single (transverse) supermode. Enhancement of the peak output intensity of the SUSY laser array has been demonstrated with high efficiency and lower lasing threshold, compared with a single laser and a conventional laser array. Our experimental findings pave the way towards broad-area and high-power light generation in a scalable and stable fashion.
Linkage Analysis, Multipoint†

Multipoint linkage analysis is the analysis of linkage data involving three or more linked loci. Such analyses are carried out to order or map a set of loci, to position a new locus in relation to a mapped set of loci, or to exclude a locus from a region containing two or more loci. Multipoint linkage analysis can be viewed as an attempt to make more efficient use of recombination data in furthering the aims of linkage analysis. It is more complicated than two-point linkage analysis in several ways: the order of loci needs to be specified; a joint distribution for all recombination patterns needs to be specified; and the calculations can become prohibitive rather quickly. Likelihood methods are used in multipoint linkage analysis; there are two principal approaches to calculating likelihoods in the literature: the Elston–Stewart algorithm, which works on a relatively few loci and many individuals in a pedigree, and the Lander–Green algorithm, which is effective for many loci and relatively few individuals in human pedigrees. Keywords: recombination; genotype; haplotype; likelihood; exclusion mapping; location score; Elston–Stewart; Lander–Green; Monte Carlo
A review of derivatives research in accounting and suggestions for future work

Abstract This paper provides a review of research on financial derivatives, with an emphasis on and comprehensive coverage of research published in 15 top accounting journals from 1996 to 2017. We begin with some brief institutional details about derivatives and then summarize studies explaining when and why firms use derivatives. We then discuss the evolution of the accounting rules related to derivatives (and associated disclosure requirements) and studies that examine changes in these requirements over the years. Next, we review the literature that examines the consequences of firms’ derivative use to various capital market participants (i.e., managers, analysts, investors, boards of directors, etc.), with an emphasis on the role that the accounting and disclosure rules play in such consequences. Finally, we discuss the importance of industry affiliation on firms’ derivative use and the role that industry affiliation plays in derivatives research. Overall, our review suggests that, perhaps due to their inherent complexity and data limitations, derivatives are relatively understudied in accounting, and we highlight several areas where future research is needed.
Educational Psychology: Measuring Change Over Time†

Educational psychologists study changes over time that reflect academic, cognitive, emotional, and social development of students. The purpose of this article is to review the basic principles and procedures of the statistical applications used by educational psychologists to study change. While repeated measures ANOVA is widely used in empirical studies published recently in refereed journals, researchers are as likely to use growth-curve modeling or structural equation modeling to test their hypotheses. Both growth-curve modeling and structural equation modeling afford educational psychologists advantages in the analysis of change that overcome limitations of repeated measures ANOVA. A brief description of each statistical technique is provided with a summary of how the procedure has been applied by educational psychologists. Testing of assumptions, estimating effect sizes and power, and current statistical advances in the study of how individuals' affect, behavior, and cognition change are discussed. Keywords: repeated and related measures analysis of variance (ANOVA); post hoc comparisons; trend analysis; hierarchical linear modeling (HLM); growth-curve modeling; structural equation modeling (SEM); Rasch model
The Regulatory Failure to Define Essential Health Benefits.

Basic principles of economics suggest that health insurers should seek to avoid covering sick individuals and attempt to minimize the amount they have to spend if, despite the insurer's best effort...
School Finance Reforms, Teachers’ Unions, and the Allocation of School Resources

School finance reforms caused some of the most dramatic increases in intergovernmental aid from states to local governments in U.S. history. We examine whether teachers' unions affected the fractio...
Elevated fibrinogen, von Willebrand factor, and Factor VIII confer resistance to dilutional coagulopathy and activated protein C in normal pregnant women

Abstract Background Gestational changes in coagulation factor concentrations include elevations in fibrinogen, Factor VIII, and von Willebrand factor (vWF). We hypothesised that blood samples from term pregnant (TP) subjects are less prone to coagulation disturbances from haemodilution compared with those from non-pregnant (NP) females. Methods Blood samples were collected from 15 NP and 15 TP subjects. In vitro haemodilution with normal saline was assessed by modified Clauss fibrinogen assay, factor activity, flow-chamber assay, and thromboelastometry. The impact of human fibrinogen concentrate (hFC), cryoprecipitate, and vWF/Factor VIII (FVIII) concentrate replacement in diluted TP and NP blood was compared. Thrombin generation and activated protein C sensitivity were assessed. Results TP blood contained twice the concentrations of fibrinogen, FVIII, and vWF relative to NP blood (P Conclusions Our in vitro model showed relative resistance of TP blood to dilutional coagulation changes with respect to platelet adhesion, fibrin polymerisation, and thrombin generation. Careful therapeutic monitoring for different pro-haemostatic agents in pregnant women is warranted.
Women’s health providers’ perspectives on preimplantation genetic testing

