cssi/SciSciGPT-SciSciNet huggingface dataset:
A Data Science Solution to the Multiple-Testing Crisis in Financial Research

Most discoveries in empirical finance are false, as a consequence of selection bias under multiple testing. Although many researchers are aware of this problem, the solutions proposed in the literature tend to be complex and hard to implement. In this article, the author reduces the problem of selection bias in the context of investment strategy development to two sub-problems: determining the number of essentially independent trials and determining the variance across those trials. The author explains what data researchers need to report to allow others to evaluate the effect that multiple testing has had on reported performance. He applies his method to a real case of strategy development and estimates the probability that a discovered strategy is false.
Genetics of Alcoholism

We review the search for genetic variants that affect the risk for alcohol dependence and alcohol consumption. Variations in genes affecting alcohol metabolism (ADH1B, ALDH2) are protective against both alcohol dependence and excessive consumption, but different variants are found in different populations. There are different patterns of risk variants for alcohol dependence vs. consumption. Variants for alcohol dependence, but not consumption, are associated with risk for other psychiatric illnesses. ADH1B and ALDH2 strongly affect both consumption and dependence. Variations in many other genes affect both consumption and dependence—or one or the other of these traits—but individual effect sizes are small. Evidence for other specific genes that affect dependence is not yet strong. Most current knowledge derives from studies of European-ancestry populations, and large studies of carefully phenotyped subjects from different populations are needed to understand the genetic contributions to alcohol consumption and alcohol use disorders.
Teoría feminista y el agente social dócil: algunas reflexiones sobre el renacimiento islámico en Egipto

This article was originally published by Saba Mahmood in the journal Cultural Anthropology , volume 16, number 2, in 2001 with the title: "Feminist Theory, Embodiment, and the Docile Agent: Some Reflections on the Egyptian Islamic Revival". In 2008, the article was published in Spanish in a book edited by Liliana Suarez Navaz y Rosalva Aida Hernandez Castillo in Catedra: Descolonizando el feminismo: teorias y practicas desde los margenes . In the article, Saba Mahmood, who recently passed away, deals with a main debate in feminist theory: social agency. Through an analysis of the piety movement in Egypt in the 1990s and precisely of the study of five mosques in El Cairo, the author questions the consideration of social agency as a synonym of resistance to domination relations, which prevents the study of movements as the one she studies. She offers a conceptualization of agency as capacity of action that is habilitated and created inside specific historical relations of subordination.
Companion-driven evolution of massive stellar binaries

At least $70\%$ of massive OBA-type stars reside in binary or higher-order systems. The dynamical evolution of these systems can lend insight into the origins of extreme phenomena such as X-ray binaries and gravitational wave sources. In one such dynamical process, the Eccentric Kozai-Lidov (EKL) Mechanism, a third companion star alters the secular evolution of a binary system. For dynamical stability, these triple systems must have a hierarchical configuration. We explore the effects of a distant third companion's gravitational perturbations on a massive binary's orbital configuration before significant stellar evolution has taken place ($\leq 10$ Myr). We include tidal dissipation and general relativistic precession. With large ($38,000$ total) Monte-Carlo realizations of massive hierarchical triples, we characterize imprints of the birth conditions on the final orbital distributions. Specifically, we find that the final eccentricity distribution over the range $0.1-0.7$ is an excellent indicator of its birth distribution. Furthermore, we find that the period distributions have a similar mapping for wide orbits. Finally, we demonstrate that the observed period distribution for approximately $10$ Myr-old massive stars is consistent with EKL evolution.
Heterometal Substitution in the Dimensional Reduction of Cluster Frameworks: Synthesis of Soluble [Re6-nOsnSe8Cl6](4-n)- (n = 1−3) Cluster-Containing Solids

A general method for deconstructing cluster frameworks via heterometal substitution is demonstrated with application to the two-dimensional phase Re(6)Se(8)Cl(2). Solid-state reactions intended to replace two of the Re(III) centers in the parent compound with Os(IV)Cl units indeed yield Re(4)Os(2)Se(8)Cl(4). The crystal structure of this new phase reveals a less tightly connected two-dimensional framework, wherein face-capped octahedral [Re(4)Os(2)Se(8)](4+) cluster cores are linked through mu(2)-chloride bridges in one dimension and unsupported metal-selenium bonds in the other. Use of CsCl as a standard dimensional reduction agent in conjunction with heterometal substitution affords Cs(3)Re(5)OsSe(8)Cl(6) and Cs(2)Re(4)Os(2)Se(8)Cl(6), soluble salts containing discrete molecular clusters. Reactions employing KCl and targeting a triosmium cluster further produce the soluble mixed-cluster salt K(2)[Re(3)Os(3)Se(8)Cl(6)][Re(4)Os(2)Se(7)Cl(7)]. FT-ICR mass spectra confirm the presence of [Re(6-n)Os(n)Se(8)Cl(6)](4-n)- (n = 1-3) clusters in solutions of these solids. Metathesis reactions supply (Bu(4)N)(3)[Re(5)OsSe(8)Cl(6)] and (Bu(4)N)(2)[Re(4)Os(2)Se(8)Cl(6)], which then react with PEt(3) under forcing conditions to give [Re(5)OsSe(8)(PEt(3))(6)](3+) and [Re(4)Os(2)Se(8)(PEt(3))(6)](4+) in high yield. Analysis of the latter diosmium species by (31)P NMR spectroscopy indicates a mixture of isomers, in which 55% of the clusters have the osmium atoms disposed trans to each other, while the remainder adopt the alternative cis configuration. Cyclic voltammetry measurements reveal a reversible one-electron reduction for [Re(5)OsSe(8)Cl(6)](3-) and multiple one-electron reductions for the mono- and diosmium hexaphosphine clusters; in the latter case, the trans isomer is observed to be more easily reduced than the cis isomer. Electronic structure calculations utilizing density functional theory show the trans isomer of [Re(4)Os(2)Se(8)Cl(6)](2-) to be 4.5 kcal/mol more stable than the cis isomer, in approximate agreement with the observed ratio of reaction products. Moreover, the calculations expose significant differences in the contributions of rhenium and osmium to the frontier orbitals of the clusters, suggesting the possibility of observing metal-selective reactivity. An initial example of such behavior is provided with the synthesis of trans,trans-[Re(4)Os(2)Se(8)(PEt(3))(2)Cl(4)], wherein PEt(3) ligands preferentially bind the osmium centers.
Studies on Intramolecular Higher-Order Cycloaddition Reactions