Abstract Research question What are the perspectives of women’s health providers on the use of preimplantation genetic testing (PGT) for common medical disorders? Design A cross-sectional 15-question online anonymous survey was conducted of women’s health providers specializing in general obstetrics/gynaecology, gynaecologic oncology and infertility at a tertiary care academic institution in Massachusetts, USA. Respondents could answer ‘yes’, ‘no’ or ‘unsure’ to each thematic question. Results The survey was sent to 1060 providers and 240 providers responded (response rate 22.6%). Overall, 93% of respondents supported the use of PGT for the identification of genetic mutations which lead to childhood-onset disease, 83% supported the use of PGT for chromosomal aneuploidy screening, and 76% supported the use of PGT for cancer-related genetic disorders. Only 1.7% of respondents supported the use of PGT for non-disease-related indications, including sex selection and physical traits. Compared with general obstetrics/gynaecology providers, infertility specialists were more supportive of PGT. In total, 22.5% of respondents reported no prior knowledge of PGT. Conclusions In a sample of women’s health providers across multiple different obstetrics/gynaecology specialties, there was overall support for the use of PGT for a variety of common indications. Infertility specialists were the most supportive, which may reflect the familiarity that these providers have with this procedure. There was an overwhelmingly non-supportive response for the use of PGT for non-disease-related indications. The percentage of medical professionals working in women’s health without prior knowledge of PGT (22.5%) was higher than expected, identifying the need for more education regarding the availability and potential indications for this procedure.
Vertical Transport Properties of GaN Schottky Diodes Grown by Molecular Beam Epitaxy

Lateral and vertical electron transport parameters were investigated in lightly doped n-GaN films, grown by MBE. Diodes were fabricated by forming Schottky barriers on n−-GaN films using a mesa-etched vertical geometry. Doping concentrations and barrier heights were determined, from C-V measurements, to be 8-9×1016 cm−3 and 0.95-1.0 eV respectively. Reverse saturation current densities were measured to be in the 1-10×10−9 A/cm2 range. Using the diffusion theory of Schottky barriers, vertical mobility values were determined to be 950 cm2/V-s. Lateral mobility in films grown under similar conditions was determined by Hall effect measurements to be 150-200 cm2/V-s. The significant increase in mobility for vertical transport is attributed to reduction in electron scattering by charged dislocations.
Electrical transport of an AlGaN/GaN two-dimensional electron gas

An AlxGa1−xN/GaN two-dimensional electron gas structure with x = 0.13 deposited by molecular beam epitaxy on a GaN layer grown by organometallic vapor phase epitaxy on a sapphire substrate was characterized. Hall effect measurements gave a sheet electron concentration of 5.1×1012 cm−2 and a mobility of 1.9 × 104 cm2/Vs at 10 K. Mobility spectrum analysis showed single-carrier transport and negligible parallel conduction at low temperatures. The sheet carrier concentrations determined from Shubnikov-de Haas magnetoresistance oscillations were in good agreement with the Hall data. The electron effective mass was determined to be 0.215±0.006 m0 based on the temperature dependence of the amplitude of Shubnikov-de Haas oscillations. The quantum lifetime was about one-fifth of the transport lifetime of 2.3 × 10−12 s.
Evaluating cell lines as models for metastatic breast cancer through integrative analysis of genomic data

Cell lines are widely-used models to study metastatic cancer although the extent to which they recapitulate the disease in patients remains unknown. The recent accumulation of genomic data provides an unprecedented opportunity to evaluate the utility of them for metastatic cancer research. Here, we reveal substantial genomic differences between breast cancer cell lines and metastatic breast cancer patient samples. We also identify cell lines that more closely resemble the different subtypes of metastatic breast cancer seen in the clinic and show that surprisingly, MDA-MB-231 cells bear little genomic similarities to basal-like metastatic breast cancer patient samples. Further comparison suggests that organoids more closely resemble the transcriptome of metastatic breast cancer samples compared to cell lines. Our work provides a guide for cell line selection in the context of breast cancer metastasis and highlights the potential of organoids in these studies.
Reconstructing the yield curve

Abstract The constant maturity zero-coupon yield curve for the US Treasuries is one of the most studied datasets. We construct a new yield curve using a non-parametric kernel-smoothing method with a novel adaptive bandwidth specifically designed to fit the Treasury yields. Our curve is globally smooth while still capturing important local variation. Economically, we show that applying our data leads to different conclusions from using the leading alternative data of Gurkaynak et al. (2007) (GSW) when we repeat two popular studies of Cochrane and Piazzesi (2005) and Giglio and Kelly (2018). Statistically, we show our dataset preserves information in the raw data and has much smaller pricing errors than GSW. Our new yield curve is maintained and updated online, complemented by bandwidths that summarize information content in the raw data.
Calcium-activated chloride channels clamp odor-evoked spike activity in olfactory receptor neurons

The calcium-activated chloride channel anoctamin-2 (Ano2) is thought to amplify transduction currents in olfactory receptor neurons (ORNs), a hypothesis supported by previous studies in dissociated neurons from Ano2−/− mice. Paradoxically, despite a reduction in transduction currents in Ano2−/− ORNs, their spike output for odor stimuli may be higher. We examined the role of Ano2 in ORNs in their native environment in freely breathing mice by imaging activity in ORN axons as they arrive in the olfactory bulb glomeruli. Odor-evoked responses in ORN axons of Ano2−/− animals were consistently larger for a variety of odorants and concentrations. In an open arena, Ano2−/− animals took longer to approach a localized odor source than Ano2+/+ animals, revealing clear olfactory behavioral deficits. Our studies provide the first in vivo evidence toward an alternative or additional role for Ano2 in the olfactory transduction cascade, where it may serve as a feedback mechanism to clamp ORN spike output.
Oxidation of thiols to disulfides with molecular bromine on hydrated silica gel support

Abstract Results of oxidation of thiols to disulfides with molecular bromine on silica gel solid support are reported. The procedure utilizes organic media and does not require a base to neutralize HBr by-products to suppress acid promoted side reactions. Utilization of silica gel support simplifies work up and product isolation.
Bandit Online Learning with Unknown Delays

This paper deals with bandit online learning, where feedback of unknown delay can emerge in non-stochastic multi-armed bandit (MAB) and bandit convex optimization (BCO) settings. MAB and BCO require only values of the objective function to become available through feedback, and are used to estimate the gradient appearing in the corresponding iterative algorithms. Since the challenging case of feedback with unknown delays prevents one from constructing the sought gradient estimates, existing MAB and BCO algorithms become intractable. Delayed exploration, exploitation, and exponential (DEXP3) iterations, along with delayed bandit gradient descent (DBGD) iterations are developed for MAB and BCO with unknown delays, respectively. Based on a unifying analysis framework, it is established that both DEXP3 and DBGD guarantee an $\tilde{\cal O}\big( \sqrt{K(T+D)} \big)$ regret, where $D$ denotes the delay accumulated over $T$ slots, and $K$ represents the number of arms in MAB or the dimension of decision variables in BCO. Numerical tests using both synthetic and real data validate DEXP3 and DBGD.
Isolation of α,α-difluoroketene silyl acetal and its application to asymmetric aldol reactions

Abstract Salt-free α,α-difluoroketene silyl acetal 1 was prepared in pure form. Aldol reactions of 1 with aldehydes catalyzed by catalytic amounts of chiral Lewis acids 2 and 3 proceeded with excellent enantiomeric excess to give optically active α,α-difluoro-β-hydroxy esters 4–11 (up to 98% ee).
Incomplete MyoD-induced transdifferentiation is associated with chromatin remodeling deficiencies

Our current understanding of cellular transdifferentiation systems is limited. It is oftentimes unknown, at a genome-wide scale, how much transdifferentiated cells differ quantitatively from both the starting cells and the target cells. Focusing on transdifferentiation of primary human skin fibroblasts by forced expression of myogenic transcription factor MyoD, we performed quantitative analyses of gene expression and chromatin accessibility profiles of transdifferentiated cells compared to fibroblasts and myoblasts. In this system, we find that while many of the early muscle marker genes are reprogrammed, global gene expression and accessibility changes are still incomplete when compared to myoblasts. In addition, we find evidence of epigenetic memory in the transdifferentiated cells, with reminiscent features of fibroblasts being visible both in chromatin accessibility and gene expression. Quantitative analyses revealed a continuum of changes in chromatin accessibility induced by MyoD, and a strong correlation between chromatin-remodeling deficiencies and incomplete gene expression reprogramming. Classification analyses identified genetic and epigenetic features that distinguish reprogrammed from non-reprogrammed sites, and suggested ways to potentially improve transdifferentiation efficiency. Our approach for combining gene expression, DNA accessibility, and protein-DNA binding data to quantify and characterize the efficiency of cellular transdifferentiation on a genome-wide scale can be applied to any transdifferentiation system.
Functional divergence of Plexin B structural motifs in distinct steps of Drosophila olfactory circuit assembly