Thermal, metal-free, and metal-promoted intramolecular higher-order cycloadditions are described. Substrates in which the tropone (2,4,6-cycloheptatrien-1-one) nucleus is tethered to various diene moieties undergo exo-selective [6π + 4π] cycloaddition under thermal conditions to afford stereochemically defined tricyclic products. The substrates employed in this study were prepared by addition of the Grignard derivative of the given diene side-chain unit to 2-chlorotropone. In each instance, the requisite 2-substituted tropone was obtained directly from these reaction sequences. A similar study was conducted on the corresponding chromium(0) complexes of related tropone and cycloheptatriene-based substrates. In the cases involving metal mediation both thermal and photochemical activation were effective for delivering cycloadducts. The metal-promoted reactions were shown to proceed exclusively via an endo-selective pathway, which is stereocomplementary to the course of the thermal, metal-free reactions. A ta...
General Synthesis of Polysubstituted Benzo[b]furans.

2-(Benzotriazol-1-ylmethyl)furans 4a−c, on treatment with n-BuLi followed by various α,β-unsaturated ketones and aldehydes, gave the adducts 6a−f which underwent intramolecular cyclization to form substituted benzo[b]furans 10a−f. Lithiation and subsequent alkylation of 4a−c afforded intermediates 8a−c, which underwent similar transformations with α,β-unsaturated ketones or aldehydes to give the corresponding polysubstituted benzo[b]furans 7a−c. o-Iodophenol (11) with 1-propargylbenzotriazole (1) in the presence of (PPh3)2PdCl2, CuI, and Et3N gave 2-(benzotriazol-1-ylmethyl)benzo[b]furan (12). The benzotriazolyl-CH2 side chain of 12 was further elaborated by (i) alkylation with trans-cinnamaldehyde to give the adduct 14, followed by intramolecular cyclization to give dibenzofuran 17; (ii) alkylation with benzyl bromide followed by elimination or nucleophilic displacement of the benzotriazolyl moiety with Grignard reagent and subsequent dehydrogenation to give 2-alkenylbenzofurans 15 or 20, respectively; (...
SYNTHESES OF (TRIFLUOROMETHYL)IMIDAZOLES WITH ADDITIONAL ELECTRONEGATIVE SUBSTITUENTS. AN APPROACH TO RECEPTOR-ACTIVATED AFFINITY LABELS

Electrophilic substitution in 2- and 4-(trifluoromethyl)imidazoles provides derivatives containing one or two nitro, chloro, bromo, or iodo groups. Fluoro and chloro derivatives were also prepared by photochemical trifluoromethylation of the respective haloimidazole. The results demonstrate that (trifluoromethyl)imidazoles behave fairly typically under the conditions of electrophilic nitration and halogenation. Of the alternative routes to the desired bifunctional and trifunctional imidazoles, electrophilic substitution on the preformed (trifluoromethyl)imidazole appears to be the method of choice in most cases. A large number of the products show herbicidal or insecticidal activity.
Synthesis of both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand via convergent routes and application to rhodium-catalyzed asymmetric hydrogenation of CI-1008 (pregabalin).

Both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand are synthesized via two convergent methods. The first method relies on the chiral alkylation of 1-((−)-menthoxy)phospholaneborane using a s-BuLi/(−)-sparteine derived chiral base. Only one enantiomer of the catalyst could be synthesized via this method because only one antipode of sparteine is available in nature. The second route relies on the combination of methylphosphine borane and a chiral 1,4-diol. Either enantiomer of the ligand can be synthesized via the second route from the appropriate enantiomer of the 1,4-diol. Asymmetric hydrogenation using catalyst precursor 36 on acetamidoacrylic acid derivatives provided modest to good enantioselectivity (77−95% ee) under low H2 pressure (30 psi). Asymmetric hydrogenation of CI-1008 (pregabalin) precursors, 39 and 40, provided good enantioselectivities (92%) at high catalyst loading (1 mol %) and low pressure (30 psi). Enantiomeric excesses dropped sharply with catalyst loading at this pres...
Characterizing variants of unknown significance in rhodopsin: A functional genomics approach.