Plexins exhibit multitudinous, evolutionarily conserved functions in neural development. How Plexins employ their diverse structural motifs in vivo to perform distinct roles is unclear. We previously reported that Plexin B (PlexB) controls multiple steps during the assembly of the Drosophila olfactory circuit (Li et al., 2018b). Here, we systematically mutagenized structural motifs of PlexB and examined the function of these variants in these multiple steps: axon fasciculation, trajectory choice, and synaptic partner selection. We found that the extracellular Sema domain is essential for all three steps, the catalytic site of the intracellular RapGAP is engaged in none, and the intracellular GTPase-binding motifs are essential for trajectory choice and synaptic partner selection, but are dispensable for fasciculation. Moreover, extracellular PlexB cleavage serves as a regulatory mechanism of PlexB signaling. Thus, the divergent roles of PlexB motifs in distinct steps of neural development contribute to its functional versatility in neural circuit assembly.
Catalytic Hydrosilylation of Carbonyl Compounds with Cationic Oxorhenium(V) Salen

High-valent cationic oxorhenium(V) salen complexes efficiently catalyze the reduction of carbonyl compounds by organosilanes under mild, open-flask conditions. Good to excellent yields of silyl-protected alcohols are obtained in one step, and a variety of functional groups are compatible.
Identification of the (H-)(H2)12 Hydride Anion Cluster in Solid Hydrogen

Pulsed-laser ablation of metals with normal hydrogen [deuterium] condensing at 3.5 K produces a strong 3972.0 [2869.8] cm-1 absorption the same as high energy irradiation of solid hydrogen [deuteri...
The unexpected isolation of CTP-431, a novel thiopyrone from the sponge Cacospongia mycofijiensis.

A reinvestigation of a Fijian collection of Cacospongia mycofijiensis has yielded the known mycothiazole and a novel heterocyclic, CTP-431 (1). Its structure including absolute configuration as 8R,9R,10S,13S was established using NMR data, calculated DFT 13C chemical shifts and results from X-ray crystallography. It is possible that the tricyclic skeleton of CTP-431 (1) is biosynthetically related to the macrolide latrunculin A, however the thiopyrone moiety of 1 has no previous precedent in natural products chemistry.
Aza-[1,2]-Wittig rearrangements of N-benzyl glycine methyl esters. A new approach to the synthesis of N-aryl phenylalanine derivatives

Treatment of N-(arylmethyl)-N-aryl glycine methyl ester derivatives with Bu2BOTf and iPr2NEt effects an aza-[1,2]-Wittig rearrangement that provides N-aryl phenylalanine methyl esters in good yields. Analogous substrates bearing N-carbonyl groups are converted to 1,4,2-oxazaborole derivatives under similar conditions.
Fluorodediazoniation in ionic liquid solvents: new life for the Balz–Schiemann reaction

Abstract Drawbacks associated with the classic Balz–Schiemann reaction are eliminated in a series of examples by conducting fluorodediazoniation in ionic liquid solvents, thus opening up a new horizon for a much in demand process.
Hydrophobic and Hydrogen-Bonding Effects on the Rate of Diels−Alder Reactions in Aqueous Solution

Using a combined quantum mechanical and molecular mechanical (QM/MM) potential, we have carried out Monte Carlo simulations to investigate the hydrophobic and hydrogen-bonding effects on Diels−Alder reactions in aqueous solution. Two prototypical systems were considered, including the reaction of cyclopentadiene (CP) with methyl vinyl ketone (MVK) and the reaction of cyclopentadiene with isoprene. Analysis of the simulation results revealed that the hydrophobic effect is significant in both reactions. Since hydrogen bonding interactions are not involved in the reaction of CP and isoprene, the entire transition-state stabilization (4.6 ± 0.3 kcal/mol) can be attributed to the hydrophobic effect. In the reaction of CP and MVK, enhanced hydrogen-bonding interaction and the hydrophobic effect contribute equally to the transition state stabilization (−3.5 ± 0.4 kcal/mol). These findings are compared with the experimental results and predictions from previous theoretical studies.
Homoaromaticity and homoconjugation in the quinacenes: Biquinacene, triquinacene, and hexaquinacene

A thermodynamic criterion for aromatic and conjugative interactions is proposed. Enthalpies of stepwise hydrogenation of, for example, three double bonds are compensated for strain energy changes during hydrogenation. Strain energies are calculated by molecular mechanics. If the compensated values show a monotonic increase from bond 3 to bond 1, the molecule is conjugatively stabilized. If the initial rise is sharp followed by a constant ΔHh for bonds 2 and 1 and the molecule is cyclic, stabilization is aromatic. If the compensated ΔHh decreases, the interaction is destabilizing. By this set of criteria, biquinacene is unstabilized, triquinacene is homoaromatically stabilized, hexaquinacene is homoconjugatively stabilized, and cis,cis,cis-1,4,7-cyclononatriene is homoaromatically destabilized. New experimental data are presented for the biquinacenes (bicycloocta-1,7-diene and its hydrogenation products) and the hexaquinacenes.
Efficient diastereoselective synthesis of anti-α-bromo-β-hydroxyketones

Abstract anti-α-Bromo-β-hydroxyketones were synthesized in high diastereoselectivity via the enolboration of a representative series of bromomethylketones using dicyclohexylboron chloride, followed by aldolization with aldehydes.
Exogenous Substrate Reactivity with a [Cu(III)2O2]2+ Core: Structural Implications

Reactions of Cu(I) complexes with dioxygen are known to generate a structurally diverse array of oxidants in industrial and biological processes. Much effort has been directed toward the spectroscopic and structural characterization of the reactive species. The combination of low-temperature and bulky ligands has proven to be useful for successfully stabilizing and characterizing CuO{sub 2} intermediates. However, the reactivities of these intermediates are usually limited to intramolecular ligand oxidation or intermolecular oxidation of readily oxidized substrates. In the latter case, the observed reactivity is plausibly explained by an atom-transfer mechanism involving the dioxygen derived ligands without precoordination of the substrate to the metal center. A balanced ligand design that precludes deleterious bimolecular reactions, yet allows substrate binding to the copper centers, is an attractive and intuitive means of converting these well-characterized Cu/O{sub 2} intermediates into synthetically useful oxidants.
Enspara: Modeling molecular ensembles with scalable data structures and parallel computing

Markov state models (MSMs) are quantitative models of protein dynamics that are useful for uncovering the structural fluctuations that proteins undergo, as well as the mechanisms of these conformational changes. Given the enormity of conformational space, there has been ongoing interest in identifying a small number of states that capture the essential features of a protein. Generally, this is achieved by making assumptions about the properties of relevant features—for example, that the most important features are those that change slowly. An alternative strategy is to keep as many degrees of freedom as possible and subsequently learn from the model which of the features are most important. In these larger models, however, traditional approaches quickly become computationally intractable. In this paper, we present enspara, a library for working with MSMs that provides several novel algorithms and specialized data structures that dramatically improve the scalability of traditional MSM methods. This includes ragged arrays for minimizing memory requirements, message passing interface-parallelized implementations of compute-intensive operations, and a flexible framework for model construction and analysis.Markov state models (MSMs) are quantitative models of protein dynamics that are useful for uncovering the structural fluctuations that proteins undergo, as well as the mechanisms of these conformational changes. Given the enormity of conformational space, there has been ongoing interest in identifying a small number of states that capture the essential features of a protein. Generally, this is achieved by making assumptions about the properties of relevant features—for example, that the most important features are those that change slowly. An alternative strategy is to keep as many degrees of freedom as possible and subsequently learn from the model which of the features are most important. In these larger models, however, traditional approaches quickly become computationally intractable. In this paper, we present enspara, a library for working with MSMs that provides several novel algorithms and specialized data structures that dramatically improve the scalability of traditional MSM methods. This include...
Absolute Measurements of mRNA Translation in Caulobacter crescentus Reveal Important Fitness Costs of Vitamin B 12 Scavenging.

ABSTRACT Caulobacter crescentus is a model for the bacterial cell cycle which culminates in asymmetric cell division, yet little is known about the absolute levels of protein synthesis of the cellular parts needed to complete the cell cycle. Here we utilize ribosome profiling to provide absolute measurements of mRNA translation in C. crescentus, providing an important resource with quantitative genome-wide measurements of protein output across individual genes. Analysis of protein synthesis rates revealed ∼4.5% of cellular protein synthesis is for genes related to vitamin B12 import (btuB) and B12-independent methionine biosynthesis (metE) when grown in common growth media lacking B12. While its facultative B12 lifestyle provides a fitness advantage in the absence of B12, we find that it provides a fitness disadvantage of the cells in the presence of B12, potentially explaining why many Caulobacter species have lost the metE gene and become obligates for B12. IMPORTANCECaulobacter crescentus is a model system of the bacterial cell cycle culminating in asymmetric cell division, with each daughter cell inheriting a distinct set of proteins. While a genetic network of master transcription factors coordinates the cell cycle timing of transcription for nearly 20% of Caulobacter genes, we lack knowledge of how many of each protein “part” encoded in the genome are synthesized. Therefore, to determine the absolute production rates across the genome, we performed ribosome profiling, providing, for the first time, a quantitative resource with measurements of each protein “part” needed to generate daughter cells. This resource furthers the goal of a systems-level understanding of the genetic network controlling asymmetric cell division. To highlight the utility of this data set, we probe the protein synthesis cost of a B12 utilization pathway and provide new insights into Caulobacter’s adaptation to its natural environments. Author Video: An author video summary of this article is available.
A new protecting group for the synthesis of complex sulfonates

Abstract The isobutyl ester proved to be a useful protecting group for the construction of sulfonate-containing analogs of nucleosides. The syntheses of useful uridine or adenosine 3′-C-methanesulfonate analogs 1a or 1b that fail when using ethyl or isopropyl sulfonate esters, are readily accomplished with the isobutyl ester as a protecting group. In addition, alkylation reactions to give homologated sulfonates such as 2 are also much more facile when using the isobutyl protecting group.
The Transcriptional landscape of Streptococcus pneumoniae TIGR4 reveals a complex operon architecture and abundant riboregulation critical for growth and virulence