Characterizing the pathogenicity of DNA sequence variants of unknown significance (VUS) is a major bottleneck in human genetics, and is increasingly important in determining which patients with inherited retinal diseases could benefit from gene therapy. A library of 210 rhodopsin (RHO) variants from literature and in-house genetic diagnostic testing were created to efficiently detect pathogenic RHO variants that fail to express on the cell surface. This study, while focused on RHO, demonstrates a streamlined, generalizable method for detecting pathogenic VUS. A relatively simple next-generation sequencing-based readout was developed so that a flow cytometry-based assay could be performed simultaneously on all variants in a pooled format, without the need for barcodes or viral transduction. The resulting dataset characterized the surface expression of every RHO library variant with a high degree of reproducibility (r2 = 0.92-0.95), recategorizing 37 variants. For example, three retinitis pigmentosa pedigrees were solved by identifying VUS which showed low expression levels (p.G18D, p.G101V, and p.P180T). Results were validated across multiple assays and correlated with clinical disease severity. This study presents a parallelized, higher-throughput cell-based assay for the functional characterization of VUS in RHO, and can be applied more broadly to other inherited retinal disease genes and other disorders.
Formation of Urea, Isourea, and Triazine Derivatives from Diisopropylcyanamide with Trifluoroacetic Anhydride and Trifluoromethanesulfonic Anhydride: Thermal Instability of Urea and Isourea Derivatives

Diisopropylcyanamide reacts exothermically with trifluoroacetic anhydride to give 2, an equilibrium mixture, in C6D6 solution, of 1:1 adducts, N,N-diisopropyl-N‘,O-bis(trifluoroacetyl)isourea, 2a (10%), and N,N-diisopropyl-N‘,N‘-bis(trifluoroacetyl)urea, 2c (90%), at 27 °C. Compound 2c is a colorless solid, mp 49−51 °C. Thermolysis of 2, at 117 °C, shows first-order kinetics with the intital products being trifluoroacetonitrile, 4, and diisopropylcarbamic trifluoroacetic mixed anhydride, 3. Trifluoroacetonitrile trimerizes to 2,4,6-tris(trifluoromethyl)-1,3,5-triazine, and 3 is thermally labile giving diisopropyltrifluoroacetamide and CO2. In the thermolysis reaction 4 reacts with 2a to give a small amount of 4-(diisopropylamino)-4-(trifluoroacetoxy)-2,6-bis(trifluoromethyl)-4H-1,3,5-oxadiazine, 7. A related compound, 4,4-bis(diisopropylamino)-2,6-bis(trifluoromethyl)-4H-1,3,5-oxadiazine, 8, is formed from 7 and 2c going through a concentration maximum at 4000 s in the kinetic run. Compound 8 thermolytica...
First General Method for Direct Formylation of Kinetically-Generated Ketone Enolates†

2,2,2-Trifluoroethyl formate reacts rapidly at −78 °C with preformed ketone enolates to give α-formyl ketones in good yields. In addition, this procedure allows for complete reversal of the regioselectivity of the classical Claisen reaction and provides a superior method for the α‘-formylation of α,β-unsaturated ketones.
Preparation and applications of a polymer-supported phosphoryl azide

A polymer-supported diphenylphosphoryl azide was prepared. This polymer-supported version of DPPA is useful due to its lower toxicity, moisture tolerance and ease of workup after reaction. The synthetic application of this solid-phase reagent was explored by conversion of a variety of carboxylic acids to urethanes and ureas through Curtius rearrangement reactions. Carboxylic acids bearing different functional groups (aromatic, aliphatic and heterocyclic carboxylic acids) were subjected to the reaction. The corresponding products were isolated with satisfactory yields.
ProteomeVis: a web app for exploration of protein properties from structure to sequence evolution across organisms' proteomes.

Motivation Protein evolution spans time scales and its effects span the length of an organism. A web app named ProteomeVis is developed to provide a comprehensive view of protein evolution in the Saccharomyces cerevisiae and Escherichia coli proteomes. ProteomeVis interactively creates protein chain graphs, where edges between nodes represent structure and sequence similarities within user-defined ranges, to study the long time scale effects of protein structure evolution. The short time scale effects of protein sequence evolution are studied by sequence evolutionary rate (ER) correlation analyses with protein properties that span from the molecular to the organismal level. Results We demonstrate the utility and versatility of ProteomeVis by investigating the distribution of edges per node in organismal protein chain universe graphs (oPCUGs) and putative ER determinants. S.cerevisiae and E.coli oPCUGs are scale-free with scaling constants of 1.79 and 1.56, respectively. Both scaling constants can be explained by a previously reported theoretical model describing protein structure evolution. Protein abundance most strongly correlates with ER among properties in ProteomeVis, with Spearman correlations of -0.49 (P-value < 10-10) and -0.46 (P-value < 10-10) for S.cerevisiae and E.coli, respectively. This result is consistent with previous reports that found protein expression to be the most important ER determinant. Availability and implementation ProteomeVis is freely accessible at http://proteomevis.chem.harvard.edu. Supplementary information Supplementary data are available at Bioinformatics online.
Synthesis of the spirocyclic cyclohexadienone ring system of the schiarisanrins.