Efficient and highly organized regulation of transcription is fundamental to an organism's ability to survive, proliferate, and quickly respond to its environment. Therefore, precise mapping of transcriptional units and understanding their regulation is crucial to determining how pathogenic bacteria cause disease and how they may be inhibited. In this study, we map the transcriptional landscape of the bacterial pathogen Streptococcus pneumoniae TIGR4 by applying a combination of high-throughput RNA-sequencing techniques. We successfully map 1864 high confidence transcription termination sites (TTSs), 790 high confidence transcription start sites (TSSs) (742 primary, and 48 secondary), and 1360 low confidence TSSs (74 secondary and 1286 primary) to yield a total of 2150 TSSs. Furthermore, our study reveals a complex transcriptome wherein environment-respondent alternate transcriptional units are observed within operons stemming from internal TSSs and TTSs. Additionally, we identify many putative cis-regulatory RNA elements and riboswitches within 5'-untranslated regions (5'-UTR). By integrating TSSs and TTSs with independently collected RNA-Seq datasets from a variety of conditions, we establish the response of these regulators to changes in growth conditions and validate several of them. Furthermore, to demonstrate the importance of ribo-regulation by 5'-UTR elements for in vivo virulence, we show that the pyrR regulatory element is essential for survival, successful colonization and infection in mice suggesting that such RNA elements are potential drug targets. Importantly, we show that our approach of combining high-throughput sequencing with in vivo experiments can reconstruct a global understanding of regulation, but also pave the way for discovery of compounds that target (ribo-)regulators to mitigate virulence and antibiotic resistance.
A genome-wide survey of mutations in the Jurkat cell line.

The Jurkat cell line has an extensive history as a model of T cell signaling. But at the turn of the 21st century, some expression irregularities were observed, raising doubts about how closely the cell line paralleled normal human T cells. While numerous expression deficiencies have been described in Jurkat, genetic explanations have only been provided for a handful of defects. Here, we report a comprehensive catolog of genomic variation in the Jurkat cell line based on whole-genome sequencing. With this list of all detectable, non-reference sequences, we prioritize potentially damaging mutations by mining public databases for functional effects. We confirm documented mutations in Jurkat and propose links from detrimental gene variants to observed expression abnormalities in the cell line. The Jurkat cell line harbors many mutations that are associated with cancer and contribute to Jurkat’s unique characteristics. Genes with damaging mutations in the Jurkat cell line are involved in T-cell receptor signaling (PTEN, INPP5D, CTLA4, and SYK), maintenance of genome stability (TP53, BAX, and MSH2), and O-linked glycosylation (C1GALT1C1). This work ties together decades of molecular experiments and serves as a resource that will streamline both the interpretation of past research and the design of future Jurkat studies.
Metabolic Modeling of Cystic Fibrosis Airway Communities Predicts Mechanisms of Pathogen Dominance

Cystic fibrosis (CF) is a fatal genetic disease characterized by chronic lung infections due to aberrant mucus production and the inability to clear invading pathogens. The traditional view that CF infections are caused by a single pathogen has been replaced by the realization that the CF lung usually is colonized by a complex community of bacteria, fungi, and viruses. To help unravel the complex interplay between the CF lung environment and the infecting microbial community, we developed a community metabolic model comprised of the 17 most abundant bacterial taxa, which account for >95% of reads across samples, from three published studies in which 75 sputum samples from 46 adult CF patients were analyzed by 16S rRNA gene sequencing. The community model was able to correctly predict high abundances of the "rare" pathogens Enterobacteriaceae, Burkholderia, and Achromobacter in three patients whose polymicrobial infections were dominated by these pathogens. With these three pathogens removed, the model correctly predicted that the remaining 43 patients would be dominated by Pseudomonas and/or Streptococcus. This dominance was predicted to be driven by relatively high monoculture growth rates of Pseudomonas and Streptococcus as well as their ability to efficiently consume amino acids, organic acids, and alcohols secreted by other community members. Sample-by-sample heterogeneity of community composition could be qualitatively captured through random variation of the simulated metabolic environment, suggesting that experimental studies directly linking CF lung metabolomics and 16S sequencing could provide important insights into disease progression and treatment efficacy. IMPORTANCE Cystic fibrosis (CF) is a genetic disease in which chronic airway infections and lung inflammation result in respiratory failure. CF airway infections are usually caused by bacterial communities that are difficult to eradicate with available antibiotics. Using species abundance data for clinically stable adult CF patients assimilated from three published studies, we developed a metabolic model of CF airway communities to better understand the interactions between bacterial species and between the bacterial community and the lung environment. Our model predicted that clinically observed CF pathogens could establish dominance over other community members across a range of lung nutrient conditions. Heterogeneity of species abundances across 75 patient samples could be predicted by assuming that sample-to-sample heterogeneity was attributable to random variations in the CF nutrient environment. Our model predictions provide new insights into the metabolic determinants of pathogen dominance in the CF lung and could facilitate the development of improved treatment strategies.
A novel route to 1,3-dienyl-2-boronic esters providing simple syntheses of conjugated [E,E]-dienes and conjugated [E]-alkenones.

Abstract A highly stereo- and regioselective synthesis of [ E ]-2-(1′-[ E ]-alkenylsubstituted-1′-alkenyl)-l,3,2-dioxaborinanes has been achieved for the first time via the nucleophilic substitution of [ Z ]-(1-bromo-1- alkenyl)boronic esters with [ E ]-l-lithio-l-alkenes. These are novel boron intermediates, which are converted into conjugated [ E,E ]-dienes and conjugated [ E ]-alkenones in good yields and in excellent stereochemical purities.
Scalable Deniable Group Key Establishment.

The popular Katz-Yung compiler from CRYPTO 2003 can be used to transform unauthenticated group key establishment protocols into authenticated ones. In this paper we present a modification of Katz and Yung’s construction which maintains the round complexity of their compiler, but for ‘typical’ unauthenticated group key establishments adds authentication in such a way that deniability is achieved as well. As an application, a deniable authenticated group key establishment with three rounds of communication can be constructed.
Facile alkylation of 2-methyl-2-oxazoline: Synthesis of novel 2-substituted-2-oxazolines

Abstract The synthesis, mechanism of formation and purification of new oxazolines containing binaphthyl and biphenyl moieties based on alkylation of 2-methyl-2-oxazoline with alkyl halides are described. Yields up to 87 % have been realized, and the method is applicable to the syntheses of other 2-substituted-2-oxazolines.
GEOMetaCuration: a web-based application for accurate manual curation of Gene Expression Omnibus metadata.

Abstract Metadata curation has become increasingly important for biological discovery and biomedical research because a large amount of heterogeneous biological data is currently freely available. To facilitate efficient metadata curation, we developed an easy-to-use web-based curation application, GEOMetaCuration, for curating the metadata of Gene Expression Omnibus datasets. It can eliminate mechanical operations that consume precious curation time and can help coordinate curation efforts among multiple curators. It improves the curation process by introducing various features that are critical to metadata curation, such as a back-end curation management system and a curator-friendly front-end. The application is based on a commonly used web development framework of Python/Django and is open-sourced under the GNU General Public License V3. GEOMetaCuration is expected to benefit the biocuration community and to contribute to computational generation of biological insights using large-scale biological data. An example use case can be found at the demo website: http://geometacuration.yubiolab.org. Database URL: https://bitbucket.com/yubiolab/GEOMetaCuration
Conformationally restricted analogues of trimethoprim: 2,6-diamino-8-substituted purines as potential dihydrofolate reductase inhibitors from Pneumocystis carinii and Toxoplasma gondii

Twenty-two 2,6-diamino-8-substituted purines (2-23) were synthesized, in which rotation around the two flexible bonds of trimethoprim (TMP), linking the pyrimidine ring to the side chain phenyl ring, was restricted by incorporation into a purine ring, in an attempt to increase the potency and selectivity of TMP against dihydrofolate reductase (DHFR) from the organisms that often cause fatal opportunistic infections in patients with AIDS, i.e., Pneumocystis carinii (pc) and Toxoplasma gondii (tg). The syntheses of analogues 2-20 were achieved via a one-pot reaction of 2,4,5,6-tetraaminopyrimidine and the appropriately substituted benzaldehyde or phenyl acetaldehyde, in acidic methoxyethanol. Analogues 21-23 were synthesized via nucleophilic displacement of 2,6-diamino-8-(chloromethyl)purine with the appropriate anilines or 2-naphthalenethiol. The compounds were evaluated as inhibitors of pcDHFR and tgDHFR with rat liver (rl) DHFR as the mammalian reference enzyme. Compound 11, the 3',4'-dichlorophenyl analogue, was as potent as TMP and had a selectivity ratio of 13 for pcDHFR, which ranked it as one of the three most selective inhibitors of pcDHFR (compared to rlDHFR) known to date. It also displayed a selectivity ratio of 38 for tgDHFR. None of the other analogues showed any improvement compared to TMP in potency or selectivity. In the preclinical in vitro screening program of the National Cancer Institute, compound 11 showed a GI50 of 10(-6) M for the inhibition of the growth of 17 tumor cell lines.
Machine Learning Versus Logistic Regression Methods for 2-Year Mortality Prognostication in a Small, Heterogeneous Glioma Database.