Studies on the synthesis of the spirocyclic cyclohexadienone ring system 2 of the schiarisanrin family of natural products 1 are described and were based on the Lewis acid-promoted C-alkylation of the corresponding phenolic precursor.
Evolution of C2B4 carborane chemistry : from early years to the present

A review of the chemistry of polyhedral cluster complexes in which s-, p-, d- and f-block metals are incorporated mainly into Ccage-trimethylsilyl-substituted C2B4 carborane cages is presented. While the main thrust of this review is on the results obtained in authors' laboratories, comparisons are made to similar systems and to those involving both large- and small-cage carboranes. In this way we hope to demonstrate the unique chemistry of the small-C2B4-cage systems that has emerged over the last 40 years. However, a full picture of the chemistry of these systems cannot be presented without heavy reference to the larger, more stable 11- and 12-vertex cages, which in many ways preceded their more diminutive cousins. The focus of much of the current research is directed toward systematizing the chemistry of metallacarboranes with the aim of promoting their use as possible electronic, ceramic, and/or catalytic materials. However, such endeavors are based on our knowledge about the fundamental interactions ...
CRISPulator: a discrete simulation tool for pooled genetic screens.

The rapid adoption of CRISPR technology has enabled biomedical researchers to conduct CRISPR-based genetic screens in a pooled format. The quality of results from such screens is heavily dependent on the selection of optimal screen design parameters, which also affects cost and scalability. However, the cost and effort of implementing pooled screens prohibits experimental testing of a large number of parameters. We present CRISPulator, a Monte Carlo method-based computational tool that simulates the impact of screen parameters on the robustness of screen results, thereby enabling users to build intuition and insights that will inform their experimental strategy. CRISPulator enables the simulation of screens relying on either CRISPR interference (CRISPRi) or CRISPR nuclease (CRISPRn). Pooled screens based on cell growth/survival, as well as fluorescence-activated cell sorting according to fluorescent reporter phenotypes are supported. CRISPulator is freely available online ( http://crispulator.ucsf.edu ). CRISPulator facilitates the design of pooled genetic screens by enabling the exploration of a large space of experimental parameters in silico, rather than through costly experimental trial and error. We illustrate its power by deriving non-obvious rules for optimal screen design.
HIV protease inhibitory bis-benzamide cyclic ureas: a quantitative structure-activity relationship analysis.

A series of N,N‘-disubstituted cyclic urea 3-benzamides has been synthesized and evaluated for HIV protease inhibition and antiviral activity. Some of these benzamides have been shown to be potent inhibitors of HIV protease with Ki < 0.050 nM and IC90 < 20 nM for viral replication and, as such, may be useful in the treatment of AIDS. The synthesis and quantitative structure−activity relationship for this benzamide series will be discussed.
Chiral Auxiliary-Bearing Isocyanides as Synthons: Synthesis of Strongly Fluorescent (+)-5-(3,4-Dimethoxyphenyl)-4-[[N- [(4S)-2-oxo-4-(phenylmethyl)-2-oxazolidinyl]]carbonyl]oxazole and Its Enantiomer.

Both (4S-(+)-3-(isocyanoacetyl)-4-(phenylmethyl)-2-oxazolidinone (R)-1 and its enantiomer (S)-1 have been synthesized as potentially useful synthons in asymmetric synthesis. Optically active (+)-5-(3,4-dimethoxyphenyl)-4-[[N-[(4S)-2-oxo-4-(phenylmethyl)-2-oxazolidinyl]]carbonyl] oxazole (S)-2 and its enantiomer (R)-2 obtained by treating 3,4-dimethoxybenzoyl chloride with (S)-1 and (R)-1, respectively, in the presence of the nonionic superbase P(MeNCH2CH2)3N, have high fluorescence quantum yields. The molecular structure of (S)-2 obtained by X-ray means is also presented.
A general and convenient synthesis of N-aryl piperazines

A general and convenient synthesis of N-aryl piperazines from bis(2-chloroethyl)amine hydrochloride and a broad range of anilines in diethylene glycol monomethyl ether is described.
The metal chemistry of the carbahemiporphyrazines

Over fifty years ago, Linstead and Elvidge described the syntheses of phthalocyanine-like macrocycles in which one or two of the interior metal-binding nitrogen atoms were replaced with aromatic C-H groups. We review here the coordination chemistry of two of these systems, dicarbahemiporphyrazine and benziphthalocyanine, and we emphasize the unusual reactivity displayed by these macrocycles and the varying extent to which the C-H groups are activated by metal-binding.
Single Stereodifferentiation Associated with Carbon Atom Insertion during the Oxonium Ion-Initiated Pinacol Rearrangement of Dihydrofuranyl and Dihydropyranyl Carbinols

The stereoselectivity of the acid-promoted rearrangement of dihydrofuranyl and dihydropyranyl carbinols to spirocyclic ketones has been examined. These kinetically controlled isomerizations result in the ring expansion of the hydroxyl-substituted ring with generation of a newly stereogenic spirocyclic carbon atom. All of the adducts formed from several 4,5-dihydrofurans and cyclobutanone, cyclopentanone, and 2,2-dimethylcyclopentanone proved to be reactive. Of the 5,6-dihydropyrans examined, only the cyclobutanone adducts were sufficiently reactive to warrant study. The product distributions arising from the furanoid systems were characterized by modest discrimination in most cases. The more stereodifferentiating pyranoid systems show product distributions as high as 30:1. These results are explained in terms of transition state geometries (conformationally more flexible in the five-membered examples) while also taking into account the principle of stereoelectronic control.
Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo

Small interfering RNA (siRNA)-based therapies are proving to be efficient for treating liver-associated disorders. However, extra-hepatic delivery remains challenging, limiting therapeutic siRNA utility. We synthesized a panel of fifteen lipid-conjugated siRNAs and systematically evaluated the impact of conjugate on siRNA tissue distribution and efficacy. Generally, conjugate hydrophobicity defines the degree of clearance and the liver-to-kidney distribution profile. In addition to primary clearance tissues, several conjugates achieve significant siRNA accumulation in muscle, lung, heart, adrenal glands and fat. Oligonucleotide distribution to extra-hepatic tissues with some conjugates was significantly higher than with cholesterol, a well studied conjugate, suggesting that altering conjugate structure can enhance extra-hepatic delivery. These conjugated siRNAs enable functional gene silencing in lung, muscle, fat, heart and adrenal gland. Required levels for productive silencing vary (5-200 μg/g) per tissue, suggesting that the chemical nature of conjugates impacts tissue-dependent cellular/intracellular trafficking mechanisms. The collection of conjugated siRNA described here enables functional gene modulation in vivo in several extra-hepatic tissues opening these tissues for gene expression modulation. A systemic evaluation of a panel of conjugated siRNA, as reported here, has not previously been investigated and shows that chemical engineering of lipid siRNAs is essential to advance the RNA therapeutic field.
Total Syntheses of (−)-Haemanthidine, (+)-Pretazettine, and (+)-Tazettine

The total syntheses of the amaryllidaceae alkaloids haemanthidine, pretazettine, and tazettine as optically pure enantiomers are reported. Using d-mannose as the starting material, the critical rel...
Electrophilic fluorinating reagent mediated synthesis of fluorinated α-keto ethers, benzil, and 6,6'-dialkoxy-2,2'-bipyridines

Interactions of various fluorinated and nonfluorinated alcohols with trans-stilbene in the presence of electrophilic reagents were studied. Under neat conditions, reactions of trans-stilbene (1) wi...
Unhydrated Cr(V) Peroxychromates M3CrO8 (M = Na, K, Rb): Low-Dimensional Antiferromagnets Exhibiting Large Specific Heats at mK to 5 K Temperatures

The alkali-metal Cr(V) peroxychromates with the general formula M3CrO8 (M = Na, K, Rb, and combinations thereof) and the 3d1 ground state have been characterized by X-ray diffraction, variable frequency and variable temperature EPR, magnetic susceptibility, and thermodynamic techniques. K3CrO8 and Rb3CrO8 are isomorphous, with space groups as I42m, whereas Na3CrO8 and K2NaCrO8 exhibit the orthorhombic space groups Cmc2 and Pbcm, respectively. Lattice parameters are presented for all of these compounds and are shown to depend sensitively on the cation. EPR measurements reveal that while the electronic ground state of Na3CrO8, K3CrO8, and Rb3CrO8 is 3dx2-y2, that of the mixed salts, such as K2NaCrO8 and Rb2NaCrO8, is 3dz2; the origin of this switch is not yet clear. Specific heat measurements showed that K3CrO8 undergoes an antiferromagnetic ordering transition at TN = 0.38 K and displays a broad peak around 0.8 K, which can be interpreted in terms of a Bonner−Fisher model. Rb3CrO8 behaves similarly, with ...
Ultra-Fast Identity by Descent Detection in Biobank-Scale Cohorts Using Positional Burrows-Wheeler Transform.

With the availability of genotyping data of very large samples, there is an increasing need for tools that can efficiently identify genetic relationships among all individuals in the sample. One fundamental measure of genetic relationship of a pair of individuals is identity by descent (IBD), chromosomal segments that are shared among two individuals due to common ancestry. However, the efficient identification of IBD segments among a large number of genotyped individuals is a challenging computational problem. Most existing methods are not feasible for even thousands of individuals because they are based on pairwise comparisons of all individuals and thus scale up quadratically with sample size. Some methods, such as GERMLINE, use fast dictionary lookup of short seed sequence matches to achieve a near-linear time efficiency. However, the number of short seed matches often scales up super-linearly in real population data. In this paper we describe a new approach for IBD detection. We take advantage of an efficient population genotype index, Positional BWT (PBWT), by Richard Durbin. PBWT achieves linear time query of perfectly identical subsequences among all samples. However, the original PBWT is not tolerant to genotyping errors which often interrupt long IBD segments into short fragments. We introduce a randomized strategy by running PBWTs over random projections of the original sequences. To boost the detection power we run PBWT multiple times and merge the identified IBD segments through interval tree algorithms. Given a target IBD segment length, RaPID adjust parameters to optimize detection power and accuracy. Simulation results proved that our tool (RaPID) achieves almost linear scaling up to sample size and is orders of magnitude faster than GERMLINE. At the same time, RaPID maintains a detection power and accuracy comparable to existing mainstream algorithms, GERMLINE and IBDseq. Running multiple times with various target detection lengths over the 1000 Genomes Project data, RaPID can detect population events at different time scales. With our tool, it is feasible to identify IBDs among hundreds of thousands to millions of individuals, a sample size that will become reality in a few years.
Yield and Reliability Challenges at 7nm and Below

Layout Design Rules have been scaled very aggressively to enable the 7nm technology node without EUV. As a result, achieving acceptable performance and yield in High Volume Manufacturing (HVM) has become an extremely challenging task. Systematic yield and parametric variabilities have become quite significant. Moreover, due to overlay tolerance requirements and diminishing process windows, reliability risks due to soft shorts/leakages and soft opens for both FEOL and BEOL have also increased to a critical level. Introduction of EUV at the second wave of 7nm and 5nm will not help significantly due to increased detectivity and significant increases in Local Edge Roughness. New characterization techniques are necessary to identify the yield and reliability risks. After reviewing the evolution of design rules and classifying the yield and reliability risks, we will present examples from Design-For-Inspection™ (DFI™) and the novel VarScan methodology to "detect the undetectable" defects and characterize variability for both FEOL and BEOL 7nm and below technologies.
Quantifying Uncertainty and Robustness in a Biomathematical Model-Based Patient-Specific Response Metric for Glioblastoma.