Background Machine learning (ML) is the application of specialized algorithms to datasets for trend delineation, categorization, or prediction. ML techniques have been traditionally applied to large, highly dimensional databases. Gliomas are a heterogeneous group of primary brain tumors, traditionally graded using histopathologic features. Recently, the World Health Organization proposed a novel grading system for gliomas incorporating molecular characteristics. We aimed to study whether ML could achieve accurate prognostication of 2-year mortality in a small, highly dimensional database of patients with glioma. Methods We applied 3 ML techniques (artificial neural networks [ANNs], decision trees [DTs], and support vector machines [SVMs]) and classical logistic regression (LR) to a dataset consisting of 76 patients with glioma of all grades. We compared the effect of applying the algorithms to the raw database versus a database where only statistically significant features were included into the algorithmic inputs (feature selection). Results Raw input consisted of 21 variables and achieved performance of accuracy/area (C.I.) under the curve of 70.7%/0.70 (49.9–88.5) for ANN, 68%/0.72 (53.4–90.4) for SVM, 66.7%/0.64 (43.6–85.0) for LR, and 65%/0.70 (51.6–89.5) for DT. Feature selected input consisted of 14 variables and achieved performance of 73.4%/0.75 (62.9–87.9) for ANN, 73.3%/0.74 (62.1–87.4) for SVM, 69.3%/0.73 (60.0–85.8) for LR, and 65.2%/0.63 (49.1–76.9) for DT. Conclusions We demonstrate that these techniques can also be applied to small, highly dimensional datasets. Our ML techniques achieved reasonable performance compared with similar studies in the literature. Although local databases may be small versus larger cancer repositories, we demonstrate that ML techniques can still be applied to their analysis; however, traditional statistical methods are of similar benefit.
Optimization of Smooth Functions With Noisy Observations: Local Minimax Rates

We consider the problem of global optimization of an unknown non-convex smooth function with noisy zeroth-order feedback. We propose a local minimax framework to study the fundamental difficulty of optimizing smooth functions with adaptive function evaluations. We show that for functions with fast growth around their global minima, carefully designed optimization algorithms can identify a near global minimizer with many fewer queries than worst-case global minimax theory predicts. For the special case of strongly convex and smooth functions, our implied convergence rates match the ones developed for zeroth-order convex optimization problems. On the other hand, we show that in the worst case no algorithm can converge faster than the minimax rate of estimating an unknown function in the $\ell _\infty $ -norm. Finally, we show that non-adaptive algorithms, though optimal in a global minimax sense, do not attain the optimal local minimax rate.
A convenient synthesis of 1,2-disubstituted cyclooctatetraenes

Abstract Substituted cyclooctatetraenes can be prepared in two steps employing a Cr-(0)-promoted [6 π +2 π ] thiepin dioxide-alkyne cycloaddition followed by photoactivated sulfur dioxide extrusion.
tert-Butyl Substituent as a Regiodirecting and Novel C−H Protecting Group in Cyclobutenedione-Based Benzannulation Chemistry

2-Unsubstituted hydroquinone monoacetates, quinones, and 3-unsubstituted quinolizinones were synthesized in moderate to high yields via tert-butyl and trimethylsilyl substituted cyclobutenediones. ...
(2-Vinylcyclopropyl)carbenes. More Stepwise Mechanisms for Ring-Expansion

A simple vinyl group is sufficient to induce a stepwise mechanism for the ring expansion of cyclopropylcarbenes.
A Practical method for preparation of β-glycosides of N-acetylglucosamine

Abstract A mild and efficient method for preparation of GlcNAc derivatives by reaction of glycosyl acceptors with glycosyl oxazolines has been developed. The key feature is use of Yb(OTf) 3 as promoter, requiring moderate reaction times and equivalence stoichiometry. We anticipate application in the preparation of a wide range of derivatives of this biologically important class of building blocks.
An olefination approach to the enantioselective syntheses of several styryllactones

A flexible enantioselective route to highly functionalized α,β-unsaturated δ-lactones, has allowed for the syntheses of the styryllactones: altholactone, isoaltholactone, 3-epi-altholactone, 2-epi-altholactone and 5-hydroxy goniothalamin in 2.5, 10, 5, 1 and 13% overall yields from furfural, respectively. This approach derives its asymmetry by applying the Sharpless catalytic asymmetric dihydroxylation to vinylfuran. The resulting diols are produced in high enantioexcess and can be stereoselectively transformed into α,β-unsaturated-δ-lactones via a short highly diastereoselective oxidation and reduction sequence. Wittig olefination or Julia olefination reactions were used to introduce the phenyl group side chain either cis or trans selectively and these intermediates were further elaborated into the altholactone isomers via selective epoxidation reactions.