PurposeGlioblastomas, lethal primary brain tumors, are known for their heterogeneity and invasiveness. A growing body of literature has been developed demonstrating the clinical relevance of a biom...
Multi-Source Cross-Lingual Model Transfer: Learning What to Share

Modern NLP applications have enjoyed a great boost utilizing neural networks models. Such deep neural models, however, are not applicable to most human languages due to the lack of annotated training data for various NLP tasks. Cross-lingual transfer learning (CLTL) is a viable method for building NLP models for a low-resource target language by leveraging labeled data from other (source) languages. In this work, we focus on the multilingual transfer setting where training data in multiple source languages is leveraged to further boost target language performance. Unlike most existing methods that rely only on language-invariant features for CLTL, our approach coherently utilizes both language-invariant and language-specific features at instance level. Our model leverages adversarial networks to learn language-invariant features, and mixture-of-experts models to dynamically exploit the similarity between the target language and each individual source language. This enables our model to learn effectively what to share between various languages in the multilingual setup. Moreover, when coupled with unsupervised multilingual embeddings, our model can operate in a zero-resource setting where neither target language training data nor cross-lingual resources are available. Our model achieves significant performance gains over prior art, as shown in an extensive set of experiments over multiple text classification and sequence tagging tasks including a large-scale industry dataset.
Spatio-temporal models for big multinomial data using the conditional multivariate logit-beta distribution

We introduce a Bayesian approach for analyzing high‐dimensional multinomial data that are referenced over space and time. In particular, the proportions associated with multinomial data are assumed to have a logit link to a latent spatio‐temporal mixed effects model. This strategy allows for covariances that are nonstationarity in both space and time, asymmetric, and parsimonious. We also introduce the use of the conditional multivariate logit‐beta distribution into the dependent multinomial data setting, which leads to conjugate full‐conditional distributions for use in a collapsed Gibbs sampler. We refer to this model as the multinomial spatio‐temporal mixed effects model (MN‐STM). Additionally, we provide methodological developments including: the derivation of the associated full‐conditional distributions, a relationship with a latent Gaussian process model, and the stability of the non‐stationary vector autoregressive model. We illustrate the MN‐STM through simulations and through a demonstration with public‐use quarterly workforce indicators data from the longitudinal employer household dynamics program of the US Census Bureau.
Sensitive and specific post-call filtering of genetic variants in xenograft and primary tumors.

Motivation Tumor genome sequencing offers great promise for guiding research and therapy, but spurious variant calls can arise from multiple sources. Mouse contamination can generate many spurious calls when sequencing patient-derived xenografts. Paralogous genome sequences can also generate spurious calls when sequencing any tumor. We developed a BLAST-based algorithm, Mouse And Paralog EXterminator (MAPEX), to identify and filter out spurious calls from both these sources. Results When calling variants from xenografts, MAPEX has similar sensitivity and specificity to more complex algorithms. When applied to any tumor, MAPEX also automatically flags calls that potentially arise from paralogous sequences. Our implementation, mapexr, runs quickly and easily on a desktop computer. MAPEX is thus a useful addition to almost any pipeline for calling genetic variants in tumors. Availability and implementation The mapexr package for R is available at https://github.com/bmannakee/mapexr under the MIT license. Contact mannakee@email.arizona.edu or rgutenk@email.arizona.edu or eknudsen@email.arizona.edu. Supplementary information Supplementary data are available at Bioinformatics online.
Evolutionary Dynamics of Male Reproductive Genes in the Drosophila virilis Subgroup.

Postcopulatory sexual selection (PCSS) is a potent evolutionary force that can drive rapid changes of reproductive genes within species, and thus has the potential to generate reproductive incompatibilities between species. Male seminal fluid proteins (SFPs) are major players in postmating interactions, and are important targets of PCSS in males. The virilis subgroup of Drosophila exhibits strong interspecific gametic incompatibilities, and can serve as a model to study the genetic basis of PCSS and gametic isolation. However, reproductive genes in this group have not been characterized. Here we utilize short-read RNA sequencing of male reproductive organs to examine the evolutionary dynamics of reproductive genes in members of the virilis subgroup: D . americana , D. lummei , D. novamexicana , and D. virilis . We find that the majority of male reproductive transcripts are testes-biased, accounting for ∼15% of all annotated genes. Ejaculatory bulb (EB)-biased transcripts largely code for lipid metabolic enzymes, and contain orthologs of the D. melanogaster EB protein, Peb-me, which is involved in mating-plug formation. In addition, we identify 71 candidate SFPs, and show that this gene set has the highest rate of nonsynonymous codon substitution relative to testes- and EB-biased genes. Furthermore, we identify orthologs of 35 D. melanogaster SFPs that have conserved accessory gland expression in the virilis group. Finally, we show that several of the SFPs that have the highest rate of nonsynonymous codon substitution reside on chromosomal regions, which contributes to paternal gametic incompatibility between species. Our results show that SFPs rapidly diversify in the virilis group, and suggest that they likely play a role in PCSS and/or gametic isolation.
Studies in selective 6-membered bromoether formation via bromonium and thiiranium-induced cyclizations

The formation of 6-endo bromoether ring systems from linear alkenol precursors through bromonium-induced cyclizations has historically proven challenging, with 5-exo products typically predominating, even on rigid scaffolds. This Letter describes our efforts to achieve such cyclizations directly using new bromonium sources such as BDSB (Et2SBr·SbCl5Br) as well as two alternative, stepwise approaches based on either thiiranium-induced cyclization and subsequent sulfur manipulation or bromonium-induced closure of secondary alcohols and oxidative functionalization to generate fully substituted carbon centers. In some cases, 6-endo bromoethers could be controllably formed without generating 5-exo alternatives.
SNAP23 is required for constitutive and regulated exocytosis in mouse oocytes

Mammalian oocytes are stored in the ovary for prolonged periods, and arrested in meiotic prophase. During this period, their plasma membranes are constantly being recycled by endocytosis and exocytosis. However, the function of this membrane turnover is unknown. Here, we investigated the requirement for exocytosis in the maintenance of meiotic arrest. Using Trim-away, a newly developed method for rapidly and specifically depleting proteins in oocytes, we have identified the SNARE protein, SNAP23, to be required for meiotic arrest. Degradation of SNAP23 causes premature meiotic resumption in follicle-enclosed oocytes. The reduction in SNAP23 is associated with loss of gap junction communication between the oocyte and surrounding follicle cells. Reduction of SNAP23 protein also inhibits regulated exocytosis in response to a Ca2+ stimulus (cortical granule exocytosis), as measured by lectin staining and cleavage of ZP2. Our results show an essential role for SNAP23 in two key processes that occur in mouse oocytes and eggs.
Diastereoselective Synthesis of Cyclopentanoids with Hydantoin and Isoxazoline Substituents.

Exploiting 1,3-dipolar cycloaddition and urea → hydantoin cyclization transformations, novel spiro[cyclopenta[d]isoxazole-4‘,5-imidazolindine] heterocycles of generalized structure I have been prepared. The 1-amino-3-cyclopentenecarboxylate precursor II was prepared from a suitably activated/protected derivative of glycine and the bis-alkylating agent cis-1,4-dichloro-2-butene.
The (SO2)2N3- anion.

Abstract : The recently proposed (S02)2N3(-) anion was structurally characterized by single crystal X-ray diffraction of the Cs(S02)2N3 salt (P21/c, a = 8.945(2) A, b = 10.454(2) A, c = 8.152(2) A, a(^) = 109.166(3)(sup o), Z = 4, and R1 = 0.0329 at 130 K). In the (SO2)2N3(-) anion, both SO2 ligands are coordinated to one terminal nitrogen atom of the N3-(-) anion.
Catalyst selection for metal carbene transformations

Abstract Recent work has led to a greater understanding of the unique catalytic capabilities of chiral dirhodium(II) carboxamidates. High levels of product control, especially enantioselectivity, can be achieved with these catalysts in a wide variety of metal carbene transformations. Catalyst selection is the key to these applications that include addition, insertion, and ylide porcesses. Often two chiral dirhodium(II) carboxamidate catalysts applied to the same substrate provide exceptional selectivity, but for different products.
Sequence-specific modification of guanosine in DNA by a C60-linked deoxyoligonucleotide: Evidence for a non-singlet oxygen mechanism

Abstract A C60-linked deoxyoligonucleotide (C60-DON-1) was prepared from bromoacetate 3. This C60-oligonucleotide conjugate was hybridized to a complementary single-stranded DNA. This system reacted with light and oxygen to damage only guanosines in the single-stranded region which are closest to C60. The damage did not involve 1O2 as the active species but rather resulted from a single electron-transfer mechanism between guanosine and 3C60, as shown by comparison experiments with eosin-attached DON-1 and by the use of singlet oxygen quenchers.
Sequenced Reactions with Samarium(II) Iodide. Tandem Nucleophilic Acyl Substitution/Ketyl−Olefin Coupling Reactions

Samarium(II) iodide has been employed to promote a tandem intramolecular nucleophilic acyl substitution/intramolecular ketyl−olefin coupling cyclization sequence, generating bicyclic, tricyclic, and spirocyclic ring systems in excellent yield and with high diastereoselectivity. This versatile reaction sequence allows entry to several different naturally occurring tricyclic systems containing the angular and linear triquinane framework.
Task‐evoked functional connectivity does not explain functional connectivity differences between rest and task conditions

During complex tasks, patterns of functional connectivity differ from those in the resting state. However, what accounts for such differences remains unclear. Brain activity during a task reflects an unknown mixture of spontaneous and task-evoked activities. The difference in functional connectivity between a task state and the resting state may reflect not only task-evoked functional connectivity, but also changes in spontaneously emerging networks. Here, we characterized the differences in apparent functional connectivity between the resting state and when human subjects were watching a naturalistic movie. Such differences were marginally explained by the task-evoked functional connectivity involved in processing the movie content. Instead, they were mostly attributable to changes in spontaneous networks driven by ongoing activity during the task. The execution of the task reduced the correlations in ongoing activity among different cortical networks, especially between the visual and non-visual sensory or motor cortices. Our results suggest that task-evoked activity is not independent from spontaneous activity, and that engaging in a task may suppress spontaneous activity and its inter-regional correlation.
Amine nucleophilic addition to nitroalkene as a new practical approach for the synthesis of fully substituted isoxazoline-N-oxide

The secondary amine nucleophilic addition to the nitroalkene was used to generate the active nitronate intermediate, followed by the sequential addition to aldehyde and ylide, giving the fully substituted isoxazoline-N-oxide in one-pot fashion. Mechanistic studies revealed the equilibrium nature of the diene intermediates, which provide the foundation for the asymmetric synthesis of this interesting heterocycles.
Synthesis of spirocyclopentene-indolines by intramolecular alkylidine insertion reactions

Abstract Intramolecular 1,5 CH insertion of unstabilized carbenes into the tertiary carbon of a substituted indoline generates spiro[cyclopent[2]ene-1,2′-indolines] in good yields and excellent enantioselectivities.
Acid-catalyzed ortho-alkylation of anilines with styrenes: an improved route to chiral anilines with bulky substituents.

Reaction of para-substituted anilines with styrene derivatives at elevated temperatures, when catalyzed by CF3SO3H, results in highly chemoselective ortho-alkylation of the aniline. When R = H, dialkylation can be achieved by varying the ratio of styrene to aniline. Several different substituted anilines and styrenes were examined, and good yields (42−87%) were obtained, except in the case where electron-withdrawing substituents are present on the styrene.
Recent developments in chiral phospholane chemistry

Abstract Phospholanes have attracted considerable attention as ligands for asymmetric catalysis. The DuPHOS family of ligands reported by Burk et al. in 1991 has found considerable success as ligands for asymmetric hydrogenations. An overview of recent synthetic approaches to chiral phospholanes is presented. Also included are some of the more recent applications of phospholanes in asymmetric catalysis.
Estimation of the lag time in a subsequent monomer addition model for fibril elongation

Fibrillogenesis, the production or development of protein fibers, has been linked to protein folding diseases. The progress curve of fibrils or aggregates typically takes on a sigmoidal shape with a lag phase, a rapid growth phase, and a final plateau regime. The study of the lag phase and the estimation of its critical timescale provide insight into the factors regulating the fibrillation process. However, methods to estimate a quantitative expression for the lag time rely on empirical expressions, which cannot connect the lag time to kinetic parameters associated with the reaction mechanisms of protein fibrillation. Here we introduce an approach for the estimation of the lag time using the governing rate equations of the elementary reactions of a subsequent monomer addition model for protein fibrillation as a case study. We show that the lag time is given by the sum of the critical timescales for each fibril intermediate in the subsequent monomer addition mechanism and therefore reveals causal connectivity between intermediate species. Furthermore, we find that single-molecule assays of protein fibrillation can exhibit a lag phase without a nucleation process, while dyes and extrinsic fluorescent probe bulk assays of protein fibrillation do not exhibit an observable lag phase during template-dependent elongation. Our approach could be valuable for investigating the effects of intrinsic and extrinsic factors to the protein fibrillation reaction mechanism and provides physicochemical insights into parameters regulating the lag phase.
Cyclic di-GMP Increases Catalase Production and Hydrogen Peroxide Tolerance in Vibrio cholerae.

ABSTRACT Vibrio cholerae is a Gram-negative bacterial pathogen that causes the disease cholera, which affects nearly 1 million people each year. In between outbreaks, V. cholerae resides in fresh and salt water environments, where it is able to persist through changes in temperature, oxygen, and salinity. One key characteristic that promotes environmental persistence of V. cholerae is the ability to form multicellular communities, called biofilms, that often adhere to biotic and abiotic sources. Biofilm formation in V. cholerae is positively regulated by the dinucleotide second messenger cyclic dimeric GMP (c-di-GMP). While most research on the c-di-GMP regulon has focused on biofilm formation or motility, we hypothesized that the c-di-GMP signaling network encompassed a larger set of effector functions than reported. We found that high intracellular c-di-GMP increased catalase activity ∼4-fold relative to strains with unaltered c-di-GMP. Genetic studies demonstrated that c-di-GMP mediated catalase activity was due to increased expression of the catalase-encoding gene katB. Moreover, c-di-GMP mediated regulation of catalase activity and katB expression required the c-di-GMP dependent transcription factors VpsT and VpsR. Lastly, we found that high c-di-GMP increased survival after H2O2 challenge in a katB-, vpsR-, and vpsT-dependent manner. Our results indicate that antioxidant production is regulated by c-di-GMP uncovering a new node in the growing VpsT and VpsR c-di-GMP signaling network of V. cholerae. IMPORTANCE As a result of infection with V. cholerae, patients become dehydrated, leading to death if not properly treated. The aquatic environment is the natural reservoir for V. cholerae, where it can survive alterations in temperature, salinity, and oxygen. The second messenger molecule c-di-GMP is an important signal regulating host and aquatic environmental persistence because it controls whether V. cholerae will form a biofilm or disperse through flagellar motility. In this work, we demonstrate another function of c-di-GMP in V. cholerae biology: promoting tolerance to the reactive oxygen species H2O2 through the differential regulation of catalase expression. Our results suggest a mechanism where c-di-GMP simultaneously controls biofilm formation and antioxidant production, which could promote persistence in human and marine environments.